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EARLY DETECTION, DIAGNOSIS AND
INTERVENTION FOR ADULT-ONSET
DIABETES MELLITUS
IN NEW ZEALAND
A review of literature relevant to the development
of policies for diabetes services
L J Brown
R S Scott
Department of Health
TETARI ORA
HEALTH RESEARCH SERVICES - 1992
EARLY DETECTION, DIAGNOSIS AND
INTERVENTION FOR ADULT-ONSET
DIABETES MELLITUS
IN NEW ZEALAND
A review of literature relevant to the development
of policies for diabetes services
LJBrown
R S Scott
Lipid and Diabetes Research Group,
Princess Margaret Hospital, Christchurch
OflO37
A report for the Personal and Public Health Policy Section
Prepared by Health Research Services,
DEPARTMENT OF HEALTH, P0 BOX 5013, WELLINGTON
March 1992
Information Centre
Ministry of Health
Wellington
Contents
Executive Summary
1. INTRODUCTION
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2. THE EPIDEMIOLOGY OF ADULT-ONSET DIABETES IMPORTANCE OF
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EARLY DETECTION AND INTERVENTION 7
2.1 Definition and classification of adult onset diabetes 8
2.2 Prevalence and incidence
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2.3 Risk factors for diabetes in adults 12
2.4 Summary
3. EARLY DETECTION AND DIAGNOSIS
3.1 Principles of early detection of adult onset diabetes
3.2 Diagnostic criteria
3.3 Clinical assessment
3.4 Biochemical diagnostic procedures
3.5 Summary and protocol for early detection of diabetes
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4. EARLY DETECTION OF DIABETES MELLITUS: NEW ZEALAND
EXAMPLES
4.1 Workforce Diabetes Survey
4.2 The Waikato 'Discover Diabetes' Project
4.3 Detection and Intervention for lOT
4.4 Diabetes in the Elderly
4.5 Diabetes Community Awareness Programmes
4.6 Other strategies: Integrated screening
programmes
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5. INTERVENTION AND TREATMENT
5.1 Primary prevention
5.2 IGT: Prevention of progression to diabetes
5.3 Secondary intervention: treatment approaches following diagnosis of
diabetes
Summary
5.4
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6. CONCLUSIONS
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APPENDIX 1: LIST OF PUBLISHED GUIDELINES
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APPENDIX 2: TECHNICAL
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REFERENCES AND BIBLIOGRAPHY
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Executive Summary
Purpose of the review
To summarise relevant literature as a basis for Area Health Board policy on the most
appropriate methods for diagnosis and therapeutic intervention for Adult-Onset
Diabetes Mellitus, and indicating the advantages and disadvantages of various
methods.
This document presents a critical review of published and unpublished literature both
in New Zealand and overseas since 1981 on early detection of and intervention for
adult-onset diabetes. The Review examines the rationale and scientific evidence for
the advantages and disadvantages of different methods of early diagnosis and
therapeutic intervention. Discussion on specific details of day-to-day diabetes
management is not provided. Neither Insulin Dependent Diabetes Mellitus (IDDM)
nor gestational diabetes are covered. The primary prevention of adult-onset diabetes
and Impaired Glucose Tolerance (IGT) is discussed, but secondary prevention of
diabetes microvascular, macrovascular and neuropathic complications involve quite
separate issues and are excluded.
Epidemiology of adult-onset diabetes
In total, 3-4% of adult New Zealanders have diabetes. About half of all diabetic
cases in the age group 20-65 years are undiagnosed. The most important risk factors
for adult-onset diabetes are age, obesity, positive family history, non-white race, lOT,
gestational diabetes, hypertension and hyperlipidaemia. The risk of developing
diabetes increases substantially if individuals have multiple risk factors.
The cause of diabetes in adults is underlying genetic susceptibility unmasked by
environmental factors. An estimated 10-15% of individuals developing diabetes in
adulthood show characteristics of insulin deficiency typical of childhood diabetes.
Many patients with adult-onset diabetes are asymptomatic and hyperglycaemia may go
undetected for years. Individuals often present at the time of diagnosis with well
established long-term complications of diabetes. The rate of mortality in persons with
adult-onset diabetes is double that in non-diabetic individuals matched for age and
sex.
Adult-onset diabetes is part of a wider non-communicable disease syndrome
compromising multiple risk factors for cardiovascular disease. Persons with adultonset diabetes are commonly found to have a metabolic clustering of hyperglycaemia,
hyperinsulinemia, obesity, hypertension, lipid abnormalities and smoking.
IGT represents the intermediate zone between normality and diabetes. While many
individuals with IGT revert to normal glucose tolerance or do not progress to
diabetes, lOT warrants detection because of its risk association with diabetes and
coronary artery disease. The rate of progression from IGT to diabetes is 2-6% per
annum.
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Early detection of adult-onset diabetes
Early detection of diabetes involves clinical assessment of risk factors and symptoms
of diabetes, and biochemical assessment of hyperglycaemia. Mass indiscriminate
screening for diabetes is inappropriate. Early detection programmes should focus on
those who are asymptomatic or mildly symptomatic, and are at high risk of
developing the disorder.
Diagnostic criteria are those recommended by WHO. Screening procedures may
differ between clinical and epidemiological settings.
A positive screening test conveys a high probability the detected individual has
diabetes but this requires confirmation through follow-up testing.
The diagnosis of diabetes is seldom problematic in subjects presenting with diabetes
symptoms and unequivocal hyperglycaemia. A random venous plasma or capillary
blood glucose measurement ^: ll.lmmol/l is sufficient to confirm the diagnosis of
diabetes in symptomatic individuals. For asymptomatic individuals, biochemical
assessment is essential. This may be achieved by fasting or random blood glucose
measurement, confirmed through repeat testing or via an Oral Glucose Tolerance
Test.
From a practical point of view, random blood testing is the easiest method to perform
both in the surgery or at a survey site, but random measurements are insensitive if
hyperglycaemia is not markedly elevated. Fasting blood glucose is the more favoured
predictor of diabetes. A fasting glucose reading on more than one occasion
^:7.8mmol/l is diagnostic and specific for diabetes. In most clinical situations, the
OG1T is required infrequently for detecting and diagnosing adult onset diabetes.
Glycated haemoglobin and fructosamine are not recommended as screening tests for
diabetes. Both detect well marked hyperglycaemia but perform poorly in screening
for diabetes in patients with normal or near-normal fasting plasma glucose and mild
impairment of glucose tolerance.
Primary prevention
The epidemiology and natural history of adult-onset diabetes present realistic
opportunities for primary prevention by Area Health Boards of this disorder. Primary
prevention aims to reduce the incidence of diabetes by reducing the risk of its onset,
and thereby its prevalence in the population. This can be achieved through either: 1)
a population strategy which seeks to remove or reduce causes of diabetes in the
community as a whole; or 2) a high risk strategy where preventive measures are
implemented selectively in individuals or groups that are at a specific high risk of
developing the disorder. Either approach is applicable. Adult-onset diabetes fits well
into the public health approach and can be incorporated in integrated intervention
programmes aimed at lifestyle related non-communicable disorders, such as heart
disease.
Secondary intervention: therapeutic approaches
Early detection and intervention is promulgated through the belief that treatment,
restoring the metabolic abnormalities present in adult-onset diabetes as close to normal
as possible, will prevent or delay the development of diabetes complications, and
improve quality and duration of life. Elevated blood glucose concentrations are not
the sole metabolic manifestation of adult-onset diabetes, and as great an emphasis
needs to be placed on cardiovascular risk association of raised total cholesterol and
triglycerides, depressed HDL-cholesterol, high blood pressure and smoking.
Intervention has to be multifactorial addressing all metabolic abnormalities, if longterm health outcomes are to be improved.
The therapeutic means of achieving these goals are dietary intervention, exercise, and
pharmacological treatment. There are two aspects to dietary intervention: 1) control
of total energy intake; and 2) modification of dietary composition especially
reduction in dietary fat. Weight loss is the most important and fundamental
physiological approach to the treatment of overweight individuals with adult-onset
diabetes.
Physical activity can be as powerful a therapeutic tool as diet in the modulation of
insulin activity in individuals with adult-onset diabetes. However diet plus exercise is
more effective than either alone in helping overweight patients to lose weight and in
conferring metabolic benefits.
Individuals with adult-onset diabetes are typically on multiple drug therapies
prescribed for the treatment of the co-existing morbidities prevalent in these
individuals. Drug intervention for control of glucose metabolism is an adjunct to and
is not a substitute for changing dietary behaviour and levels of physical activity.
Effectiveness of all forms of intervention is greatly enhanced by patient education.
While therapeutic intervention has been shown to improve metabolic control in adultonset diabetes in the shorter term, as yet there is little conclusive scientific evidence
that improvements in health outcomes and changes in resource utilisation are sustained
over the longer term.
Conclusions
Early detection of adult-onset diabetes is justiable on the following grounds:•there are high rates of diabetes prevalence and incidence in adults, particularly
in elderly and non-whites
•risk factors for diabetes and diabetes complications, especially heart disease,
have been identified
•there is good understanding of the causation and patho-physiological defects
present in adult-onset diabetes
•the natural history of the disorder indicates opportunities for early intervention
•individuals incur morbidity prior to diagnosis, with complications being
already present in many at diagnosis
•there is international consensus on the definition of and diagnostic criteria for
diabetes
•screening and diagnostic methods exist which are both effective and practical,
•therapeutic measures are available which do modify risk factors and intervene
in the pathogenesis of adult-onset diabetes at least in the short term,
early
detection allows the disease to be treated at an early stage, thus
•
increasing the chances of improved control.
Short-term and cross-sectional studies consistently show diet, exercise and drug
therapies to be beneficial in improving both glycaemic and lipid abnormalities in
individuals with adult-onset diabetes. These forms of intervention have the potential
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for being effective in the long-term, if facilitated by individual patient factors and the
health service. Success of treatment implies a high degree of patient participation and
ongoing clinical and educational support.
While there is no data in the literature reporting cost-benefit analyses, it seems
prudent to screen for adult-onset diabetes and intervene early in its natural history.
However, the consequence of the metabolic clustering of hyperglycaemia, obesity,
lipid abnormalities, hypertension and heart disease is that health intervention viz.
detection and treatment must be multifactorial. The traditional focus on detection and
treatment of hyperglycaemia and perturbations in glucose metabolism in persons with
adult-onset diabetes is inappropriate if this is done in isolation from other morbidities.
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1. Introduction
Purpose of the review
To summarise relevant literature as a basis for Area Health Board policy on the
most appropriate methods for diagnosis and therapeutic intervention for AdultOnset Diabetes Mellitus, indicating the advantages and disadvantages of various
methods.
Diabetes Mellitus should be of interest to Area Health Boards (Regional Health
Authorities) because of its enormous impact on the community and implications for
the allocation of scarce health care resources. Adult-Onset Diabetes Mellitus affects
3-6% of individuals in Western caucasoid populations and up to 35% of individuals in
certain races such as Micronesian, Melanesian and Polynesian Pacific Island
populations, American Indians and migrant Asians and Indians (Zimmet, 1982;
Bennett, 1990). The prevalence of the disorder increases markedly with age. As our
population ages and the racial structure changes, the impact of this disorder on health
services will be significant.
Often individuals have co-morbidities of obesity, abnormal blood fats (lipids),
hypertension and heart disease (Zimmet et al. 1986; Zimmet, 1989).
The short and long-term complications of diabetes result in increased morbidity,
reduced quality of life and shortened lifespan. Mortality in persons developing
diabetes in middle life is double that in the matched non-diabetic population and life
expectancy can be reduced by up to 10 years (Panzram, 1987; Morrish et al., 1990).
Adult-onset diabetes mellitus particularly affects the blood vessels causing heart attack
and stroke. It also damages small vessels and capillaries affecting the eyes and
kidneys. Some of these long-term complications may be already present at the time of
diagnosis of diabetes.
Individuals with diabetes require lifelong treatment and ongoing contact with the
health system. The majority of those with adult-onset diabetes receive care from
general practitioners without specialist backup (Dunn and Cutfield, 1988). Adultonset diabetes is often perceived as 'mild' and without 'health risk', and is not
aggressively treated by either the doctor or the patient. While such attitudes and
practices persist, this disorder will remain a substantial cost to the health service.
(Brown and Beaven unpublished data; Brown et al., 1985).
This document summarises a critical review of published and unpublished literature
both in New Zealand and overseas since 1981 on early detection of and intervention
for adult-onset diabetes. This review addresses three key issues;
•the epidemiology and the natural history of adult-onset diabetes (Chapter 2).
These justify and provide the rationale for early detection and treatment;
• the technical aspects of early detection and diagnosis of diabetes (Chapter 3).
To be useful diagnostic criteria and screening methods for diabetes must be
both effective and practical; New Zealand examples are set out in Chapter 4;
and
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• treatment approaches (Chapter 5). If therapeutic measures are available which
modify risk factors and intervene successfully in adult-onset diabetes, then
issues of efficient case detection become important.
A full review of the literature appears in the Technical Appendix to this document.
The Technical Appendix reviews the rationale and scientific evidence for the
advantages and disadvantages of different methods of early diagnosis and intervention
for adult-onset diabetes. The purpose of the Review is not to provide detailed
discussion of day-to-day diabetes management.
The literature search was restricted to the field of diabetes. It did not extend to
general literature concerning broader issues of health screening, health intervention
and strategies for health maintenance. The review does include discussion on
Impaired Glucose Tolerance (IGT) as this has implications for adult-onset diabetes,
but neither Insulin Dependent Diabetes Mellitus (IDDM) nor gestational diabetes are
covered. While those developing diabetes during pregnancy may go on to develop
IDDM or NTDDM, gestational diabetes is a very specific topic on which considerable
literature already exists and screening guidelines have been established overseas and
are currently practised widely in New Zealand.
The primary prevention of NIDDM and IGT is discussed, but secondary prevention of
diabetes microvascular, macrovascular and neuropathic complications involve quite
separate issues and are excluded.
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2. The epidemiology of adult-onset diabetes: importance of early
detection and intervention
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This section provides an epidemiological overview of adult onset diabetes mellitus
from which the appropriateness and significance of early diagnosis and intervention
can be assessed. It introduces the established classifications of diabetes and diagnostic
terminology. Insulin-dependent diabetes mellitus (IDDM) and gestational diabetes are
excluded. Readers are referred to the National Diabetes Data Group (NDDG) (1979)
and WHO (1985) classifications for further information.
Data on the epidemiology and the natural history of adult-onset diabetes are presented
as these provide the rationale for early detection and treatment and also influence the
approach to screening and intervention programmes.
2.1 Definition and classification of adult onset diabetes
Diabetes is a heterogeneous disorder. The common feature is derangement in glucose
metabolism with resultant hyperglycaemia. There are two widely accepted
classification schemes defining diabetes and impaired glucose tolerance (IGT): that
originally developed by an international workshop sponsored by the National Diabetes
Data Group (NDDG) of the NIH (1979); and a slightly modified version subsequently
adopted by the WHO Study Group on Diabetes Mellitus (1985). There is very little
difference between these two classifications. Both were established through the need
for uniformity and consistency in the definition of diabetes.
A summary of the classification of diabetes mellitus with a description of NIDDM and
IGT is provided in Table 1.
Classes of diabetes are mutually exclusive but over , time individuals may shift between
categories. Most adults presenting with diabetes mellitus meet criteria for NIDDM
but strictly, the term NIDDM should be reserved for those subjects meeting criteria
laid down by WHO. Others are more difficult to categorize (Wilson et al., 1985;
Laasko and Pyorala, 1985) because they need insulin or they show characteristics
more typical of IDDM. Some authors suggest that 10-15% of all adult onset cases are
insulin dependent (Irvine, 1984; Scott and Brown, 1991).
IGT represents the grey zone between normality and diabetes. IGT is included in this
literature review as probably it precedes frank diabetes in most cases. The category
of IGT was developed to replace previous diffuse terms such as subclinical, chemical,
borderline or latent diabetes. The labelling of IGT as 'diabetes' was considered
unjustified given the lack of severity of glucose intolerance (NDDG, 1979) and the
fact that the majority of subjects remain IGT or return to normal glucose tolerance.
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The above terminology and definitions are internationally accepted but it should be
remembered that these are arbitrary classifications representing a compromise of
al., 1986). At a practical
views and current understanding of diabetes (Turner
level, early diagnosis and treatment of individuals developing diabetes in adulthood is
needed, and a specified disease classification is largely irrelevant.
a
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1 tioL1Diai.s
a)NIDDM - Non-Insulin Dependent Diabetes Mellitus b)IGT - Impaired Glucose Tolerance
Subgroups - Obese, non-obese
Characteristics:
Not dependent on insulin for survival or prone to ketosis under
normal conditions;
• May use insulin for treatment of hyperglycaemia or during stress
conditions (insulin-requiring for health not the prevention of ketosis);
Endogenous insulin levels may be normal, elevated or depressed;
Most individuals are hyperinsulinaemic and insulin resistant;
60-90% are obese;
onset is predominantly >40 years of age but can occur at any
age;
Aetiology is strongly genetic (familial aggregation; high concordance monozygotic twins).
Patients may be asymptomatic for years and only show slow
progression of the disease
Individuals develop typical chronic diabetes complications
S
S
S
S
S
S
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Subgroups - Obese, non-obese, associated with certain conditions
Characteristics:
Fasting glucose levels must not be diagnostic for diabetes, and
glucose response to standard glucose challenge is intermediate
between normal and diabetic
Not defined by clinical manifestations of hyperglycaemia rather
by glucose response
Clinically significant renal and eye complications of diabetes are
absent but individuals may be at increased risk of cardiovascular disease.
C)
Insulin Dependent Diabetes Mellitus (IDDM)
d) Gestational Diabetes
(There is also a special subclass within NIDDM for maturity onset
diabetes in youth (MODY). This has specific characteristics, occurs
very infrequently and will not be addressed in this review.)
References: NDDG 1979; WHO 1985; Fajans 1990)
co
2.2 Prevalence and incidence
Several recent studies have reported the epidemiology of diabetes in New Zealand
(Brown et al., 1984; Scragg et al. 1990; Scott and Brown 1991; Lintott et al. 1991).
In total 3-4% of adult New Zealanders have diabetes. NIDDM accounts for
approximately 85% of all treated cases (Scott and Brown, 1991), and excluding
gestational diabetes, virtually all undetected cases. A Christchurch study (Brown et
al., 1984) and the more recent New Zealand Workforce Diabetes Survey both
reported prevalence of known diabetes in the workforce (age 20-65 years) to be 1.51.6% with equivalent rates of undetected diabetes (1.5-2.0%). The prevalence of
adult-onset diabetes, and the ratio of detected to undetected cases, varies substantially
between ethnic and age groups within the population.
Incidence (i.e. rate of diabetes onset) of adult onset diabetes in New Zealand is not
known, and through difficulties in case ascertainment, is infrequently reported in the
literature. Extrapolating data from Rochester, Minnesota (Melton et al., 1983) and
from the Framingham Study (Wilson et al., 1986), some 1800 New Zealanders aged
20-59 years and another 1500 persons aged ^!!60 years would develop diabetes each
year.
Many countries state that the incidence of diabetes in adults is increasing. There are a
number of reasons for this, namely increased longevity of population, increased
affluence, and adverse lifestyles. However, data supporting this view are largely
derived from non-Caucasoid groups e.g. Pacific Island populations. There is also
evidence to suggest increased prevalence.
2.3 Risk factors for diabetes in adults
Factors associated with increased risk for the development of diabetes are listed in
Table 2. Specific factors such as pancreatitis/alcohol excess, haemochronmatosis,
cystic fibrosis may lead to secondary diabetes (excluded from discussion).
TABLE 2. RISK FACTORS FOR DIABETES IN ADULT
- over 40 years, risk increases with age
Age
Obesity - BMI>25%, central adiposity
Non-white race- Polynesian (viz. Maori, Pacific Island ancestry), Asian
(e.g.Indian, Chinese) ethnicity
Positive family- 1 St degree relatives viz, parents or siblings of history
diabetic persons
Previously identified IGT Co-morbidities
- hypertension, dyslipidaemia
Female with poor obstetric history
- history of previous pregnancies producing stillbirths,
neonatal deaths, large newborn babies
Previously identified gestational diabetes
Physical inactivity
diabetes is not discussed in this review
The risk factors are outlined below. Additional information and a comprehensive
review of the natural history of diabetes, are found in the separate Technical
Appendix.
Age
In Caucasian populations in the US and Europe, age specific incidence of adult-onset
diabetes increases at least up to 70 years of age (Melton et al., 1983; Wilson et al.,
1986; Bennett, 1990). Prevalence in the elderly is commonly reported at rates in
excess of 10% in people 60 years and over (Laasko and Pyorala, 1985; Croxson et
al., 1991).
Data on the elderly in New Zealand are limited. A recent survey of a large urban
medical centre in Christchurch (Lintott et al., 1991) found an age adjusted prevalence
rate of 14.9% for those 65 and over (9.9% known and 5% previously undiagnosed).
Extrapolating the results to the general population aged 65 and above, more than
55,000 elderly New Zealanders will be expected to have diabetes, of whom 17,000
will be undiagnosed.
Maori and Pacific Island people may experience patterns similar to Pima Indians
(Bennett, 1990) where incidence peaks in the 40-50 age group and falls sharply
thereafter.
Obesity
Up to 80% of adult diabetic patients are obese at the onset of the disorder (Zimmer et
al., 1986; Jallut et al., 1990). In New Zealand, Scragg et al. (1990) report that
there is a three-fold increase in relative risk for obese compared with non-obese
individuals. The risk of developing diabetes has been shown to relate to both duration
and degree of obesity (Ohlsson et al., 1985; Bennett, 1990; Holbrook et al., 1990).
More recent research has considered the distribution of body fat as a predictor of
diabetes, and has found a significant positive association of abdominal adipose tissue
(i.e. central or android obesity) with risk of diabetes (Ohlsson et al., 1985; Haffner
etal., 1986).
Ethnicity
Increased rates of diabetes in Maori and Pacific Island communities was first
documented in New Zealand by Prior and colleagues in the early 1960s. The
Multiracial Workforce Diabetes Survey undertaken between 1988-1990 has reported
rates in the 40-64 year age group ranging from 1.85% in Europeans to 9.91% in
Maori, with the relative risk of diabetes in Maori, Pacific Island and Asian enthnic
groups being 2-6 fold higher than for Europeans after standardizing for age, income
and body mass (Scragg et al., 1991). Other factors must explain increased prevalence
of diabetes in these ethnic groups.
Positive family history
Evidence accumulated over recent years shows that family association of adult-onset
diabetes is due to an inherited defect in the genes predisposing towards diabetes
(Permutt, 1990).
The genetic importance of adult onset diabetes is shown in strong family histories, in
varying rates of diabetes in off-spring from inter-marriages and twin studies (Barnett
et al., 1981; O'Reilly et al., 1988). The risk of first degree relatives developing
diabetes before age 65 is 5-10% (Tuomilehto and Wolf, 1987), and it has been
estimated that almost 40% of siblings of diabetic individuals could be expected to
develop diabetes assuming a maximum life expectancy of 80 years (Tuomilehto,
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Previously identified Impaired Glucose Tolerance 11G T)
People with Impaired Glucose Tolerance are at increased risk of diabetes, but only a
proportion develop overt diabetes and many revert to normal glucose tolerance.
Overall British and U.S. data suggest a progression rate from IGT to diabetes of 2-3%
per annum, in caucasoid population the best predictors being the initial level of
glucose intolerance, obesity and lower insulin response to glucose (Sartor et al., 1980;
Saski et al., 1982; Jung et al., 1984). Rates of progression in Polynesians
(Tukuitonga, 1990) and Micronesians (Sicree et a! 1987) are about twice those
observed in white populations.
Associated morbidity
Risk factors for heart disease (obesity, hypertension, blood fat abnormalities,
smoking) are also commonly found in individuals with diabetes and IGT and their
presence indicates that screening may be warranted.
Many individuals with adult-onset diabetes have no symptoms of the disorder and
hyperglycaemia may go undetected for years. Therefore, at the time of diagnosis
individuals may present with well established long term complications of diabetes
(Kadowaki et al., 1984; Lehtinen et al., 1988). It has been reported that at least
20% of patients with adult-onset diabetes have evidence of retinopathy at presentation
(Owens et al., 1988) one third are likely to be hypertensive and 10% will have
symptoms of coronary artery Disease (Hadden et al. 1986). The rate of mortality in
persons with adult-onset diabetes is double that in non-diabetic individuals matched
for age and sex (Panzram, 1987).
Physical inactivity
Physical inactivity appears to increase the risk for diabetes, independently of other
risk factors (Lindgarde and Saltin, 1981; Zimmet et al., 1984). Physical activity
protects against coronary heart disease (La Porte et al., 1984) and can assist in
normalising IGT (Lindgarde and Saltin, 1981).
In New Zealand, data from the Workforce Diabetes Survey showed reduced relative
risk for diabetes among more physically active individuals, although no significant
difference was observed in the Kawerau Study (Scragg et al., 1990).
It is difficult to rank these risk factors in importance because of variations in the
characteristics of study populations and because factors may co-exist. A risk factor is
not necessarily a true determinant of diabetes, but rather is an attribute associated with
increased probability that individuals may develop the disorder (King and Dowd,
1990).
Risk for developing diabetes increases substantially when multiple risk factors are
present. Thus, the greater the number of risk factors, the greater will be the chance
of detecting diabetes. Conversely, the probability of detecting an asymptomatic
diabetic individual without risk factors through random screening is low (ADA
Position Statement, 1990).
Data on the relationship of socio-economic status and prevalence and incidence of
diabetes are sparse. Limited US data suggest lower income and educational
attainment for both white and black Americans may relate to increased risk for
diabetes, but operating indirectly through the relationship of increased obesity,
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physical inactivity and poor diet with lower social class (Bennett, 1990). It is not
unlikely that a similar situation operates in New Zealand. Results from the
Multiracial Workforce diabetes Survey found that the relative risks for both diabetes
and IGT were inversely associated with gross annual household income independent
of age and ethnicity. However, there was no relation between the Elley-Irving socioeconomic level and risk of diabetes or IGT (Scragg et al., 1991).
2.4 Summary
• Most adults presenting with diabetes mellitus meet criteria for Non-Insulin
Dependent Diabetes Mellitus. Others are more difficult to categorise because
they need insulin therapy or they show characteristics more typical of Insulin
Dependent Diabetes Mellitus.
• Impaired Glucose Tolerance (IGT) is the intermediate zone between normality
and diabetes. While many individuals with IGT revert to normal glucose
tolerance or do not progress to diabetes, IGT warrants detection because of its
risk association with diabetes and coronary artery disease. The rate of
progression from IGT to diabetes is around 2-3% per annum in white
populations and about double in Polynesians and Micronesians.
•Three to four percent of adult New Zealanders have diabetes. About half of
all diabetic cases in the age group 20-65 years are undiagnosed.
• Risk factors for adult-onset diabetes are age, obesity, Asian and Polynesian
ethnicity, positive family history, IGT gestational diabetes, inactivity,
hypertension and lipid abnormalities. Fifteen percent of individuals aged ^t 65
years have diabetes. Since both prevalence of diabetes and IGT increase with
age, many more people will develop diabetes in the future as the population
ages. There is a 3 fold increase in relative risk for diabetes for individuals
who are obese. Up to 80% of adult diabetic patients are overweight at the
onset of the disorder. Prevalence of diabetes in the Maori population is 8.9%,
with the relative risk of diabetes in Maori and Pacific Island groups being 4-5
fold higher than for Europeans.
•The risk of developing diabetes increases substantially if individuals have
multiple risk factors.
•The cause of diabetes in adults, although still unclear, is underlying genetic
susceptibility unmasked by environmental factors.
• Many people with adult-onset diabetes have no obvious symptoms and may go
undetected for years. Individuals often present at the time of diagnosis with
well established long-term complications of diabetes.
•The rate of mortality in persons with adult-onset diabetes is double that in nondiabetic individuals matched for age and sex.
•Adult-onset diabetes is part of a wider non-communicable disease syndrome
compromising multiple risk factors for cardiovascular disease.
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3. Early detection and diagnosis
3.1 Principles of early detection of adult onset diabetes
Early detection implies some form of screening. The primary objective of
opportunistic, selective or mass screening is to identify asymptomatic individuals
meeting diagnostic criteria for diabetes. Early detection is undertaken for two
reasons:
•to identify prevalence of diabetes and IGT in a population for the purpose of
planning services and resource allocation.
• for individual case finding for clinical reasons. This is more directly
concerned with detection of the undiagnosed individual and implementation of
therapy.
A screening programme for adult-onset diabetes can be justified if:•adult-onset diabetes has significant effect on quality and duration of life
•there is a high probability of detecting an abnormality in glucose tolerance
•some form of acceptable therapy exists
•detection and treatment reduces morbidity and/or mortality
•treatment in the asymptomatic phase yields results superior to that obtained by
delaying treatment until symptons appear
•the necessary facilities for treatment are already available
•the screening procedure is relatively cheap and simple
•screening techniques are sufficiently sensitive and specific, and the predictive
value is acceptable
• incidence of adult-onset diabetes and prevalence of undiagnosed diabetes are
sufficient to justify cost of screening (Bennett 1984; Frame, 1986; Singer et
al., 1988; Trilling, 1988).
The impact of adult-onset diabetes on morbidity and mortality is highlighted in the
separate Technical Appendix. The costs of screening for diabetes and implications for
resource allocation are unknown. The Waikato 'Discover Diabetes' Project will
provide New Zealand data on these issues.
In practice early detection of diabetes involves three associated strategies:
•Agreement on diagnostic criteria;
•Clinical assessment for symptoms and risk factors; and
•Biochemical testing.
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These are summarised in subsequent sections (3.2 - 3.4) and presented in full in
Appendix 3. It is important to distinguish between the processes of screening for and
diagnosing diabetes. A positive screening test is not definitive for the diagnosis of
diabetes but rather conveys a high probability the detected individual has diabetes.
The diagnosis requires confirmation. Furthermore, if an individual ests negative in
the screen, this does not rule out the possibility that she/he may develop diabetes in
the future, and negate the need for future screening. The interval for retesting will
depend on the risk for diabetes e.g. an overweight individual with a family history of
diabetes should have regular surveillance.
3.2 Diagnostic criteria
Diagnostic criteria now routinely used for IGT and diabetes in non-pregnant adults are
those recommended either by NDDG or WHO. These have been redefined and
standardised at levels higher than those commonly used in the 1960's and 70's. These
new values were determined in -the light of epidemiological data and results from
several U.S. and British studies, and are based on values of glucose intolerance
believed to be predictive of microvascular complications, and IGT levels indicative of
increased risk of cardiovascular complications and progression to diabetes.
Adjustment for age of subjects is unnecessary with these diagnostic values.
The differences in diagnostic levels between the two classifications (NDDG or WHO)
reflect the fundamental difference between epidemiological and clinical reasons for
detection. For practical reasons, simplified procedures are required for large scale
field work and population programme, and these are reflected in WHO
recommendations. The NDDG criteria are aimed primarily at testing individual
patients in a clinical setting (Fajans, 1990; Harris, 1985).
3.3 Clinical assessment
The first step in individual case detection ils clinical assessment for risk factors and
symptoms indicative of diabetes. This would most commonly be undertaken in
general practice, either opportunistically when an individual visits or planned because
there are risk factors present. The purpose of this is to avoid biochemical testing in
those unlikely to have diabetes. Individuals with risk factors, but without symptoms
are the major target group for early detection.
While diagnosis of diabetes is not usually problematic in those presenting with
symptoms, many individuals developing diabetes in adult life are asymptomatic and
may present with long-term diabetes following years of unsuspected hyperglycaemia.
Biochemical assessment is essential for this group.
3.4 Biochemical diagnostic procedures
Random Blood Glucose
There is controversy over the usefulness of random blood glucose measurements for
diagnostic purposes and over choice of diagnostic levels. A high proportion of casual
blood tests fall into the uncertain zone neither confirming nor excluding a diagnosis of
adult-onset diabetes. For those in the uncertain, confirmation is required by the more
expensive and time consuming OGTF.
14
In the epidemiological setting, random blood glucose levels underestimate diabetes
prevalence compared with estimates derived from a complete OGTT (Simon et al.,
1985; Ferrell et al., 1984). Finch et al. (1990) conclude that use of random blood
glucose is inappropriate for the purpose of epidemiological studies and that
perforning data on smaller representative samples will provide more accurate data at
less cost. Many investigators do not recommend use of random blood glucose in
research as either a definitive screening procedure or as a satisfactory epidemiological
tool.
Fasting Blood Glucose
This is the classical predictive test for diabetes, and involves the subject consuming no
food or beverage other than water for at least three hours before testing (ADA, 1990).
A repeated elevated fasting plasma glucose (e.g. ^!t 7.8 mmol/l) is specific for
diabetes i.e. true normals will most likely have screening values below the cut-off.
Fasting values do, however, lack sensitivity. Effectiveness of fasting glucose
concentrations in detecting glucose abnormality is lower where there is milder
impairment of glucose tolerance (Fajans, 1990).
OGTT and postload glucose
OGTT is the most certain way of making the diagnosis of adult-onset diabetes in the
asymptomatic individual (Reaven, 1989). OGTT should be performed in the morning
after at least 3 days of unrestricted diet and usual physical activity, but with the test
being preceded by an overnight fast. However, OGTT is more expensive than other
diagnostic tests, is time consuming, lasting at least two hours, requires a higher
degree of patient co-operation, is cumbersome, involves multiple samples, and is
impractical in many field situations and epidemiological surveys (Papoz, 1990).
In spite of its established place as a diagnostic tool, the OGTT is influenced by many
factors and characterised by significant within-individual variation i.e. individual
responses are not consistent over several OGT1's (Olefsky and Reaven, 1974);
Alberti, 1988).
Glycated haemoglobin (GHb)
Glycated haemoglobin is a relatively new measure, most commonly used in the
clinical setting for estimating glycaemic control in diagnosed diabetics (Goldstein et
al., 1982; Smart et al., 1988). This method has only recently been introduced as a
screening method and there is divergence of views on its effectiveness. GHb methods
tend to be costly and are not yet well standardized (Home, 1990), although it has the
advantage of being a single diagnostic test with no preparation prior to testing. Glib
as a single diagnostic criterion is superior to random blood glucose. It detects well
marked hyperglycaemia but performs poorly as a screening test for diabetes in people
with normal or near-normal fasting plasma glucose (Orchard et al., 1982; Veriollo et
al., 1983). Glib tends to give rise to substantial misclassification when results are
compared with OGTF.
Fructosamine
The fructosamine assay, developed by Baker and colleagues in Auckland, has been
suggested as an alternative to GHb partly through its technical simplicity,
reproducibility of measurements, and relatively low costs (Baker et al., 1985;
Cockram et al., 1990). While fructosamine results correlate well clinically with those
from GHb assays and fasting glucose concentrations in diabetic and non-diabetic
15
individuals (Cockram et al., 1990), considerable overlap in range of values between
normal, IGT and diabetes indicates that fructosamine is inadequate for screening
purposes (Scragg et al., 1990; Swai et al., 1988; Guillausseau et al., 1990. As for
GHb, fructosamine has low sensitivity although specificity is relatively high (Fagans
1990). Fructosamine may perform better in populations where individuals are
characterised by marked glycaemic elevations rather than mild glucose tolerance,
situations where casual glycaemic determination may suffice.
The effectiveness of these screening tests in terms of their sensitivity and specificity
are summarised in Table 3-3.
Table 3-3 Asessment of diagnostic tests
Blood Glucose
Random
Fasting
2h Post-load Glucose Glycated Haemoglobin Fructosamine Sensitivity
Specificity
++
++
++++
+
+
++
++++
++++
+++
Other measures
Measures such as glycosuria, ketosis, islet cell antibodies, HLA antigens, insulin
secretion defined by C-peptide assays, intravenous glucose tolerance tests or mixed
meal tests are inappropriate for screening adult-onset diabetes at present.
Reflectance meters
Use of reflectance meters and test strips is now widespread especially in home
monitoring of glycaemic control in diagnosed cases. However, their effectiveness for
screening and as a diagnostic tool is not well established. The consensus is that
reflectance meters should only be used for screening under strictly controlled
conditions.
3.5 Summary and protocol for early detection of diabetes
A protocol for early detection of adult-onset diabetes is given in Figure 1. The initial
cut-off value for screening recommended (6.5 mmol/l) is that set by the European
NIDDM Policy Group (1990). This venous plasma blood value may be used to rule
out the likelihood of diabetes but is not diagnostic and should not be confused with the
venous whole blood value of 6.7 mmol/l - the WHO and NDDG diagnostic criterian
(refer to Technical Appendix) for fasting glucose concentrations.
Early detection of diabetes is undertaken for: 1) for epidemiological purposes
to identify the prevalence of diabetes and IGT in the population; and 2) for
individual case finding for clinical reasons.
Detection involves: 1) clinical assessment of risk factors and symptoms of
diabetes; and 2) biochemical assessment of hyperglycaemia.
16
•Diagnostic criteria recommended by either NDDG or WHO are routinely used
for defining IGT and diabetes in non-pregnant adults.
•Mass indiscriminate screening for diabetes is inappropriate. Asymptomatic or
mildly symptomatic individuals at high risk of developing diabetes are the
focus of early detection programmes.
• Screening procedures may differ between clinical and epidemiological settings.
A positive screening test conveys a high probability the detected individual has
diabetes but this requires confirmation through follow-up testing.
•Mechanisms must be in place for follow-up evaluation, and initiation of
treatment if needed, of individuals detected by the screening test.
•The diagnosis of diabetes is seldom problematic in subjects presenting with
diabetes symptoms and unequivocal hyperglycaemia.
•For asymptomatic individuals, a variety of diagnostic procedures and screening
tests are available for measuring glucose intolerance and making a diagnosis
for diabetes.
•Biochemical assessment commonly involves initial detection by fasting or
random blood glucose measurement, confirmed through repeat testing or via
OGTF.
•From a practical point of view, random blood testing is the easiest method to
perform both in the surgery or at a survey site. However, random
measurements are insensitive in detecting diabetes, other than or where
hyperglycaemia is markedly elevated.
Fasting blood glucose is the more favoured predictor of diabetes.
• For asymptomatic patients in whom fasting blood glucose fails to confirm
diabetes, OGTT remains the most sensitive and effective diagnostic test for
diabetes and IGT. However, the OGTT is more expensive than other
diagnostic tests, is time consuming, more demanding on the patient and has
problems with reproducibility. In most clinical situations, the OGTT is
required infrequently for detecting and diagnosing adult onset diabetes.
• Glycated haemoglobin and fructosamifle are not recommended as screening
tests for diabetes. Both detect well marked hyperglycaemia but perform
poorly in screening for diabetes in patients with normal or near-normal fasting
plasma glucose and mild impairment of glucose tolerance.
17
Figure 1: Protocol for Diagnosis of Diabetes Mellitus (Venous Plasma Blood)
Clinical Assessment
Patients at Risk
Elderly, positive family history, obese,
dyslipidaemic, hypertensive, non-white, previous IGT or gestational diabetes, poor obstetric history, inactive
Symptoms of Diabetes
Weight loss, thirst, polyuria, lethargy
Biochemical testing
Fasting blood glucose if possible, otherwise random measurement
Random Blood Glucose 6.5-11.1 mmol/L
>-11.1 mmol/L
Fasting Blood Glucose 00
-4
>7.8 mmol/L
<6.5 mmol/L
Diabetes unlikely 6.5-7.8 mmol/L
No further action
Perform 75gm OGTT interpret
according to WHO criteria
Normal
Impaired Glucose Tolerance
No further action JI Test Fasting Blood Glucose at least annually
In the abence of obvious
symptoms, only if value is
confirmed at least once
II DIABETES MELLITUS
4. Early detection of diabetes mellitus: New Zealand examples
This is not a comprehensive list of activities or research projects on early detection of
adult-onset diabetes mellitus undertaken in New Zealand. Key projects such as the
Workforce Diabetes Survey and the Waikato "Discover Diabetes" Project are
discussed plus several examples indicative of alternative approaches to screening.
4.1 Workforce Diabetes Survey
Project Co-ordinator: Dr Robert Scmgg
The Multiracial Workforce Diabetes Survey, is an epidemiological screening
programme aimed at identifying prevalence of IGT and diabetes, and associated risk
factors, in workers aged 40-64 years. The project commenced in 1988. There were 3
main aspects: 1) study of the occurrence of metabolic disorders e.g. diabetes,
dyslipidaemia, obesity; 2) renal function viz. proteinuria, bacteriuna; and 3)
industrial health (J Baker, pers comm.)
In recognition of ethnic sensitivity to research activities, screening was undertaken in
mixed racial workforces but worksites were selected for their high representation of
Maori and Pacific Island workers. A total of 41 companies were surveyed in
Auckland and five in Tokoroa. A team of interviewers, survey leader, phlebotomist
and biochemistry assistant visited each site. All participants underwent an OGTT with
fasting and 2h venous samples taken, with clinical assessment (e.g. weight, height,
blood pressure) and health questionnaire. WHO diagnostic criteria were used (Scragg
etal., 1991).
Overall, there was a good response rate with 82% of companies aproached and 67%
of staff agreeing to participate in the screening programme. However, because lower
numbers of undiagnosed diabetic individuals were detected in workforces initially
screened than expected from previous epidemiological data, the survey was extended
in duration to allow for sufficient statistical power. By the conclusion of the survey,
5927 individuals had been interviewed, 5677 of whom were aged 40 years or more
(70.6% being male; 7.7% Maori, 11.7% Pacific Islander, 1.8% Asian and 78.8%
European). (Scragg et al., 1991).
The survey showed the prevalences of diabetes and IGT were similar for both male
and female but increased with age. Age standardized prevalence of new and known
diabetes combined was 1.85% in Europeans, 9.91% in Maori, 8.87% in Pacific
Islanders and 7.54% in Asians. The relative risk of diabetes was also found to be
inversely related to gross household income (Scragg et al., 1991) and level of physical
activity (Scragg, RACP and NZSSD Annual Scientific Meeting, Auckland, 1990).
4.2 The Waikato 'Discover Diabetes' Project
Project Co-Ordinator: Dr Ross Lawrenson
This is a community based programme developed by the Waikato Area Health Board
as a regional health goal to improve detection and management of non-insulin
dependent diabetes. This is a comprehensive early detection programme for diabetes,
19
and exemplifies a programme undertaken not for epidemiological research but for
health intervention. The programme has been developed in conjunction with general
practice and focuses on rural communities with a high percentage of Maori people
and/or ageing population. An important feature of the Waikato "Discover Diabetes"
Project is the partnership that has been developed through the Kohikohinga Trust.
The project has been funded for a five year period, a project team appointed, facilities
provided and pilot undertaken (Lawrensen et al., NZSSD Scientific Meeting 1990).
An important aspect of the project is the incorporation of evaluation procedures for all
stages of the programme. This includes assessment of project design, procedures and
methods, results and cost-effectiveness (j)ers comm D Dury). The detection phase of
the programme is outlined below but it should be noted that the Discover Diabetes
Project is an integrated programme combining diabetes promotion and awareness,
screening and management via self-care programmes.
Detection is aimed at high risk groups viz, all adult Maori/Pacific Island Polynesians
over age 20 years; non-Maori over age 40 years; all obese people; and persons with
family history of diabetes. A pilot screening programme has been undertaken in
Matamata, one of four proposed target communities to be involved in the project.
The screening test used is the random capillary glucose (RCG) value. The approach
adopted is: RCG >I 1 .Ommol/l - refer to GP as diabetic
RCG < 6.5mmol/l - normal
RCG 6.5-8.0 -retest in 12 weeks
RCG 8.0-11.0 -OGT1' and review by GP
An initial cut-off of 6.0 mmol/1 meant that 25% of screened individuals would have
needed to been recalled for retesting (pers comm. D Dury). A comprehensive
database of all people tested is compiled, providing information on demographic,
clinical and biochemical characteristics and actions taken (Protocol).
It is estimated that the total population at risk in the Waikato is 15,000. Overall, 32%
of individuals at risk in the Matamat.a pilot participated in the first screening run (pers
comm. J Sceats). However, only 102 or 16% of the 639 Maori individuals aged >20
years regarded as being at risk of diabetes were screened.
As the Waikato Discover Diabetes Project protocol points out, not only are Maori
more likely to have diabetes than Europeans, but the economically disadvantaged
situation of many may mean that they are less likely to be diagnosed at an early stage.
4.3 Detection and Intervention for IGT
Principal Investigator: D Bourn
This study involved screening in a Dunedin general practice for IGT and adult-onset
diabetes. Screening for IGT has been advocated on the basis that lifestyle changes
may prevent progression to adult-onset diabetes and that early treatment may reduce
development of cardiovascular complications. A total of 1184 people aged 39-79
registered with 2 General Practitioners were invited to have a random blood glucose
test. Of these, 651 accepted (55% response rate). These individuals were
subsequently invited to have an OGTT. Those with high glucose levels were invited
back for 2 further OGTT.
20
Preliminary results indicated that half of those with IGT from the first test did not
-. show persistent IGT after 3 OGTFs. It appeared that through low prevalence of
undiagnosed glucose impairment, it is ineffective to screen for IGT and adult-onset
diabetes in people of European descent under 50 years of age. Random testing using
the standard cut-off of 7.8 mmol/l was an insensitive technique for detecting IGT
(Bourn, NZSSD Scientific Meeting 1990).
The survey was undertaken partly as a case finding exercise for a research project
aimed at identifying whether or not rates of progression of IGT to diabetes could be
reduced by intensive individualized lifestyle intervention through dietary and exercise
counselling, general counselling and stress management (Bourn, pers comm).
Recruitment of subjects into the programme had been problematic through low
detection and awareness of IGT in the community, despite local advertising of the
project and visits to Dunedin industries.
4.4 Diabetes in the Elderly
Principal Investigator: C Lintott
This is an example of screening for diabetes mellitus in a high risk group (viz, the
elderly) undertaken in primary care. A random sample of patients aged :^! 65 years
(N=369) were selected from a computerized patient register of a large urban medical
centre in Christchurch. The prevalence of diabetes mellitus in this age group was
investigated as part of a multidimensional health assessment of the elderly (Hanger
and Sainsbury, 1990).
A total of 599 subjects were invited but 63 had died or moved from the area, 96
refused and 71 did not respond or could not be contacted. The two most common
reasons for refusal were not interested or felt they were too healthy (J)ers comm C
Lintott). The primary screening method was random timed single venous blood
sample for determination of both glucose and glycated haemoglobin levels. OGTT
was requested within 10 days in any subject recording a random blood glucose level
^!! 7. 8mmol/l or GHb> SOmmol/mol haem excluding those subjects previously
diagnosed diabetic subjects. WHO criteria were used for classification (Lintott et al.,
1991).
This study found a combined age-adjusted (standardized to New Zealand population)
prevalence rate of 14.9%. Prevalence of known diabetes was 9.9% and previously
undiagnosed 5.0%. (Lintott et al., 1991). The sensitivity of random blood glucose
measurements was low: only 10 of the 16 (62.5%) previously undiagnosed cases
(diabetes defined by OG1T) had values ^ 7.8 mmol, and 11.9% ^t 11.1 mmol/l.
However, GHb appeared to be a more sensitive diagnostic tool with 93.8% of new
cases having values over the cut-off of SOmmol/mol heam (45 being upper limit of
normal) (Lintott et al., 1991).
These researchers, on the basis of their study, recommend routine screening in the
New Zealand elderly for diabetes mellitus.
4.5 Diabetes Community Awareness Programmes
Community screening programmes are organized annually (and intermittently) as part
of "Diabetes Awareness Week" campaigns by Diabetes New Zealand and local lay
Diabetes Societies. These are typically undertaken at local shopping malls, at work
21
sites, at local diabetes centres, and occasionally using mobile caravans. NZSSD has
developed guidelines for screening and recommends that these be undertaken (at least
supervised) by trained health professionals. Representatives from relevant
pharmaceutical companies are also involved.
However, these programmes are of limited benefit as a method for screening or early
detection of diabetes and are of concern because of the conditions under which they
tend to operate. There is a lack of quality assurance with poor diagnostic procedures
and techniques giving rise to inaccurate results; inappropriate screening cut-offs are
frequently used; there is potential for contamination, needle-pricks and infection; and
follow-up of detected cases is problematic. Furthermore, the probability of detection
of diabetes is likely to be low as those participating are self-selecting having
volunteered for the test and are not necessarily from groups at high risk of diabetes.
This approach is probably more beneficial through accompanying effects of screening
viz, accompanying promotion of diabetes and increased community awareness than
with detection per se (Moses et al., 1985). However, these benefits need to be
evaluated against the risks incurred.
4.6 Other strategies: Integrated screening programmes
Early detection for adult-onset diabetes may best be integrated with screening for comorbidities or other disorders, as in the Kawerau study (Scragg et al., 1990) where
screening for diabetes was undertaken in conjunction with the hepatitis B programme.
The clustering of metabolic disorders in at risk groups provides good rationale for
such an approach.
22
5. Intervention andtreatment
Case finding, is considered important because it is believed that subsequent treatment,
restoring the metabolic abnormalities present in adult-onset diabetes as close to normal
as possible, will prevent or delay the development of diabetes complications, and
improve quality and duration of life. If intervention is sufficiently early in the natural
history of adult-onset diabetes, then perhaps the primary defects in insulin secretion
and insulin resistance may be reversed, at least in part. If early treatment is beneficial
then pragmatic issues of efficient case detection become important.
Discussion is provided in two parts. First, primary prevention is reviewed as there is
no doubt from a health perspective that it is better to prevent diabetes from developing
than intervening after its presentation. The epidemiological characteristics and natural
history of adult-onset diabetes provide realistic opportunities for primary prevention
by Area Health Boards.
Second, the literature on therapeutic intervention following diagnosis is reviewed.
The aim of this sub-section is not to provide specific details of diabetes management.
Rather, the discussion examines the rationale of and scientific evidence for the
different therapeutic approaches to adult-onset diabetes.
5.1 Primary prevention
The aim of primary prevention is to reduce the incidence of diabetes by reducing the
risk of its onset, and thereby reduce its prevalence in the population (Tuomilehto and
Wolf, 1987). This means the attributable risk related to certain risk factors is
modified by influencing the levels of such factors (Tuomilehto, 1988).
Prevention Strategies
There are sufficient clinical and epidemiological data to initiate preventive care
programmes for adult-onset diabetes (Zimmet et al., 1986). Studies have shown
increased rates of diabetes with modernisation and westernisation of lifestyle of
selected ethnic groups, and increased risk through poor diet (viz, high fat, high
refined carbohydrate, low fibre), obesity and reduced physical activity (Zimmet,
1982; Tuomilehto, 1988). The reversal of such adverse factors are presumed to
improve health outcomes. However, the actual efficacy of lifestyle interventions
await the outcomes of long term prospective studies.
The generally accepted strategy for prevention of major non-communicable diseases
such as cardiovascular disease and diabetes, is that individual and community efforts
aim to improve nutritional status, enhance physical fitness and maximise
environmental safety. In the last decade, considerable attention has been given in
New Zealand and abroad to the prevention of both hypertension and coronary heart
disease. New Zealand's national health goals highlighted both these as well as
reduction in tobacco smoking. Intervention for adult-onset diabetes fits neatly into
this public health approach, especially since the risk factors for diabetes are common
to coronary artery disease and hypertension.
23
There are two complementary approaches to disease prevention:
the population strategy which seeks to remove or reduce causes of diabetes in
the community as a whole, and
the high risk strategy where preventive measures are implemented selectively
in individuals or groups that are at a specific high risk of developing the
disorder (Taylor, 1983; Tuomilehto and Wolf, 1987; King and Dowd, 1990).
The population approach uses community wide programmes directed at altering
environmental and lifestyle (behavioural) influences and their social and economic
determinants to change the distribution of risk factors within the population to a more
appropriate baseline, thus reducing the numbers at risk (Taylor, 1983; King and
Dowd, 1990). The population based approach has been widely advocated for
cardiovascular disease (Kotte et al., 1985; WHO, 1986) but given the higher
frequency and co-existence of atherosclerosis in adult-onset diabetes, there is a strong
case for intensified and selective intervention for those at risk of diabetes (King and
Dowd, 1990). Adult-onset diabetes is a lifestyle and multifactorial disorder. For
preventive measures to be effective in the population, diabetes should be considered
with other lifestyle related non-communicable disorders and incorporated in
integrated intervention programmes based on several potential risk factors
simultaneously (Zimmet et al., 1986; Zimmet, 1988; Tuomilehto, 1988).
If diabetes is to be targeted alone, then high risk strategies are more appropriate for
several reasons: 1) little can be done to change genetic susceptibility; 2) uncertainty
still surrounds the causal relationships between risk factors and the aetiopathogenesis
of adult-onset diabetes; and 3) perception of individual risk influences the
acceptability and response to interventive strategies. In New Zealand, cultural and
ethnic sensitivity and acceptability of health programmes must be taken into
consideration in working with Maori and Pacific Island health issues. The potential
for primary prevention is high in individuals with IGT, a positive family history of
diabetes, or other risk associations of the disorder.
Components
Central to the planning of any prevention programme for adult-onset diabetes is the
assessment of the major environnmental and behavioural determinants of diabetes in
the target community (Tuomilehto, 1988). While obesity is clearly an important risk
factor for adult-onset diabetes (Zimmet, 1982: Ohlsson et al., 1985), it would be
pointless for an Area Health Board to concentrate entirely on the prevention and
control of obesity if it was not identified as the sole or major risk factor in its
community (Zimmet, 1988). The key risk factor may be sedentary lifestyle, and a
programme aimed at increasing physical exercise may confer advantages over and
above that from associated reduction in obesity. Since individual roles are still not
clear, multiple risk factor intervention seems the most logical approach to the
prevention of adult-onset diabetes.
The following actions are recommended for groups or individuals at high risk of
diabetes0weight control when obese;
•increasing physical activity;
•modification of composition of the diet (Tuomilehto and Wolf, 1987);
•cessation of tobacco smoking (increased risk for cardiovascular complications);
and
•avoidance of stress (Zimmet etal., 1986; National Institute of Health, 1987).
24
3 ..
-.
The basic approach for prevention of non-communicable diseases at a community
level is through health education and promotion, national nutritional and health policy
and structural changes in such things as marketing and advertising, food regulations,
tax levies, and legislation e.g. laws governing smoking in public places (Taylor,
1983; Nutrition Taskforce, 1991).
The New Zealand Nutrition Taskforce (1991) identifies a joint approach between
"blanket" mass media coverage and community-based initiatives as the most effective
method for planned food and nutrition education. Nutrition education requires full
involvement of all individuals and groups within a community who have an interest in
nutrition and food, and these individuals should be central in the planning,
implementation and evaluation process. Education to achieve the food and nutritional
goals of improving health and reducing disease will be enhanced if used alongside
legislative, economic and social strategies, and appropriate food supply (Nutrition
Taskforce, 1991).
At the community level, there are few differences between preventing coronary heart
disease and adult-onset diabetes.
5.2 IGT: Prevention of progression to diabetes
Since 2-6% of those with IGT develop diabetes each year, individuals with IGT
represent an important target group for primary prevention. However, few studies
have systematically investigated the effect of intervention on IGT.
Clinical research has shown that low caloric diets can lead to improvements in glucose
tolerance and reduced insulin resistance, which may be the primary cause of
intolerance (Bennett and Knowler, 1984). DeFronzo et al. (1983) have also reported
that use of oral hypoglycaemic agents, which are commonly used in the treatment of
diabetic patients, both increases insulin secretory responses and reduces insulin
resistance in mild and moderate glucose intolerance.
A ten year follow-up of male subjects with IGT in Sweden (Sartor et al., 1980)
suggested that treatment with diet regulation, in combination with oral hypoglycaemic
drug therapy prevents or postpones progression from IGT to overt diabetes. At
follow-up, there was a significant difference in the rate of development of diabetes
between those individuals randomized to treatment and 'no treatment'. However,
some caution is needed in interpreting these results. The analysis was not by groups
of initial treatment, subjects continuing drug therapy represented only half of those
randomized to this group at baseline and the dietary intervention was inadequately
described in the paper. It is difficult to determine if there was a true therapeutic
effect, or whether the results reflect self-selection bias.
These results were not confirmed in the Whitehall Study where randomized allocation
to drug and/or diet therapy did not significantly affect either mortality rates or the
proportions (of men with IGT) worsening to diabetes over a similar follow-up period
(Jarret et al., 1984). The Whitehall Study used a diet based on restriction of
carbohydrate which is considered inapropriate today. As Bennett and Knowler (1984)
point out, if treatment of IGT with drugs, diet or exercise can delay or prevent
diabetes, the detection and treatment of persons at this stage would dramatically
reduce the incidence of adult-onset diabetes. While lifestyle intervention is credible,
because of uncertainties in outcomes and cost-implications, widespread drug
25
intervention is not recommended for the prevention of progression from IGT to
diabetes other than on an experimental basis.
5.3 Secondary intervention: treatment approaches following diagnosis of
diabetes
The aim of this section is not to provide specific details of diabetes management.
Rather, the discussion examines the rationale and scientific evidence for the different
therapeutic approaches to adult-onset diabetes. From the therapeutic standpoint, there
are three basic measures available which improve the metabolic abnormalities in
adult-onset diabetes: 1) dietary modification; 2) a regular programme of physical
activity; and 3) pharmacological intervention with oral hypoglycaemic agents and/or
insulin. It is now accepted that the effectiveness of these forms of intervention is
greatly enhanced by patient education and that active participation by the patient is
crucial to treatment success. These interventions are summarised below and discussed
in detail in the separate Technical Appendix.
Dietary intervention
Dietary modification is useful in reducing fasting hyperglycaemia, in moderating
glucose response to food, and in improving insulin action through reduction in body
weight. The two main aspects to dietary intervention for individuals with adult-onset
diabetes are restriction of total energy intake and modification of dietary composition
(Larkins, 1987). Weight loss and reduction in dietary fat are of central importance
since excess body fat characterizes adult-onset diabetes; since most diabetic patients
die of heart disease; and since a low fat diet improves insulin .secretion, glucose
disposal, and glucose tolerance independent of weight changes (Chan et al., 1988;
Swinburn et al., 1991).
Dietary therapy alone may be sufficient in up to half of all adult-onset diabetic
patients in controlling glycaemic and lipid abnormalities, but it is important that
dietary management is not separated from other aspects of lifestyle (Nutrition Task
Force, 1991). Effectiveness of dietary intervention is influenced by at least six
factors:
•patient understanding of the need for weight loss;
•individualised and flexible dietary guidance;
•monitoring of clinical progress;
•continued reinforcement of education;
•realistic goals; and
•adequacy of resources for behavioural support.
Exercise
Regular exercise is an important component of the total therapeutic approach to adultonset diabetes. However, this position has not been without its critics, and as Reaven
(1989, p.54) states "very little experimental data is available which permits the
clinician to come to a rational decision as to the clinical utility of exercise in any
given patient with adult-onset diabetes." Exercise studies have typically been
undertaken using insulin dependent patients, and it is only recently that there has been
clarification of potential benefits for those with adult-onset diabetes. Still unanswered
are the long-term effects of exercise on glucose metabolism, blood pressure and
coronary risk factors.
26
Reaven (1989) states that although it is not widely appreciated, differences in level of
physical activity are as powerful as variations in obesity in the modulation of insulin
activity. However, the level of exercise necessary to ensure this effect may be quite
unrealistic for older people or those in otherwise poor health. Nevertheless, even
moderate exercise has overall health benefits and may also provide important
psychological benefits to those with diabetes by enhancing self esteem, and by
improving motivation and the quality of life.
Diet plus physical activity is more effective than diet alone in helping overweight
patients lose weight and in conferring metabolic benefits (Schneider et al., 1984;
Marcus et al., 1987). For the overweight NIDDM patient, reduction in overall
calorie consumption is the first line of therapy, with exercise being complementary
and not a substitute.
Pharmacological intervention
Pharmacological intervention is the second approach to the treatment of adult-onset
diabetes, after a lifestyle approach. There are two aspects of the pharmacological
approach:
• Drug treatment is not typically limited to control of hyperglycaemia, but often
is required for the control of the co-existing morbidities in those experiencing
adult-onset diabetes.
• Pharmacological intervention is an adjunct to and not a substitute for changing
dietary behaviour and levels of physical activity. Use of medication does not
indicate cause for relaxation of dietary principles.
Diabetes education
There is an abundance of literature on this topic, a large part of which concerns the
philosophy and details of delivery of diabetes education and a much lesser part formal
scientific evaluation. It is accepted that the effectiveness of the interventions
described above is greatly enhanced by patient education, with active participation of
the patient being a pre-requisite for treatment success. However, some claims made
on behalf of diabetes education must be treated with caution. Recent research that is
both sound and appropriate in study design and methods has demonstrated that
diabetes education programmes as developed have often not shown longer term (e.g.
beyond one year) or sustained benefits with respect to health outcomes or patterns of
resource use (Kaplan and Davies, 1986; Dun and Turtle, 1987; Brown 1988).
The evaluation and reporting of findings on diabetes education often suffer from
major research problems, including the absence of experimental controls and objective
outcomes, inadequate cost-benefit analysis, the lack of a research model which
integrates education within total patient care and isolates the influence of education
from other important factors, and the absence of long-term prospective and controlled
studies (Dunn and Turtle, 1987; Beaven et al., 1988).
27
5.4 Summary
Primary Prevention
• Given the epidemiology and natural history of adult-onset diabetes, primary
prevention is an appropriate and realistic goal for Area Health Boards to
pursue.
• Reduction in the incidence of diabetes can be achieved through either: 1) a
population strategy which seeks to remove or reduce causes of diabetes in the
community as a whole; or 2) a high risk strategy where preventive measures
are implemented selectively in individuals or groups that are at a specific high
risk of developing the disorder.
• Adult-onset diabetes fits well into a public health approach and can be
incorporated in integrated intervention programmes aimed at lifestyle related
non-communicable disorders, such as heart disease.
• Since 2-6% of those with IGT develop diabetes each year, individuals with
IGT represent an important target group for primary prevention through
lifestyle changes.
Secondary intervention
Early detection and intervention is promulgated through the belief that
treatment, restoring the metabolic abnormalities present in adult-onset diabetes
as close to normal as possible, will prevent or delay the development of
diabetes complications, and improve quality and duration of life.
Elevated blood glucose concentrations are not the sole metabolic manifestation
of adult-onset diabetes, and as great an emphasis needs to be placed on
cardiovascular risk association of raised total cholesterol and triglycerides,
depressed HDL-cholesterol, high blood pressure and smoking.
Therapeutic approaches
•The therapeutic means of achieving these goals are dietary intervention,
exercise, and pharmacological treatment.
• There are two aspects to dietary intervention for individuals with adult-onset
diabetes: 1) control of total energy intake; and 2) modification of dietary
composition, especially reduction in dietary fat.
•Weight loss is the most important and fundamental physiological approach to
the treatment of overweight individuals with adult-onset diabetes.
•Physical activity is a powerful therapeutic tool in the modulation of insulin
activity in individuals with adult-onset diabetes.
•Exercise exerts both acute and long-term effects on glucose metabolism, and
confers a number of health benefits.
28
•Individuals with diabetes should be encouraged to remain at least as physically
active as their non-diabetic counterparts.
•Diet plus exercise is more effective than either alone in helping overweight
patients to lose weight and in conferring metabolic benefits.
• Individuals with adult-onset diabetes are typically on multiple drug therapies
prescribed for the treatment of the co-existing morbidities prevalent in these
individuals.
• Drug intervention is an adjunct to and is not a substitute for changing dietary
behaviour and levels of physical activity. Oral hypoglycaemic agents and/or
insulin should only be used when dietary therapy and exercise are insufficient
to achieve adequate metabolic control.
• Adherence to dietary recommendations and lifestyle changes are not sustained
in many individuals beyond 12 months post intervention. Similarly, the
effectiveness of oral hypoglycaemic agents in the treatment of individuals with
adult-onset diabetes for periods greater than five years is often poor.
• Effectiveness of these forms of intervention is greatly enhanced by patient
education, but there is little scientific evidence for long-term improvements in
health outcomes and patterns of resource utilization.
29
6. Conclusions
This review has presented relevant scientific evidence for early detection and
ther'peutic intervention in adult-onset diabetes mellitus. Many previous obstacles to
screening for diabetes have been overcome, at least in part. Early detection of
diabetes in adulthood can be justified on the following grounds:•there are high rates of diabetes prevalence and incidence in adults, particularly
in elderly and and non-whites;
•risk factors for diabetes and diabetes complications, especially heart disease,
have been identified;
•there is good understanding of the causation and patho-physiological defects
present in adult-onset diabetes;
•the natural history of the disorder indicates opportunities for early
intervention;
•individuals incur morbidity prior to diagnosis, with complications being
already present in many at diagnosis;
•there is international consensus on the definition and diagnostic criteria of
diabetes;
•screening and diagnostic methods exist which are both effective and practical;
•therapeutic measures are available which do modify risk factors and intervene
in the pathogenesis of adult-onset diabetes; and
•early detection allows the disease to be treated at an early stage, thus
increasing the chances of improved metabolic control.
Short-term and cross-sectional studies consistently show diet, exercise and drug
therapies to be beneficial in improving both glycaemic and lipid abnormalities in
individuals with adult-onset diabetes. These forms of intervention have the potential
for being effective in the long-term, if facilitated by both individual patient factors
and the provision of appropriate health resources. Success of treatment implies a high
degree of patient participation and ongoing clinical and educational support.
While there is no data in the literature reporting cost-benefit analyses, it seems
prudent to screen for adult-onset diabetes and intervene early in its natural history.
However, the consequence of the metabolic clustering of hyperglycaemia, obesity,
lipid abnormalities, hypertension and heart disease is that health intervention viz.
detection and treatment will have to be multifactorial. The traditional focus on
detection and treatment of hyperglycaemia and perturbations in glucose metabolism in
persons with adult-onset diabetes is inappropriate if this is done in isolation to existing
co-morbidities. The fact that the co-morbidities of obesity, hyertension and
hyperlipidaemia are amenable to treatment is good argument alone for screening
persons at high risk for diabetes.
31
Appendix 1
Current guidelines
National Diabetes Data Group.
Classification and Diagnosis of Diabetes Mellitus and Other Categories of Glucose
Intolerance.
Diabetes 1979; 28:1039-1057.
World Health Organization.
Diabetes Mellitus.
Report of a WHO Study Group. Technical report series no.727.
WHO Geneva. 1985.
American Diabetes Association.
Clinical Practice Recommendations.
Diabetes Care 1991; 14.
European NIDDM Policy Group.
Alberti KGMM, Gries FA. A Desktop Guide for the Management of Non-insulindependent Diabetes Mellitus (NIDDM).
IDF Bulletin, 1990; XXXV.
Alberti KGMM, Gries F1.
Management of Non-insulin-dependent Diabetes Mellitus in
Europe: a concensus view.
Diabetic Medicine 1988;5:275-281.
New Zealand Society for the Study of Diabetes
Dunn P, Cutfield R. Diabetes Mellitus: Management Guidelines.
New Ethicals 1988; 25:47-59.
33
Appendix 2: Technical
Contents
1. EPIDEMIOLOGICAL BACKGROUND
1. 1 Risk factors
1.2 Aetiopathogenesis
1.3 Natural history
37
37
38
39
2. EARLY DETECTION AND DIAGNOSIS
2.1 Diagnostic criteria
2.2 Clinical assessment
2.3 Biochemical diagnostic procedures
53
53
3. SECONDARY INTERVENTION: TREATMENT APPROACHES
FOLLOWING DIAGNOSIS OF DIABETES 3.1 General therapeutic considerations
3.2 Dietary Intervention
3.3 Exercise
3.4 Pharmacological intervention
3.5 Diabetes education
55
56
65
65
67
72
74
77
79
BIBLIOGRAPHY
REFERENCES AND BIBLIOGRAPHY
35
1. Epidemiological background
1.1 Risk factors
In Caucasian populations in the US and Europe, age-specific incidence of adult-onset
diabetes increases at least up to 70 years of age (Melton et al., 1983; Wilson et al.
1986; Bennett, 1990). Maori and Pacific Islanders may, however, be more like Pima
Indians where incidence peaks in the 40-50 year age group and falls sharply thereafter
(Bennett, 1990). In Framingham, annual incidence of diabetes in men aged 40-49
years was 300 per 100,000 and 570 per 100,000 for those aged 50-59 years (Wilson
et al., 1986).
Prevalence of diabetes in the elderly is commonly reported at rates in excess of 10%
in persons aged ^!t60 years (Laasko and Pyorala, 1985; Wilson et al., 1986; Harris et
al., 1987; Croxson et al., 1991). Data on the elderly in New Zealand are however
limited. A recent survey of a large urban medical centre in Christchurch (Lintott et
al., 1991) found an age-adjusted prevalence rate (standardized to the New Zealand
population age structure) of 14.9%. Prevalence of known diabetes was 9.9% and
previously undiagnosed 5.0%. This gives a ratio of 1:2 for undiagnosed to diagnosed
diabetic cases, suggesting higher detection of diabetes in elderly patients in general
practice than perhaps commonly thought. Extrapolating the results to the general
population aged ^- 65 years, more than 55,000 elderly New Zealanders would be
expected to have diabetes, of whom 17,000 will be undiagnosed.
Since both prevalence of diabetes and IGT increase with age, many more people will
be at risk of developing diabetes as New Zealand's population ages.
For general review of diabetes pathogenesis, diagnosis and treatment in the elderly see
Lipson 1986; Goldberg and Coon, 1987.
Obesity
Up to 80% of adult diabetic patients are obese at onset of the disorder. Numerous
cross-sectional and longitudinal studies support a strong positive causal relationship
between obesity and diabetes in adults, although the impact varies between different
populations and sexes within populations (Zimmet et al., 1986; Jallut et al., 1990).
The Rochester data showed incidence of adult-onset diabetes 1960 to 1969 in the 2059 year age group was 100 per 100,000 for obese subjects and 60 per 100,000 for
non-obese. Incidence increased to 375 per 100,000 in obese patients aged ^!t 60 years
and 250 in non-obese individuals (Melton et al., 1983). In New Zealand, Scragg et
al. (1990) report that there is a 3 fold increase in relative risk for diabetes for obese
individuals (body mass index (BMI) ^!: 25 for males and ^!! 27 for females) compared
to non-obese individuals.
The risk of developing diabetes has been shown to relate to both duration and degree
Tuomilehto and Wolf, 1987;
of obesity (Ohlsson et al., 1985; Modan et al., 1986;1990).
The effect of past and
et
al.,
Saad et al., 1988; Bennett, 1990; Holbrook
concurrent body mass index on prevalence of IGT and adult onset diabetes was
demonstrated in the Israel study of glucose intolerance, obesity and hypertension in
persons aged 40-70 years (Modan et al., 1986). The authors concluded that BMI
^!!27 leads to impairment of glucose tolerance and a prolonged period of obesity is
required for development of NIDDM.
37
More recently, attention has turned to the distribution of body fat as a predictor of the
development of diabetes. Studies similarly show that there is a significant positive
association of abdominal adipose tissue i.e. central or android obesity (measured by
waist-hip ratio) with risk of diabetes and this is independent of the degree of obesity
(Ohisson etal., 1985; Haffner etal., 1986).
Ethnicity
Epidemiological studies have shown wide differences in the prevalence of diabetes
between ethnic groups, with genetic admixture and in groups with mixed ethnic
origins. Increased rates of diabetes in Maori and Polynesian Pacific Island
communities was first documented in New Zealand by Prior and colleagues in the
early 1960s. The differential in risk between European and Polynesian populations
has been maintained, although prevalence of diabetes in genetically susceptible
populations may not be as high as first indicated in earlier studies. The Workforce
Diabetes Survey undertaken between 1988-1990 reported rates in the 40-65 year age
group ranging from 1.9% in Europeans to 8.9% in Maori, with the relative risk of
diabetes in Maori, Pacific Island and Asian ethnic groups being 4-5 fold higher than
for Europeans (NZSSD Annual Scientific Meeting, 1990).
Higher rates of diabetes in Maori and Pacific Island populations partly reflect
increased obesity. However, in subjects surveyed in Kawerau, the relative risk of
diabetes amongst Maori compared to non-Maori was 2.1 adjusting for age and 1.7
adjusting for age and BMI (Scragg ci al., 1990).
Physical inactivity
Physical inactivity appears to increase risk for diabetes, and results from crosssectional studies suggest that lack of physical exercise is independent of other risk
factors. (Lindgarde and Saltin, 1981; Zimmet et al., 1984). Physical activity also
seems to protect against coronary heart disease (Salonen ci al., 1982; LaPorte ci al.,
1984) a common co-morbidity with adult onset diabetes. Lindgarde and Saltin (1981)
found that individuals with IGT can normalize glucose tolerance by increase in their
weekly physical activity pattern.
Frisch ci al. (1986) reported a lower prevalence of diabetes in female former college
athletes (0.57%) than nonathletic classmates (1.3%). In Malta, the age-standardized
two-year risk of diabetes was consistently and inversely related to the level of physical
activity. In subjects with normal glucose tolerance at baseline, those with low activity
levels had a two-fold risk of diabetes during the follow-up than those with high
physical activity (Tuomilehto, 1988). In New Zealand, data from the Workforce
Diabetes Survey showed reduced relative risk for diabetes amongst more physically
active individuals although no significant difference was observed in the Kawerau
study (Scragg ci al., 1990).
1.2 Aetiopatho genesis
The exact primary defects in adult-onset diabetes are still not known and research
opinion varies considerably over aetiopathogenesis. There is little doubt that an
underlying genetic susceptibility for adult onset diabetes is unmasked by
environmental factors (i.e. factors external to the individual human host - Last,
1988). It is now accepted that the basic defect in most adult onset diabetic cases is the
inability of pancreatic • -cells to release insulin, coupled with resistance of peripheral
38
tissues to the action of insulin i.e. the disorder is characterized by •-cell
dysfunctioning and insulin resistance (DeFronzo et al., 1983; Ward et al., 1984;
Reaven 1988; Cameron et al., 1989; Leahy, 1990). While insulin deficiency is
regarded as only relative, individuals with adult onset diabetes exhibit a wide
spectrum of insulin responses to glucose and mixed meal challenges (Scott et al.
1986).
The genetic importance of adult-onset diabetes is shown in strong family histories,
through varying rates of diabetes in off-spring from inter-marriages (genetic
admixture), and concordance rates of 55-100% for monozygotic twins (% pairs of
twins where the other twin develops diabetes if one twin is already affected (Barnett
et al., 1981; 0' Rahilly et al., 1988). The risk of first degree relatives developing
diabetes before age 65 is reported to be 5-10% (Tuomilehto and Wolf, 1987). It has
been estimated that almost 40% of siblings of diabetic individuals could be expected
to develop diabetes assuming a maximum life expectancy of 80 years (Tuomilehto,
1988). Evidence accumulated over recent years shows that the familial aggregation
seen in adult-onset diabetes is due to an inherited defect in the genes predisposing to
diabetes (Permutt, 1990; O'Rahilly et al., 1988).
1.3 Natural history
There are six identifiable stages in the natural history of NIDDM which provide for
possible intervention:1)
Genetic susceptibility
2)
State of potential abnormality of glucose tolerance (a statistical risk class that
includes subjects who have normal glucose tolerance but by virtue of other
characteristics are at substantially increased risk of diabetes)
3)
Impairment of glucose tolerance
4)
Diabetes mellitus without complications (stage where chronic hyperglycaemia
is present with or without symptoms)
5)
Diabetes with complications but without associated symptomatology or
disability, and
6)
Diabetes in which complications lead to functional impairment (Bennett and
Knowler, 1984).
Primary prevention targets Stages 1,2 and 3 before glucose intolerance reaches
diagnostic levels for diabetes. Complications, particulary vascular disease, may occur
even during phase 3, highlighting the importance for primary prevention. Secondary
prevention occurs after diagnosis, with intervention aimed at preventing, delaying or
minimising the development and impact of the microvascular, macrovascular and
neuropathic complications of diabetes.
Progression from IG T
Persons with IGT are at increased risk of diabetes but only a proportion develop overt
diabetes and many revert to normal glucose tolerance. Progression of IGT to diabetes
(mainly NTDDM but also IDDM) has been studied in a variety of populations, and
while sample sizes (typically < 300 persons), diagnostic levels and periods of follow-
39
up (approx. 10 years) have varied, not dissimilar results have been found. For
example, in Bedford (UK) after 10 years follow-up, 15% IGT subjects had worsened
to diabetes; 53% had reverted to normoglycaemia; and 23% remained intolerant (9%
had insufficient data for re-classification) (Keen et al., 1982). The Whitehall Study
found 29.4% of men with IGT worsened to diabetes after ten years, a rate higher than
the Bedford population (Jarrett et al., 1984). The difference can however be
attributed to differences in criteria for entry into the study and for worsening to
diabetes. In a Japanese study, Kadowaki et al. (1984) found 17% of 288 IGT subjects
worsened to adult-onset diabetes over 5-12 years. In a sample of 266 IGT individuals
from the high risk Nauruan population, 26% had deteriorated to adult-onset diabetes
after six years follow-up (c.f. 7% of normoglycaemic persons at baseline) but 39%
had reverted to normal (King et al., 1984, Sicree et al., 1987).
Overall, the British and US data suggest the rate of progression from IGT to diabetes
is around 2-3% per annum in caucasoid populations. Progression rates are
approximately double in Micronesian and Polynesian populations (King et al., 1986;
Sicree et al. 1987; Tukuitonga, 1990). Tukuitonga (1990) reports a rate of 6% per
year in Niueans.
The initial degree of glucose intolerance measured by elevated fasting and postprandial blood glucose, obesity (higher body mass index) and lower insulin response
to glucose are the best predictors of decompensation to diabetes (Sartor et al., 1980;
Sasaki et al., 1982; Keen et al., 1982; Kadowaki et al., 1984; King et al., 1984;
Sicree et al., 1987). The duration of the IGT phase varies markedly between
individuals, with the progression from IGT to diabetes spanning many years in some
cases. Probably not all adult diabetic subjects will have a long or obvious
intermediate stage of glucose intolerance, and many may have a conversion from
normality to frank diabetes without passage through IGT.
Morbidity and mortality
Many patients with adult-onset diabetes are asymptomatic and the hyperglycaemia
may go undetected for years. Individuals often present at the time of diagnosis with
well established long-term complications of diabetes (Kadowaki et al. 1984; Owens et
al., 1988; Standi et al., 1988; Lehtinen et al., 1989). It has been reported that at
least 20% of patients with adult-onset diabetes have evidence of retinopathy at
presentation, with approximately 2 to 5% having sight threatening proliferative
changes (Owens et al., 1988). One third of patients are likely to be hypertensive and
10% will have established symptomatic CAD (Hadden et al., 1986).
Rates of renal failure and blindness are considerably higher than for non-diabetic
persons. Recent research in New Zealand indicates renal disease in diabetic Maori
and Pacific Island populations is more prevalent and more aggressive compared to
diabetic persons of European ancestry (Lunt et al., 1990; Thompson et al., 1991).
The microvascular complications of retinopathy and nephropathy are very specific to
diabetes. The risk of microvascular complications are strongly dependent on the
duration of diabetes and to a lesser extent on the level of hyperglycaemia (Jarrett,
1986; Klein 1988; Diabetes Drafting Group, 1985). Controversy still persists as to
whether or not achievement of near-normal glucose levels will alter an individual's
risk of developing, or the rate of progression, of these microvascular complications.
Macrovascular disease manifested as cardiovascular, peripheral vascular and cerebrovascular disease is also significantly associated with diabetes but appears less well
associated with duration of diabetes or severity of hyperglycaemia (Jarrett, 1984;
Singer et al. 1988; Haffner, 1990). Overall, diabetes confers a 2-3 fold increase in
40
I
risk for coronary artery and congestive heart failure, which is of concern as New
Zealand is already characterized by high rates of cardiovascular disease (8th highest in
the world for males in 1985).
Even though approximately 75 % of persons with IGT do not progress to diabetes over
10 years, IGT does warrant detection because of clustering of metabolic abnormalities
and its association with coronary artery disease (CAD). The Paris Prospective Study
shows for example that rates of CAD mortality are twice normal for persons with
IGT, are not different to those with newly diagnosed diabetes but are less than those
in whom diabetes is well established (Fontbonne et al., 1989).
Mortality in persons with adult-onset diabetes is double that in the non-diabetic
population matched for age-sex (Panzram, 1987). Life expectancy is reduced by 5-10
years in individuals developing adult-onset diabetes before 50 years of age (Panzram,
1987). Loss of life expectancy reduces as age of onset increases and is negligible at
75 years of age (Alberti and Gries, 1988). Mortality is relatively higher in females
thanmales. Hansen (1988) reports mortality in diabetic patients who are 20-30%
above ideal bodyweight is 2.5-3.3 times greater than those of normal weight, and as
much as 5-8 times higher if bodyweight is 40% above ideal.
There is unequivocal evidence that cardiovascular disease is the leading cause of death
in adult-onset diabetes patients accounting for over 60% of deaths, and
cerebrovascular disease the second cause (Jarett et al., 1982; Morrish et al., 1990).
Over 12 years of follow-up in the London cohort study, 20% of adult-onset diabetes
persons aged 35-55 years died (Morrish et al., 1990). Renal disease contributes to
only a small percentage of deaths in adult onset cases although it is important in
Maori and Pacific Island populations.
Metabolic syndrome
I
Multiple risk factors for macrovascular disease (obesity, hypertension, lipid
abnormalities, smoking) are commonly found in individuals with diabetes and IGT
(ADA Position Statement, 1990). Cardiovascular risk factors are present with much
greater frequency than those with normal glucose tolerance (Wingard et al., 1983).
There are now considerable data suggesting that: 1) adult-onset diabetes is part of a
wider non-communicable disease syndrome or complex (termed Reaven's Syndrome
or Syndrome X) compromising multiple risk factors and morbidities; and 2)
hyperglycaemia is only part of the wider metabolic disturbance present in diabetic
persons causing large vessel disease (Zimmet ci al., 1986; Reaven 1988; Editorial
Lancet 1989; Zimmet, 1989; DeFronzo and Ferrannini 1991). The excess of
cardiovascular disease at diagnosis of diabetes has led to the suggestion that the
atherogenic process evident in adult onset diabetes is largely independent of glucose
abnormalities, and occurs as a result of dyslipidaemia, hyperinsulinaemia, and other
metabolic abnormalities which characterize the diabetic state (Haffner ci al., 1990).
The consequences of this metabolic clustering is that the traditional focus on treatment
of hyperglycaemia and perturbations in glucose metabolism in adult-onset diabetes is
inappropriate if this is done in isolation to existing co-morbidities. Health
intervention for many adult onset diabetic individuals will have to be multifactonal
(Standl etal., 1985; Zimmet etal., 1986; Saudek, 1990).
41
2. Early detection and diagnosis
2.1 Diagnostic criteria
Over the last decade, considerable time and effort has been directed at defining the
level of hyperglycaemia that is necessary to warrant a diagnosis of diabetes.
Diagnostic criteria now routinely used for IGT and diabetes in non-pregnant adults are
those recommended by either NDDG or WHO. Following the format used by Harris
(1985), these criteria are listed in Table 2-1 separately for the clinical and
epidemiological setting.
Table 2-1 Recommendations of the National Diabetes Data Group (NDDG) (1979) and The
World Health Organisation (WHO) (1985)
Criteria for diagnosis in non-pregnant adults:
1. Ina clinical setting
Any one of the following is considered diagnostic of diabetes:
a Presence of the classic symptoms of diabetes, such as polyuria, polydipsia,
ketonuria and rapid weight loss, together with gross and unequivocal elevation of
plasma glucose, e.g., post-prandial or random plasma glucose concentration >
11.1 mmol/l.
bElevated fasting glucose concentration on more than one occasion:
;-- 7.8 mmol/l
venous plasma
2: 6.7 mmol/l
venous whole blood
2-- 6.7 mmol/l
capillary whole blood
If the fasting glucose concentration meets these criteria, the OGTT is not required.
Indeed, virtually all persons with FPG a: 7.8 mmol/l will exhibit an OGTT that
meets or exceeds the criteria in 1. (c) below.
Fasting glucose concentration less than that which is diagnostic of diabetes (1. (b)
above), but sustained elevated glucose concentration during the OGIT. The NDDG
requires that both the 2-hour sample and some other sample taken between
administration of the 75-gram glucose dose and 2 hours later, meet the following
criteria; the WHO requires only that the 2-hour sample meet these criteria:
venous plasma^: 11.1 mmol/l
venous whole blood a 10.0 mmol/l
capillary whole blood ^: 11 .1 mmol/l
43
2. In an epidemiologic setting
In epidemiologic research or during screening for diabetes, it will generally be impossible to
conduct the careful plasma glucose measurements above. Any one of the following
criteria, which are compromises, is considered diagnostic of diabetes in these
circumstances:
aMedical history of diabetes diagnosed by a physician.
bA single fasting glucose concentration:
a 7.8 mmol/l
venous plasma
a 6.7 mmol/I
venous whole blood
a 6.7 mmol/l
capillary whole blood
CA
single glucose concentration 2 hours after ingesting a 75-gram glucose dose:
11.1 mmol/I
venous plasma
2: 10.0 mmol/I
venous whole blood
;2t 11.1 mmol/l
capillary whole blood
B. Criteria for diagnosis of impaired glucose tolerance:
1. Ina clinical setting
The NOOG requires that the three criteria (a), (b) and (c) must be met. The WHO requires
only that criteria (a) and (b) be met.
(a)
Fasting glucose concentration:
venous plasma
venous whole blood
capillary whole blood
< 7.8 mmol/l
< 6.7 mmol/I
< 6.7 mmol/l
(b)
Glucose concentration at 2 hours after ingesting 75 rams of oral glucose:
between 7.8 and 11.1 mmol/l
venous plasma
between 6.7 and 10.9 mmol/l
venous whole blood
between 7.8 and 11.1 mmol/l
capillary whole blood
(c)
Glucose concentration at mid-test ( '/2 hour, 1 hour, or 1
grams of oral glucose:
11.1 mmol/l
venous plasma
a 10.0 mmol/l
venous whole blood
11.1 rnmol/l
capillary whole blood
Y2
hours) after ingesting 75
2. In an Epidemiologic Setting
In epidemiologic studies on diabetes, it may be impossible or impractical to meet the
requirement of obtaining two or three blood samples. Consequently a modification is
recommended whereby a single blood sample should be drawn 2 hours after a 75-gram
oral glucose challenge. If the glucose concentration meets the criteria below, the individual
may be assigned to the IGT class for epidemiologic purposes. However, this results in
twice the prevalence of IGT that is obtained when the mid-test value is also imposed.
Glucose concentration at 2 hours after ingesting 75-gram oral glucose:
between 7.8 and 11.1 mmol/l
venous plasma
between 6.7 and 10.0 mmol/l
venous whole blood
between 7.8 and 11.1 mmol/l
capillary whole blood
44
Diagnostic criteria for diabetes and IGT were redefined and standardized by NDDG
and WHO at levels higher than those commonly used in the 1960s and 1970s. These
values were determined in light of epidemiological data and results from several US
and British long-term prospective studies indicating that:
•most persons with mild abnormalities of glucose tolerance do not progress to
diabetes;
•risk for development of specific microvascular lesions of diabetes appear to be
limited to patients with marked hyperglycaemia;
• in ethnic groups where diabetes is particularly prevalent, the population blood
glucose distribution is bimodal with optimal separation between diabetic and
non-diabetic at a relatively high level; and
• using lower glycaemic thresholds means large proportions of older persons are
classified as having asymptomatic diabetes (a consequence of progressive
glucose intolerance with ageing) (NDDG 1979; Modan 1984; Singer et al.,
1988; Stern, 1988; Finch et al., 1990).
Thus, current criteria are based on values of glucose intolerance believed to be
predictive of diabetes microvascular complications, and for IGT levels indicative of
increased risk of cardiovascular disease and decompensation to diabetes. Adjustment
for age of subjects is unnecessary with these diagnostic values.
The differences in diagnostic levels between the two classifications reflect the
fundamental difference between epidemiological and clinical reasons for detection.
The demands of epidemiological studies are different from those encountered in a
clinical setting. For practical reasons, simplified procedures are required for large
scale field work and population screening programmes. The NDDG criteria are
aimed primarily at testing individual patients in the clinical setting whereas WHO
recommendations are directed more at screening large population groups (Fajans,
1990; Harris, 1985). NDDG argue that the diagnosis of diabetes depends on the
magnitude of hyperglycaemia as well as its duration i.e. there has to be evidence of
sustained glycaemic elevation.
2.2
Clinical assessment
The first step in individual case detection is clinical assessment for risk factors and
symptoms indicative of diabetes. This would most commonly be undertaken in
general practice, either opportunistically when an individual visits for other reasons or
planned through a suspicion of the diagnosis. The purpose of this is to avoid
biochemical testing in those unlikely to have diabetes. Individuals with risk factors
but without symptoms are the major target group for early detection.
The diagnosis of diabetes should not be problematic in subjects presenting with
symptoms of diabetes (polydipsia, polyuria, glycosuria, weight loss, infection, visual
impairment); or diabetic complications; and unequivocal hyperglycaemia. A single
random (casual) venous plasma or capillary blood glucose measurement ^!t 11. 1
mmol/l is sufficient to confirm diagnosis of diabetes in symptomatic individuals
(Table 2-1).
45
However, many individuals developing diabetes in adult life are asymptomatic and
may present with long-term diabetes complications following years of undetected
hyperglycaemia. Biochemical assessment of hyperglycaemia is essential for the
diagnosis of diabetes in asymptomatic individuals.
2.3 Biochemical diagnostic procedures
There are a variety of diagnostic procedures and screening tests for measuring glucose
intolerance and for making a diagnosis for diabetes. Guidelines for use of different
diagnostic tests and criteria are provided by NDDG and WHO (Table 2-1). The most
common approach to biochemical assessment is to do a fasting or random blood
glucose measurement which if elevated is followed by repeat testing or OGTF.
General considerations
The reproducibility and effectiveness, as measured by sensitivity, specificity and
predictive value (Table 2-2), of different diagnostic methods and cutpoints used in
diabetes detection are presented below. Overall, a test must be sensitive enough to
identify most diabetic individuals but be relatively inexpensive, safe, practical (quick
and easy to perform) and acceptable. The positive predictive value, the proportion of
positive screens that are correct, must also be reasonable so that more specific and
costlier follow-up diagnostic work-ups yield high returns, and the social and
psychological impact of misclassification are minimized (Modan et al., 1984;
Trilling, 1988).
Glucose concentrations vary by type of analysis (plasma vs whole blood) and by site
of sampling (venous vs capillary). In New Zealand, blood glucose samples are
typically analyzed as venous plasma glucose or as capillary whole blood when dry
chemistry test strips and reflectance meters are used. Measurement of blood glucose
is not exact (Burrin and Alberti, 1990), but this is of little importance in individual
case detection programmes.
Table 2-2 Derivation and meaning of sensitivity, specificity and positive predictive values
of a screening test
Screening
Diabetes (True Status)
Test
Present
Absent
Total
Positive
a
b
a+b
Negative
C
d
c+d
Total
a+c b+d +b +c +d
a = true positive; b = false positive; c = false negative; d = true negative
Sensitivity=
ES
a/(a+c)
% of persons who truly have diabetes in the screenedpopulation who
are identified diabetic by the test (% above selected cutoff with true
diabetes)
measure of the probability of correctly diagnosing a case, or 1probability of a false negative
46
Specificity =d/(b+d)
=% of truly non-diabetic persons who are so identified by the screening
test (% below selected cutoff with normal glucose tolerance)
=measure of the probability of correctly identifying a non-diabetic
person, or 1-probability of a false positive
Predictive Value of a positive test result = a/(a + b)
=% individuals with a positive test who actually have diabetes
(References: Last, 1988; Trilling, 1988)
Evaluation of Methods
The available diagnostic or screening tests are reviewed below and their effectiveness
summarized in Table 3-3
Table 2-3 Assessment of biochemical tests for diabetes
screening
TBlood Glucose Sensitivity Specificity
++
Random
++
Fasting
2h Post-load Glucose+ + + +
Glycated Haemoglobin+
+
Fructosamine
++
++++
(After Alberti, 1988)
Random Blood Glucose
There is controversy over the usefulness of random blood glucose measurements for
diagnostic purposes and over choice of diagnostic levels. NDDG does not provide for
random blood glucose testing as being diagnostic except where hyperglycaemia is
unequivocal (^!t 11. lmmol/l). However, both the WHO Study Group and the
American Diabetes Association (1991) make provision for casual blood glucose
testing. WHO identified unstandardized (casual, random) blood glucose values (Table
2-4) indicative of whether diabetes is likely, uncertain or unlikely. To a much greater
extent than any of the other methods, random blood glucose measurement minimizes
precision by ignoring the prandial state.
The European NIDDM Policy Group (Alberti and Gries, 1990) has argued that the
WHO cutoff of 5.5 mmol/l (venous plasma) as an initial screen for exclusion of
diabetes was set too low for clinical purposes and have recommended a level of 6.5
mmol/l as being more realistic. This is the level adopted in this review. In their
1990 position statement, ADA reported a non-fasting random plasma glucose reading
of ^t 8.9 mmol/l (cf. 11.1) was considered positive for diabetes. If the patient is
asymptomatic and/or the glucose level is only slightly elevated then one additional
elevated sample is needed to confirm the initial test. A high proportion of casual
blood tests fall into the uncertain zone neither confirming or excluding a diagnosis of
adult-onset diabetes. For those in the uncertain range, confirmation is required by the
more expensive and time consuming OGTT.
47
In the epidemiological setting, random blood glucose levels like fasting
measurements, underestimates diabetes prevalence compared to that derived from a
complete OGTT (Simon et al., 1985; Modan et al., 1984; Ferrell et al., 1984). For
example, in 337 Nauruans (high prevalence population) who were screened on the
basis of their random plasma glucose levels, age adjusted prevalence based on the cutoff of 11.1 mmol/l underestimated prevalence based on a complete 0G1T by 42% in
males and 63% in females, and at a level of 7.8mmol/1 by 16% and 38% respectively
(Finch et al., 1990). These authors conclude that use of random blood glucose to
determine diabetes prevalence seems inappropriate in epidemiological studies and that
performing OGTT on smaller representative population samples will provide more
accurate data at less cost.
In a study of adult-onset diabetes in Mexican Americans, Ferrell et al. (1984) found
the optimum resolution (sensitivity =specificity) for casual blood glucose
determination from capillary blood samples was 7.2 mmol/l. This was not as
sensitive or specific as a single criterion as either fasting blood glucose or
glycosylated haemoglobin. Random blood glucose measurements are only
unequivocal when values are ^?: 11.1 (Alberti, 1988). In terms of their overall
effectiveness they rank poorly (Table 2-3). Other than for the symptomatic patient or
where hyperglycaemia is markedly elevated, random blood sugars should be regarded
at best as only an indication of glycaemic control. Use of this measurement will mean
many patients will have to be recalled for retesting. Many researchers do not
recommend random blood glucose testing as a definitive screening procedure for
diabetes and regard it as unsatisfactory for epidemiological studies.
Fasting blood glucose
This is the classical predictive test for diabetes. A patient need not be symptomatic to
warrant a diagnosis of diabetes if fasting glucose on more than one occasion ^t
7.8mmol/l. This is diagnostic for diabetes (NDDG, 1979; WHO 1985; Table 3).
ADA (1990) defines fasting as no consumption of food or beverage other than water
for at least 3h before testing.
Taylor and Zimmet (1981) have however investigated the limitations of a single
fasting plasma glucose (FPG) 2^ 7.8 mmol/l as being diagnostic for diabetes (defined
by OGTI' as 2h plasma glucose ^!: 11.1 mmol/l) in a large epidemiological study of
three ethnic groups (Micronesian, Melanesian and Polynesian). They found FPG was
highly specific (98.1 %-99.7%) but sensitivity was not high and varied greatly
between the study populations (46.2%-79.0%). The predictive value was low when
diabetes prevalence was low, and improved in higher prevalence groups.
Haffner et al. (1984) found similar results. They examined changes in sensitivity,
specificity and predictive values with changes in FPG levels for detecting adult-onset
diabetes in a sample of 130 Mexican American (MA) and 50 Anglo-American (AA)
subjects aged 25-64 years from the San Antonio Heart Study (Table 3-4). The
sensitivity of the WHO and NDDG cutoff was low for both Anglo and Mexican
Americans, and was related to age-adjusted prevalence rates of diabetes (AA 4.9%
and MA 10.9%). FBG ranked poorly in comparison to the lh and 2h postglucose
load criteria of ^t 11. 1 mmol/l which had good sensitivity and specificity in both ethnic
groups. By lowering the FPG level to improve sensitivity to a level achieved with 2h
postload values, over 20% of the population would have had to been recalled for
testing by OGTT.
48
Table 2-4 Unstandardized random (casual) blood glucose levels
Diabetes Unlikely
Whole Blood - Venous:54.4
- Capillary 4.4
Plasma- Venous 5.5
- Capillary:s5.5
Diabetes Uncertain
4.4-10.0
4.4-11.1
5.5-11.1
5.5-12.2
Diabetes Likely
Z-_10.0
a11.1
2:11.1
2: 12.2
(Source WHO, 1985)
-
I
Finch et al. (1990) investigated whether a different FPG cut-off other than the -.t7.8
mmol/l advocated by NDDG and WHO would be more accurate. They examined
data collected on 13 well studied Pacific populations. Estimated prevalence equals
true prevalence when the number of false positive results equals the number of false
negative results. The FPG cut-offs where this occurred was below 7.8 mmol/l in all
of the populations with the average at 6.9mmol/l. A FPG cut-off rounded to
7.0mmol/l gave estimates of prevalence not significantly different from the true rate
of diabetes prevalence as defined by 2h plasma glucose in 12 of the 13 populations.
Sensitivity, specificity, and predictive value measurements indicated that the 7.0
mmol/l FPG test performed at least as well as one based on 7.8mmol/l. In an
epidemiological setting aimed at determining diabetes prevalence, the authors
recommend use of a FPG cut-off of 7.0mmol/l in preference to the NDDG and WHO
criterion if glucose loading is not possible, although no one cut-off will be optimal in
all populations (Papoz, 1990).
Comments
Fasting glucose is ADA's screening test of choice and is historically utilized as being
diagnostic for diabetes. True fasting conditions must apply if results are to be valid.
A repeated elevated fasting plasma glucose (e.g. ^t7.8mmolll) is specific for diabetes
i.e. true normals will most likely have screening values below the cut-off. Fasting
values do however lack sensitivity in detecting undiagnosed cases. Effectiveness of
fasting glucose concentrations in detecting glucose abnormality is lower when there is
milder impairment of glucose tolerance (Fajan, 1990). Levels < 7.8 may be more
effective as screening tests e.g 7.0 mmol/l, but for clinical and epidemiological
screening, a trade-off has to be reached between low specificities for adequate
sensitivity levels (Modan et al., 1984).
OGTT and postload glucose
OGTT is the most efficient way of making the diagnosis of adult onset diabetes in the
asymptomatic individual (Reaven, 1989). Both NDDG and WHO protocols
recommend that individuals with fasting blood glucose <7.8mmol/l undergo an
OGT1' with blood glucose being measured 2h (hours) after a 75gm oral glucose
challenge. WHO requires only the 2h value (plasma glucose) to be =-I 11. 1 mmol/l
but NDDG requires a midtest sample (typically 1 h) as well as the 2h concentration to
be ^t11.1 mmol/I. Harris (1985) comments that this makes little difference as 91%
of persons in a sample surveyed in the US population who had 2h ^t 11.1 mmol/1 also
had lh > 11.1 mmol/l. The demand for a midtest sample by NDDG also occurs in the
diagnosis of IGT. However, this radically changes the prevalence of IGT. Only
about 50% of those classified by WHO as IGT would be by NDDG (Modan et al.,
1984).
49
A 2h value is sufficient in epidemiological screening but further verification is
required for individual diagnosis of diabetes in the clinical setting using NDDG
criteria. Strong correlations have been found between fasting and 2h glucose values.
Over 95% of those with 2h > 11.1 have fasting levels ^t7.8 mmol/l (Modan 1984).
OGTT should be performed in the morning after at least 3 days of unrestricted diet
and usual physical activity but with the test being preceded by an overnight fast. A
75gm glucose load is the standard challenge. OGTI' is more expensive than other
diagnostic tests, is time consuming lasting at least 2 hours, requires higher degree of
patient co-operation, is cumbersome, involves multivenipuncture, and is impractical in
many field situations and epidemiological surveys (Papoz, 1990).
In spite of its established place as a diagnostic tool, the OGTT is influenced by many
factors (Sherwin, 1977; Trilling, 1988). It is characterized by significant withinindividual variation (Olefsky and Reaven, 1974) i.e. individual responses to a
standard glucose load are not consistent over several OG1Ts. There is evidence of
regression to mean with 50% of individuals will revert to normal classification on
repeat testing. Upwards of 80% will revert to normal or lower classification retesting
(Alberti, 1988). Quoting Burrin and Alberti (1990)
"Even when an OGTT is performed, the lack of repeatability of the test
is so great that very precise and accurate measurement lends to spurious
credibility to an imperfect diagnostic tool".
The OGTT is overused, often misused and interpreted inappropriately (Fajans 1990).
However, Reaven (1989) states when performed in a standardized manner and under
controlled conditions, the information obtained is relatively precise, and OCITT is a
useful procedure being the only way to reliably diagnose adult-onset diabetes in
absence of fasting hyperglycaemia. OGTTs are certainly not needed for screening
(except under research conditions or where resources permit it), and usually blood
glucose levels are such that the OGTT is required infrequently in clinical practice for
definitive diagnosis (Alberti, 1988). They are certainly not needed if fasting blood
glucoses meet diagnostic criteria or patients clearly have unequivocal hyperglycaemia
or symptoms.
Postprandial blood glucose values can be obtained without the demands of a full
OGTT. A mid-morning 1-2h post breakfast or post lunch glucose value can be
measured through venous sampling or using reflectance meters and capillary whole
blood. Postprandial values are recommended by the New Zealand Society for the
Study of Diabetes as these are more convenient in general practice and are more
sensitive than FPG or casual measurements (Dunn and Cutfield, 1988).
Comments
The OGTF remains the most sensitive diagnostic test for diabetes and especially for
early detection of asymptomatic diabetes, glucose intolerance and cases presenting
without fasting hyperglycaemia. In epidemiological and clinical studies, true diabetes
prevalence or glycaemic state is determined from the results of OGTT using either the
2h with or without lh glucose value. However, in the clinical setting, OG1'Ts are
required infrequently for detecting and diagnosing adult onset diabetes as careful
elucidation of symptoms would facilitate the diagnosis in many cases.
50
Glyca ted haemoglobin (GHb)
Glycated haemoglobin and fructosamine are relatively new measures, most commonly
used in the clinical setting for estimating glycaemic control in diagnosed diabetic
persons (Goldstein et al., 1982; Jovanovic and Peterson, 1981; Howey et al., 1989;
Smart et al., 1988). These methods have only recently been introduced as screening
methods and there is divergence on views as to their effectiveness. Glycated
haemoglobin (GHb) is an integrated measure of glycaemic control over 2-3 months;
fructosamine over 2-3 weeks (For reviews and commentary see Goldstein et al.,
1982; Duncan and Heiss, 1984; Ryall, 1990). The attractiveness of these methods is
that they potentially provide a single diagnostic test for diabetes with no preparation
prior to testing. Highly significant correlations have been found between HbAlc and
fructosamine with fasting and post-load glucose at all levels of glucose tolerance and
area under glucose tolerance curve (Hall et al., 1984; Forrest et al., 1987; Little et
al. 1988).
However, GHb methods tend to be costly and are inadequately standardized, many
normal ranges being improperly derived (Home, 1990). GHb applies to a number of
methods of measurement including glycated Hb, glycosylated Hb, HbA1 or HbAlc.
A number of studies have examined the relationship between GHb and OGTT.
Results are difficult to directly compare as they use different diagnostic criteria and
methods for measuring GHb, and some show high interassay coefficients of variation.
While mean values for those with IGT and diabetes are significantly higher than for
normals (Hall et al., 1984; Forrest et al., 1987; Little et al., 1988), considerable
overlap exists in the ranges of GHb particularly between normal and IGT; IGT and
diabetes; and to a lesser extent normal and diabetic.
For example, in the high risk Pima Indians, compared with OGTT, HbAlc was found
to be highly specific (91%) and moderately sensitive (85%) with an elevated HbAlc
usually indicating diabetes although it was insensitive for IGT (30%). However a
normal value did not exclude a diagnosis of either diabetes or IGT (Little et al.,
1988). Of the 159 subjects classified by OGTT as normal, 14 (9%) had HbAlc above
the normal range; while most with diabetes (n=131) had markedly elevated HbA 1 c,
15% showed normal HbAlc; and 30% of the 91 with IGT had high levels. Modan et
al. (1984) report similar results in the Israel Study. Of newly detected diabetic cases
12% had definite HbAlc values in the low range and 6% of those with normal
tolerance had values in the range considered indicative of unsatisfactory glycaemic
control in a diabetic clinic. HbA Ic was less effective than FPG in screening for both
IGT and diabetes by its lower specificity and predictive value of a positive test and
higher percentage of persons requiring retesting at comparable sensitivity levels.
A situation perhaps more comparable to New Zealand is the Islington (London)
general practice diabetic screening programme. The specificity and sensitivity of
GHb was compared with capillary blood glucose 2h after oral glucose load in 1040
subjects aged 40 over years. The GHb assay was a poorer screening test for diabetes
than the single 2h postload cut-off of ^!t 11 .Ommol/I. On the basis of the 2h WHO
criterion, 2.6% of individuals were classified as diabetic and 4.1% as IGT. A
stratified sample of 223 subjects were recalled for repeat OGTfs. The results show
that the GHb assay had a lower intra-individual coefficient of variation than the 2h
postload glucose but comparison of test characteristics indicated that it was less
accurate as a screening test for diabetes. At a cut-off of 8. 1 %, the initial screening
GHb correctly identified 90% of all probable diabetic cases with a specificity of 85%
and positive predictive value of 14%. However, the specificity of the screening GHb
as a screening test for true diabetes diagnosed by follow-up OGTT was 46% at 90%
51
sensitivity, compared to 93.3% specificity for the 2h blood glucose taken at the initial
screening.
Comments
Discrepancy with OGTT results is perhaps not surprising given that the two
techniques measure quite different aspects of glucose metabolism (Little et al., 1988).
Findings as described above, tend to preclude use of glycated haemoglobin as a
definitive diagnostic tool. GHb as a single diagnostic criterion is superior to
determination by random blood glucose in both sensitivity and specificity. GHb
detects well marked hyperglycaemia but performs poorly as a screening test for
diabetes in patients with normal or near-normal fasting plasma glucose (Orchard et
al., 1982; Simon et al., 1985; Veriulo et al., 1983). GHb tends to give rise to
substantial mis-classification when results are compared to OGTT. Values greater
than the reference range are almost certainly diagnostic of diabetes, but many cases
will be missed if these tests are used alone. Unless it can be demonstrated that GHb
is as good as a single-fasting or 2h postload plasma glucose in detecting diabetes, this
procedure cannot be recommended as a substitute for existing screening methods.
Fructosamine
The fructosamine assay, developed by Baker and colleagues in Auckland, has been
suggested as an alternative to GHb partly through its technical simplicity,
reproducibility of measurements and relatively low costs (Baker et al., 1985; Hindle
et al., 1985; Cockram ci al., 1990). Fructosamine results correlate well clinically
with those from glycated haemoglobin assays and fasting glucose concentrations in
diabetic and non-diabetic individuals (Baker ci al., 1983; Smart et al., 1988; Pandya
etal., 1987; Cockram etal., 1990).
Baker et al. (1983) first suggested that fructosamine may be a useful screening test for
diabetes. They found the diagnostic sensitivity of their fructosamine assay, based on a
normal range derived from 83 non-diabetic controls, to be 88% (15 of 17 individuals
diagnosed diabetic from OG1T were correctly identified). The rate of false positive
diagnoses was 9%. However, values appeared to inadequately discriminate between
normal, IGT and diabetic classes as defined by WHO criteria.
The results may also have been subject to selection bias as data was derived from 74
cases in whom diabetes was suspected and had been referred for OGTT.
Fructosamine was evaluated as a screening test in the Kawerau study (Scragg et al.,
1990). 206 persons (age> 20 years) of nearly 4000 screened, had a fructosamine test
greater than the upper limit of the assay reference interval. A sample of 302 persons
were randomly selected from individuals with normal fructosamine levels.
Undiagnosed diabetes was subsequently confirmed in 29 cases by OGTT using NDDG
criteria. However, only 24 of the 29 had been detected from the group with elevated
fructosamine and 5 were from the normal fructosamine group.
The diagnostic sensitivity and specificity for diabetes of serum fructosamine levels and
fasting blood glucose concentrations were more rigorously compared in 613 adult
Muslim Asians during a diabetes community screening programme in Dar es Salaam
(Swai et al., 1988). There were small but statistically significant differences in mean
fructosamine levels between normal, IGT, new and known diabetic subjects, but there
was major overlap in range of values between these groups such that it was not
possible to define a lower cut-off for screening purposes. Specificity (for values
above the mean +2SD normal) was 99% for abnormal glucose tolerance with
52
sensitivity of only 22% for newly detected diabetes. It was concluded that serum
fructosamine was a poor screening and diagnostic test for diabetes and for IGT.
In another recent cross-sectional study, (Iuillausseau et al. (1990) evaluated HbA1 and
fructosamine as screening tools for the detection of glucose abnormalities in a biased
sample of 144 asymptomatic French subjects referred for screening of metabolic
abnormalities. They similarly detected important overlap in HbAlc and fructosamine
values for normal, IGT and asymptomatic diabetes but to a lesser extent for those with
- overt diabetes. Specificity and sensitivity of the tests depended on which glucose
tolerance categories that were being compared. When the aim was to separate
asymptomatic diabetes from lOT and normal, specificity was high for both for HbA ic
and fructosamine (100 and 97% respectively) but sensitivity was unacceptably low (15
and 19%).
Comments
Haden and Kennedy (1984) remarked in the mid-1980s that use of fructosamine as a
screening test was still premature. There is little new evidence to suggest otherwise.
Considerable overlap in range of values between normal, IGT and diabetes indicates
that fructosamine is inadequate for screening purposes. As for GHb, fructosamine,
has low sensitivity although specificity is relatively high (Fajan, 1990). Fructosamine
may perform better in populations where individuals are characterized by marked
glycaemic elevations rather than mild glucose intolerance, situations where casual
glycaemic determination may suffice.
Other measures
Measures such as glycosuria, ketosis, islet cell antibodies, HLA antigens, insulin
secretion defined by C-peptide assays, intravenous glucose tolerance tests or mixed
meal tests are inappropriate or unhelpful in screening for adult-onset diabetes at
present.
Comment on use of reflectance meters
Use of dry chemistry viz, reflectance meters and test strips is now widespread
especially in home monitoring of glycaemic control in diagnosed cases. However,
their effectiveness for screening and as a diagnostic tool is not well established.
Examination of results from sources outside the laboratory show poor performance of
reflectance meters when compared to reference laboratory measurements. Assessment
of results indicates that variability in blood glucose readings is primarily due to
operator error i.e. poor technique by those performing the test (Begley and Forrest,
1988).
The consensus is that reflectance meters should only be used for screening purposes
under strictly controlled conditions which includes active quality assurance. These
conditions do not prevail in most instances. While reflectance meters will detect
unequivocal elevations in glycaemia, they have not been recommended because of the
high variability in glucose measurements and possibility of inaccurate interpretation of
slightly elevated readings. They are useful but laboratory based analysis must be used
to confirm any elevated blood glucose detected from reflectance meters.
53
3. Secondary intervention: treatment approaches following
diagnosis of diabetes
3.1 General therapeutic considerations
The majority of adult-onset diabetic patients receive care from their general
practitioners. The general practitioner takes central responsibility for the individual
patient, co-ordinating involvement of other professional groups within the framework
of a defined management plan (Dunn and Cutfield, 1988). The New Zealand Society
for the Study of Diabetes recommends ongoing medical review at 3 monthly intervals
with a comprehensive physical examination annually. Ideally, all adult onset diabetic
individuals should be seen on at least one occasion by a diabetic specialist and
preferably 2-3 years thereafter (Dunn and Cutfield, 1988).
Standards of diabetes care in New Zealand in both primary and secondary sectors are
highly variable and that the treatment of diabetes is often inadequate, these
-, management guidelines being seldom practised.
Resource requirements and planning guidelines for diabetes services for Area Health
Boards have been reviewed elsewhere (Beaven and Neal, 1988).
The primary objectives of early intervention and treatment are:•relief of symptoms;
•treatment of accompanying disorders;
•prevention, arrest or delayed development of acute and long-term
complications;
•improvement of quality of life, social adaptation and well-being; and
•reduction in mortality (WHO, 1985; Alberti and Gries, 1988).
Intervention for newly diagnosed individuals involves:
•full clinical evaluation including symptoms, clinical examination and
biochemical review;
establishing a self-management plan including setting achievable goals, food
plan, education in diabetes management, and instruction of self-monitoring;
and
•medical management (Dunn and Cutfield, 1988).
The aim of treatment is to facilitate achievement of clinical and biochemical goals, as
given in Table 3-1. The basic contention is that diabetes complications are more
likely to occur if biochemical and clinical parameters exceed these target values over
extended periods of time. The monitoring of metabolic control in diabetes should not
be confined to blood glucose levels. As indicated throughout the Review, these are
not the sole metabolic manifestation of this disorder, and as great an emphasis needs
to be placed on cardiovascular risk association of raised total cholesterol and
triglycerides, depressed HDL-cholesterol, high blood pressure and smoking.
55
FIGURE 1
Therapy of NIDDM
Established
NIDDM
Define Individual
Aims of Therapy
ILN0n-Obese
[Obese
rH Diet
Hypocaloric
Exercise
4
Increase
4— Ph^ ical Diet
IAc
wheree
I Seve
Sym ;re
ood I Poor Control I
J
IPo0r
ontinuel i-;--i'Add
I
IControl
Good
Control
4,
Continue
Hypocaloric
Sutfonylurea;
Fat
I Lower Lipids
Chronic{ Elevated
j
Complications
Poor Control
ood
ntroJ f
__
I'
I
I
Add
Biguanide
and/or
Sulfonylurea;
oodLower Lipids
CntroIif Elevated
Poor Control
j
_rJ1
I
Check Need
for
Medication
Periodically
Give
Deck Neednot too[
Wedication
Friodically
Control
4,.
Poor ControlInsulin
i:rsoon
jGoOd
not too
late
I Check Need for
I Insulin
Periodically
I-
(Source: kiberti and Gries, 1988).
56
The target levels identified in Table 3-1 are ideal and may be difficult or unnecessary
to achieve in certain patients. Particular care must be taken to avoid overtreatment
and setting unrealistic treatment goals in the elderly in whom life expectancy may not
be modified by the disorder (Dunn and Cutfield, 1988; Gries and Alberti, 1989).
Table 3.1 Metabolic targets
Parameter
Target
Glycaemia- fasting/preprandial mmol/l
mmol/l
- postprandial
- glycated haemoglobin(HbAlc)<9%
pmol/l
- fructosamine
4.0-7.0
<10
<300
Lipids- total cholesterol
- HDL
- Triglycerides
mmol/l
mmol/l
mmol/l
<5.2
>1.1
<1 .7
BMI- Male
- Female
kg/m2
<25
<24
Blood Pressure
mmHg
kg/m2
140/90
cessation
Smoking
The therapeutic means to achieving these goals are outlined in Figure 1 and are
discussed below. This is the management approach to adult-onset diabetes as reported
by the European NIDDM Policy Group (Alberti and Gries, 1988) and which
essentially reflects that adopted by specialist diabetes care providers in New Zealand.
3.2 Dietary Intervention
Dietary modification is useful in reducing fasting hyperglycaemia, in moderating
glucose response to food, and in improving insulin action through reduction in
bodyweight. Comprehensive reviews of the nutritional and dietary management for
diabetes mellitus are provided by National Institutes of Health (1987), Lewis-Barned
and Mann (1988) and Vinik and Wing (1990), and with specific reference to New
Zealand by the New Zealand Dietetic Association (1989) and Bremer (1989).
Essentially, the aims of dietary intervention for the patient with adult-onset diabetes
are:
•reduce or maintain bodyweight;
•minimize metabolic abnormalities;
•prevent diabetes complications; and
•ensure an adequate nutritional status (New Zealand Dietetic Association,
1989).
Dietary therapy alone may be sufficient in up to half of all adult-onset diabetic
patients to control glycaemic and lipid abnormalities, if appropriately adhered to.
- Given the health profile of individuals with adult-onset diabetes, dietary intervention
57
must target multiple risk factors. It is important however that nutritional and dietary
management is not separated from other aspects of lifestyle, and intervention is
directed at improving well-being of the whole person (Nutrition Taskforce, 1991).
There two popular dietary misconceptions concerning the relationship of sugar (i.e.
sucrose) and diabetes. First, there is a commonly held view that excess consumption
of sugar leads to the development of diabetes. While sucrose leads to abrupt rises in
blood glucose levels, there is no epidemiological or experimental evidence to
substantiate the perception that high intake of sucrose is diabetogenic (Mann, 1987;
Vinik and Wing, 1990). Second, total restriction of sucrose in the diet is no longer
considered necessary in dietary management of diabetes. For many non-obese
patients a modest amount of sucrose may enhance palatability which will aid longterm compliance to high fibre-low fat diets without inducing glycaemic responses
worse than those produced by other foods (Mann, 1987). However, such
liberalization should not be abused as deleterious effects on both carbohydrate and
lipid metabolism will occur at levels of sucrose consumption comparable to those
consumed by the general population (Hollenbeck et al., 1986).
Effectiveness of dietary intervention will be influenced by at least six factors:
•the patient understands the need for weight loss;
•dietary guidance is individualized and flexible;
•clinical progress of the patient is monitored;
•dietary education and reinforcement is ongoing;
•goals are realistic; and
•there are sufficient resources and behavioural support (Bremer, 1989;
Reaven, 1989).
There are two main aspects to dietary intervention for individuals with adult-onset
diabetes: 1) total energy intake; and 2) dietary composition especially reduction in
dietary fat (Larkins, 1987).
Weight reduction: restriction of total energy
Weight loss is the most important and fundamental physiological approach to the
treatment of adult-onset diabetes in overweight subjects. Clinical and experimental
studies show marked improvements in glucose tolerance with weight reduction in both
obese non-diabetic control and diabetic subjects (Savage et al.; 1979; Nagulesparan et
al., 1981; DeFronzo et al., 1983). Restriction of total energy has both acute and
long-term effects on glucose metabolism. Reduction in body fat is associated with a
significant decrease in fasting plasma glucose concentrations (which often return to
normal levels) and increase in postprandial glucose tolerance. Reduced bodyweight
enhances tissue sensitivity to insulin, reduces hepatic glucose production and improves
insulin secretory function of the pancreatic 8-cells (DeFronzo, 1983; Henry et al.,
1985; Henry etal., 1986; Alberti and Gries, 1988). However, glucose tolerance does
not always return completely to normal with reduction in weight and insulin secretion
remains defective (Savage eral., 1979; Bitzen eral., 1988; Vinik and Wing, 1990).
Caloric restriction affects glucose and insulin levels independent of weight loss per se
(Vinik and Wing, 1990). Improvements in glycaemic control are evident very quickly
58
after restriction of caloric iñtáke, with maximal responses being reported within
several days or weeks after initiation of the diet (Stanik and Marcus, 1980; Bitzen et
al., 1988; Vinik and Wing, 1990). This most probably occurs through a reduction in
hepatic glucose output consequent of restricted energy intake.
It is difficult to predict the degree of improvement in glucose tolerance through
weight loss for any one individual. Metabolic benefit is dependent on the severity of
the defects in insulin action and secretion, the initial starting weight and the actual
amount of weight loss (Reaven, 1989).
Weight reduction in obese diabetic individuals also reduces risk factors for
cardiovascular disease. Their overall risk profile is improved through reduction in
blood pressure, LDL-cholesterol and triglycerides, increase in HDL-cholesterol, and
improvements in blood clotting factors (New Zealand Dietetic Association, 1989;
Vinik and Wing, 1990).
Very few studies (e.g. Hadden et al., 1986; Bitzen etal., 1988) have examined longterm efficacy of weight reduction (or dietary intervention) programmes for adult-onset
diabetic individuals. Clinical experience and available research indicates that weight
loss is not sustained in many patients beyond six to 12 months post dietary
intervention. This leads to a deterioration in glycaemic and lipid parameters from
levels previously achieved, although results may remain below pre-intervention levels
(Hadden et al., 1986; Bremer et al., NZSSD Scientific Meeting, 1990).
Many patients will be asymptomatic and recommended dietary changes will impose
greatly on their lifestyle. However, while most individuals will not attain ideal
bodyweight, research shows that even relatively modest weight losses in obese
patients will confer clinical gains in improving glycaemic control and risk for
coronary artery disease (Stanik and Marcus, 1980; Bremer, 1989; Reaven, 1989;
- I Vinik and Wing, 1990). Weight loss can facilitate reduction or even withdrawal of
oral hypoglycaemic medication (Henry et al., 1986). There is evidence that early
- intervention is more successful in reducing fasting plasma glucose levels and in
-- improving insulin responses than delayed treatment in those with well established
diabetes (Nagulesparan et al., 1981).
Dietary composition: the "high carbohydrate, high fibre, low fat diet"
Diets high in complex carbohydrate, high in fibre but low in fat are now standard to
the treatment of all diabetic individuals. New Zealand guidelines for the nutritional
management of diabetes mellitus are provided in Table 3-2. There is no longer such a
thing as a "diabetic diet". Rather, dietary recommendations are not significantly
different from the prudent diet recommended for health to all New Zealanders by the
Nutrition Taskforce (1991) or the New Zealand Heart Foundation.
59
Table 3.2 Recommendations for the nutritional management of diabetes (NZ Dietetic
Association, 1989)
Energy requirements (kJ/Calories) should be adequate to achieve and maintain a
reasonable body weight, thus sparing insulin requirements and improving
general health.
2.
Foods high in unrefined carbohydrate and soluble fibre, low in saturated fat and
salt achieve the best results for glycaemic and lipid control.
3.
The carbohydrate intake should comprise at least half the total energy intake,
but must be increased gradually because fibre in unrefined carbohydrate lowers
insulin requirements and affects gastrointestinal motility.
4.
Protein should comprise approximately 12-20% of total energy, chosen from
sources lower in saturated fat.
5.
Total fat should not exceed 30% of total energy. A reduction in saturated fat
lessens the risk of macrovascular disease. Fats from saturated,
monounsaturated and polyunsaturated sources should be taken in approximately
equal proportions to influence lipid profiles.
6.
Salt intake should be restricted.
7.
The use of alternative sweeteners is acceptable in most situations.
8.
The use of alcohol as recommended for the general population is accepted, but
the dangers of hypoglycaemia and the long term effects of constant alcohol
ingestion on hypertension and diabetic complications need stressing.
9.
Choosing items from a wide variety of foods ensures optimal nutrition.
10.
Changing eating habits is not easy and is better tackled in stages, incorporating
behaviour modification techniques.
While there is international consensus on the dietary management of diabetes (e.g.
similar recommendations have been promoted by the American Diabetes Association,
British Diabetes Association, the European NIDDM Policy Group) controversy still
exists within the research community as to desirable target levels, to the modes of
action of the dietary constituents in reducing hyperglycaemia and correcting lipid
abnormalities, and to the long-term efficacy of such dietary recommendations.
Carbohydrate
Carbohydrate influences post-prandial glycaemic excursions more than any other
macronutrient (Bremer, 1989). It is important to recognise that foods containing the
same amount of carbohydrate can have vastly different effects on post-prandial
glycaemia. The Glycaemic Index was developed to measure the plasma glycaemic
response to individual foods relative to isocaloric quantities of a reference food viz.
glucose, or bread (Jenkins et al., 1981; Jenkins et al., 1983; Cooper et al.,
1987;
Riccardi and Rivellese, 1987). In general, starchy foods (e.g. legumes and grains)
have lower glycaemic indices, producing blunted blood glucose responses and are
on
associated with decreased plasma LDL-cholesterol and triglyceride values (Jenkins et
al., 1988).
However, while the glycaemic index is an interesting physiological measurement, its
clinical utility remains unclear (Coulston et al., 1984; Cooper et al., 1937; Riccardi
and Rivellese, 1987; Vinik and Wing, 1990). There is a lack of reproducibility of
responses between individuals to the same food item, although some researchers have
shown good predictive properties (Jenkins et al., 1983; Nuttall et al., 1983; Parillo
et al., 1985; Simpson et al., 1985; Hollenbeck et al., 1986; Bornet et al., 1987;
Hollenbeck et al., 1988). Research is emerging on the long-term benefits of
incorporating low glycaemic index foods into meal plans for people with adult-onset
diabetes.
In summary, diets high in carbohydrate will benefit patients, particularly those with
fasting hyperglycaemia, and will lead to improvements in glucose tolerance and
dyslipidaemia, if sufficient attention is given to the ratio of complex to simple
carbohydrate and to the fibre content, especially if this leads to reduced total energy
intake (Reaven, 1989; New Zealand Dietetic Association, 1989; Bremer, 1991).
However, individuals with poorly controlled diabetes do not tolerate any carbohydrate
well (Rasmussen and Hermansen, 1991; Neilsen and Neilsen, 1989).
Fibre
Considerable interest has been shown in therapeutic uses of fibre, although there is
uncertainty in 'dose' and outcomes (Vinik et al., 1988; Tattersall and Mansell, 1990).
The role of dietary fibre in the management of diabetes has been reviewed recently by
Bremer (1991). Increased fibre, especially soluble fibre, is recommended to diabetic
patients not only for the glycaemic and lipid lowering effects but also for effects on
aiding weight reduction through satiety, gastrointestinal functioning, and providing
essential nutrients.
Research has demonstrated that diets enriched in fibre lower plasma glucose
concentrations, improve glucose tolerance while reducing insulin secretion and plasma
insulin responses in both control and diabetic subjects (DeFronzo et al., 1983: Vinik
and Wing, 1990). Dietary fibre may explain up to 50% of variation in postprandial
glycaemic responses to food (Wolever, 1990). Diets high in fibre also significantly
reduce levels of total cholesterol, LDL-cholesterol and triglycerides; contribute to
improvements in hypertension; and help in weight loss.
The efficacy of high fibre diets will depend on the level of fibre intake, the percentage
of soluble versus insoluble fibre, addition of sucrose and fat intake in the diet
(Bremer, 1991). It would appear that short term improvements in fasting glucose
measurements and lipid parameters from use of high carbohydrate, high fibre and low
fat diets may not be sustained over time, although levels tend to remain below those
recorded pre-intervention (Barnard et al., 1983; Bremer, 1990).
Dietary fat
Reduction in total fat consumption, especially saturated fat intakes is now widely
advocated. The major reasons for this is to reduce total energy intake and improve
lipid profiles. Reduction in dietary fat cannot be stressed enough: the excess body fat
so characteristic of most adult-onset diabetic individuals comes from dietary fat; most
diabetic patients die of heart disease; and low fat diets improve insulin secretion,
glucose disposal and glucose tolerance independent of weight changes (Chen et al.,
1988; Swinburn et al., 1991). Restricting simple sugar is achieved relatively easily,
61
but reduction in dietary fat is much harder. Lower intakes of saturated fat can be
achieved either through a total reduction in fat consumption, or modification of
dietary fats through replacement of saturated fat with monounsaturated or
polyunsaturated fats. Organizations both internationally (e.g. the American Diabetes
Association, European Association for the Study of Diabetes) and in New Zealand
(e.g. the Dietetic Association and the Heart Foundation) typically advocate overall
reduction in total dietary fat, with modification of fat ratios as a consequence of this
reduction.
In contrast to saturated fat, monounsaturated and polyunsaturated fatty acids have
been shown to have beneficial effects on plasma lipoproteins (both cholesterol and
triglycerides) and in reducing hyperinsulinaemia which is common in many NTDDM
patients (Bamed and Mann, 1988; Bremer, 1989). The primary abnormality in
NTDDM patients is elevated triglycerides and depressed HDL-cholesterol levels which
are prime risk factors for atherosclerosis.
Dietary recommendations aime I at improving lipid metabolism and reduction of
coronary artery disease must be more stringent for individuals with diabetes than for
the general population.
3.3 Exercise
It is generally accepted that regular exercise is an important component of the total
therapeutic approach to adult-onset diabetes. However, in recent years the role and
value of exercise in diabetes management have come under question (Vranic et al.,
1990; ADA Technical Review, 1990). Many different practices and opinions exist,
and as Reaven (1989, p54) states "very little experimental data is available which
permits the clinician to come to a rational decision as to the clinical utility of exercise
in any given patient with adult-onset diabetes".
Exercise studies have typically been undertaken using IDDM patients and much less
information is available for adult-onset diabetes. The relevance of results derived for
IDDM subjects for adult-onset diabetes was unknown. It is only now that the
mechanisms and potential benefits of exercise are being clarified for the patients
developing diabetes in older life. Still unanswered, however, are the long-term
effects of exercise on glucose metabolism, blood pressure, and coronary risk factors.
Glycaemic control
Reaven (1989) states that although it is not widely appreciated, differences in level of
physical activity (as measured by maximal aerobic capacity) are as powerful as
variations in the degree of obesity in the modulation of insulin activity. Exercise
exerts both short and long-term effects of exercise on glucose metabolism (Vranic et
al., 1990). A single bout of exercise will frequently decrease plasma glucose levels in
adult-onset diabetic patients, and improvements in glucose tolerance may persist over
succeeding hours or days (Schneider et al., 1986; Devlin et al., 1987). However, it
remains unclear whether the benefits of exercise for these patients, relate more to the
cumulative effects of the individual bouts of exercise on metabolism than to the longterm effects of physical fitness per se (Reaven, 1989; Koivisto etal., 1986; Schneider
etal., 1986).
Changes induced by physical training involve long-term adaptations which can affect
metabolic processes during rest and exercise (Vranic et al., 1990). A programme of
long-term physical training can significantly augment tissue sensitivity to insulin i.e.
62
•.'
stimulate glucose uptake, thus improving glucose tolerance, and at the same time,
lower plasma insulin response. to glucose (De Fronzo et al., 1983; Schneider et al.,
1984; Trovati et al., 1984; Krotkiewski ci al., 1985; Koivisto et al., 1986; Horton,
1988). This later effect is important given that hyperinsulinaemia has been identified
as an atherogenic risk factor (Reaven, 1988; Stout, 1985; Stout, 1987; Jarrett, 1988).
The degree to which regular physical activity improves glucose tolerance in adultonset diabetes is not clearly defined. Most studies (e.g. Schneider et al., 1984;
Trovati et al., 1984; Reitman et al., 1984) indicate that the patients most likely to
respond favourably to exercise are those with IGT or diabetes characterized by mild to
moderate glucose intolerance, and those with hyperinsulinaemia (ADA Position
Statement and Technical Review, 1990). This is consistent with results showing that
exercise acts to reverse insulin resistance. While all individuals should be encouraged
to remain physically active, it would seem that if any metabolic benefits are to be
gained then patients will need to embark on a relatively intense and regular program
of exercise training (Reaven, 1989).
Exercise has the potential of being an extremely physiological approach to the
treatment of adult-onset diabetes (Reaven, 1989), although it may be unrealistic for
older patients to maintain levels of exercise necessary to see desired improvements.
Metabolic effects of exercise will only be sustained if the exercise programme is
sustained.
Other benefits
Exercise has overall health benefits (Table 3-3), e.g. reducing total plasma
cholesterol and triglycerides while increasing HDL-cholesterol, reduces bodyweight
and hypertension, and improves cardiovascular functioning (DeFronzo et al., 1983;
Harris et al., 1989). Epidemiological data, animal studies and studies on the effects
of exercise on atheroscletoric risk factors, all indicate that physical training may
retard the development of vascular disease in the general population (Vranic et al.,
1990). Exercise has been shown to have favourable effects on lipid metabolism in
non-diabetic individuals. Compared to control groups, plasma triglyceride and total
cholesterol levels fell and HDL-cholesterol increased significantly in response to
exercise (Schwartz RS, 1987; Wood et al., 1988). As stated previously patients with
adult-onset diabetes are often characterized by elevated triglycerides and depressed
HDL, and thus increased physical activity may be very beneficial in aiding correction
of these co-existing lipid abnormalities, although these studies have not as yet been
undertaken in diabetic subjects.
63
Table 3-3 Beneficial effects of physical training
CardiovascularImproved myocardial circulation
Improved myocardial metabolism
Enhanced myocardial contractility and cardiac output
Decreased heart rate
Decreased blood pressure
Decreased catecholamine response
Pulmonary Increased vital capacity
MusculoskeletalIncreased muscle size and strength
Increased mitochondrial number and size
Increased adenosine triphosphate content
Increased aerobic enzymes
HaematologicIncreased haemoglobin
Lipid Decreased plasma triglyceride levels
Decreased plasma cholesterol levels
Increased high density lipoproteins
CarbohydrateImproved insulin sensitivity
Improved glucose tolerance
Weight Loss
PsychosocialImproved self image
Improved sense of well-being
(Source: DeFronzo, Ferrannini and Koivisto, 1983).
Exercise also has important psychological benefits for individuals, improving, selfesteem, well-being and quality of life. Individuals with diabetes should be
encouraged to remain at least as physically active as their non-diabetic counterparts.
Weight reduction
Diet plus increased physical activity is more effective than diet alone in helping
overweight patients to lose weight and in conferring metabolic benefits (Schneider et
al., 1984; Marcus et al., 1987). However, in some situations, only a moderate
number of calories will be expended through exercise and which may be compensated
by equivalent increase in caloric consumption. For the overweight NTDDM patient,
reduction in total energy is the first line of therapy with exercise being complementary
not a substitute. Whether changes in body composition with exercise e.g. degree in
adiposity and increased muscle mass independently improve glucose tolerance and
insulin sensitivity is unclear (ADA, 1990).
3.4 Pharmacological intervention
Pharmacological intervention is the second approach to the treatment of adult-onset
diabetes after initial lifestyle intervention with diet and exercise. There are two
64
important features surrounding this approach: 1) Drug treatment is not typically
limited to control of hyperglycaemia. More often than not, individuals with adultonset diabetes are on multiple drug therapies which are prescribed for the treatment of
the co-existing morbidities prevalent in these individuals. It is not uncommon for
individuals to simultaneously be using oral hypoglycaemic agents, lipid lowering
agents, anti-hypertensives and a range of drugs for treating heart disease, including
aspirin. Only pharmacological intervention used in the control of glucose metabolism
is reviewed below; and 2) Pharmacological intervention is an adjunct to and is not a
substitute for changing dietary behaviour and levels of physical activity. Oral
hypoglycaemic agents and/or insulin should only be used when dietary therapy (and
exercise) alone is insufficient to achieve adequate metabolic control. Addition of
medication to treatment does not indicate cause for relaxation of dietary principles.
A number of drugs have been discovered which alter metabolic processes with
resultant improvements in glucose concentrations, although some appear to be toxic
and others are controversial as to whether they ire sufficiently effective and safe
enough to warrant widespread use (Lebovitz, 1990).
Suiphony/ureas
Suiphonylureas are the treatment of choice for additional therapy for glycaemic
control in adult-onset diabetic patients who are not grossly obese. These were the
only oral hypoglycaemic agent approved for clinical use in the United States up to
1990. Studies have repeatedly been shown second generation suiphonylureas (e.g.
glibenclamide, glipizide) to be clinically effective in reducing elevated fasting plasma
glucose levels and in improving glucose tolerance. Comprehensive reviews of the
pharmacology and efficacy of the suiphonylurea class of drugs are provided by
Lebovitz (1987; 1990).
While the mechanisms of action of sulphonylureas in improving glucose tolerance are
not totally clear, there is good rationale for their use in diabetic patients. They lower
blood glucose levels through two apparent effects: 1) acute actions on pancreatic 8cells in directly promoting insulin release and potentiating the stimulatory effect of
glucose on insulin secretion, both of which raise circulating plasma insulin
concentrations; and 2) chronic or long-term effects of improving insulin action i.e.
increasing insulin sensitivity and insulin-stimulated glucose uptake by peripheral tissue
(DeFronzo et al. 1983; Lockwood et al., 1984; Reaven, 1989; Lebovitz, 1990). In
adult-onset diabetes, fasting hyperglycaemia is largely due to hepatic glucose
production in the presence of low plasma insulin levels. Postprandial hyperglycaemia
in contrast results from deficient glucose uptake by peripheral tissue in the presence of
high plasma insulin levels (Lebovitz, 1987; Turner and Holman, 1990). Thus,
suiphonylureas act to correct both these componentsof hyperglycaemia.
Patient selection is important in determining the likelihood of success of this approach
to diabetes treatment. Individuals who are normal weight or mildly obese, and who
are not extremely insulin resistant appear to respond best to treatment with
suiphonylureas. In the order of 75-85 % of patients with adult-onset diabetes will
show good response for several years to this treatment (Lebovitz, 1990). Drug
intervention with sulphonylureas appears to be less successful in patients who are very
obese or below ideal bodyweight, have long durations of diabetes and have moderate
insulin requirements. Thus, sulphonylureas are not always effective in every patient.
Secondary failure (which represents initial successful response to drug therapy for at
least six months followed by subsequent failure of response) occurs at a rate of about
10% per year (Alberti and Gries, 1988). There are few side effects with the most
65
common being risk of hypoglycaemia which may in part be due to inappropriate
prescribing (Lebovitz, 1987; KralI, 1988; Alberti and Gries, 1988) or dietary factors.
Quoting Lebovitz (1990, p565),
'In spite of the lack of clear data on the long-term efficacy and safety
of oral hypoglycaemic sulphonylureas and the paucity of any long-term
data on the second generation sulphonylureas, there have been no well
designed, randomized, placebo controlled long-term studies of
sulphonylurea effectiveness carried out in the last 20 years ".
However, a large multi-centre prospective randomised study of treatment of newly
diagnosed NIDDM patients is being undertaken in the UK in (UK Prospective
Diabetes Study, 1983 and 1984). At present, the effectiveness of oral hypoglycaemic
agents in the treatment of individuals with adult-onset diabetes for periods greater than
five years is unclear.
Biguanides
In New Zealand, there is a second class of drugs viz, the biguanides (e.g.
Metformin). Biguanide derivatives are important as a first-line drug treatment of the
middle-aged obese insulin resistant and/or hyperlipidaemic diabetic patient. Specific
properties of the biguanides include hyperglycaemic and lipid lowering effects with
reduction of raised serum insulin levels (Vignen et al., 1984; Alberti and Gries,
1988). Biguanides were withdrawn from use in the US because Phenformin had
unacceptable levels of risk for lactic acidosis with subsequent potential for fatality.
This drug is not available in New Zealand. Metformin has however been used widely
around the world with safety.
Combination therapies
Biguanides are often combined with suiphonylureas if glycaemic control is poor,
following failure with weight loss and lifestyle changes.
Insulin may also be used alongside both classes of oral hypoglycaemic agents. There
are a number of reasons why this combination of therapies may be advantageous: 1)
administration of insulin at night to give constant basal supply of insulin will lower
fasting hyperglycaemia and subsequently improve insulin release from 6-cells in
response to meals; 2) sulphonylurea agents increase the number of insulin receptors in
some tissues, suggesting an increased drug action if combined with insulin; and 3)
hyperglycaemia is known to delay the absorption of some oral hyperglycaemic agents,
thus lowering glucose concentration with insulin may improve the availability and
speed of absorption of these drugs.
Insulin should only be initiated if blood glucose concentrations remain above target
levels despite strict adherence to treatment with diet, exercise and sulphonylureas.
While there are some mixed results, most studies demonstrate the addition of
supplemental insulin produces significant improvements in fasting blood glucose
concentrations and in lipid parameters, although some studies have reported weight
gains (Bachmann et al., 1981; Scarlett et al., 1982; Bruce et al., 1987; Holman et
al., 1987; Stenman et al., 1988; Scott et al., 1988; Riddle et aL, 1989). Certainly
not all patients will benefit from this treatment, however, many will. One potential
adverse effect of this treatment is use of exogenous insulin may exacerbate
hyperinsulinaemia which is implicated as a risk factor for coronary artery disease.
However, this putative effect is unlikely to offset gains made from reduction in
hyperglycaemia (Turner and Holman, 1990).
As stated earlier in the Review, approximately 15% of individuals developing diabetes
in adult-lift, will be characterized by insulin deficiency and who will be dependent on
the administration of insulin for control of hyperglycaemia. The approach to the
treatment of these individuals will be the same as for IDDM in childhood and
adolescence, although age may influence choice of insulin and method of delivery.
3.5 Diabetes education
Discussion on intervention would not be complete without at least a brief mention of
diabetes patient education. There is an abundance of literature on this topic, a large
part of which concerns philosophy and details of delivery of diabetes education and a
much lesser part formal scientific evaluation.
Diabetes education programmes were introduced into service delivery in the belief
that they represent the most important single approach to modern management of
diabetes (Beaven et al., 1988). It is widely accepted the effectiveness of the forms of
intervention described above is greatly enhanced by patient education and that active
participation by the patient is an essential requirement for treatment success.
Regarded as enormously powerful, diabetes education has been promoted as a means
of:•improving the safety of treatment;
•enhancing the quality of metabolic control;
•increasing social and psychological well-being;
•aiding the prevention of complications; and
•reducing costs (Alberti and Gnes, 1988).
Where health care intervention requires individuals to learn new knowledge, develop
new skills and change behaviour, patient education can be a powerful and costeffective strategy if implemented and used appropriately. However, some caution is
needed in endorsing claims made of diabetes educational services as currently
provided.
Expectations of what diabetes education can achieve have been unrealistic. Current
research that is both sound and appropriate in study design and methods, has
demonstrated that diabetes education programmes as developed have often not been
convincing in showing longer term (e.g beyond 1 year) or sustained benefits with
respect to health outcomes or patterns of resource utilization (Kaplan and Davies,
1986; Dunn and Turtle, 1987; Brown, 1988). The evaluation and reporting of
findings on diabetes education have suffered from several major research problems: 1)
the absence of experimental controls and objective outcomes; 2) inadequate costbenefit analyses; 3) the lack of a research model which integrates education within
total patient care and service organization, and which isolates the independent effects
of education from other influential factors; and 4) absence of long-term prospective
and controlled studies (Dunn and Turtle, 1987; Beaven etal., 1988).
67
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Department of Health
TE TARI ORA
HEALTH RESEARCH SERVICES - 1992