Download Characteristics of Non-Insulin- Dependent Diabetes Mellitus in

International Journal of Epidemiology
O International Epldemtok>gical Association 1996
Vol. 25, No. 2
Printed In Great Britain
Characteristics of Non-InsulinDependent Diabetes Mellitus in
Elderly Men: Effect Modification by
Family History
JOLANDA M A BOER,*** EDITH J M FESKENS* AND DAAN KROMHOUT+
Boer J M A (Department of Chronic Disease and Environmental Epidemiology, National Institute of Public Health and
Environmental Protection, PO Box 1, NL-3720 BA Bllthoven, The Netherlands), Feskens E J M and Kromhout D.
Characteristics of non-lnsulin-dependent diabetes mellitus in elderly men: Effect modification by family history. International Journal of Epidemiology 1996; 25: 394-402.
Background. Heredity, obesity and fat distribution may interact with each other in their association with diabetes risk.
Therefore we tned to elucidate the role of familial diabetes as effect modifier In the association of obesity, glucose
metabolism and lipoprotelns with non-insulin-dependent diabetes mellitus.
Methods. A cross-sectional study was carried out among 468 elderly men. Within strata of family history, men with diabetes and normal glucose tolerance were compared with respect to anthropometry, characteristics of glucose metabolism
and serum lipids.
Results. Of the participants, 14.5% were diabetic. In diabetic men a family history of diabetes occurred more often (22.1%)
than in men with normal (6.8%, P < 0.001) or impaired glucose tolerance (8.5%). In diabetic men with a family history,
the ratio of fasting insulin to glucose and the ratio of areas under the insulin and glucose curves during oral glucose
tolerance testing were lower compared to men with normal glucose tolerance. In men without a family history, these
differences were smaller (Interaction P = 0.06). In diabetic men without a family history, fasting Insulin levels were
markedly elevated (P < 0.001), whereas in men with a family history there was only a slight elevation. The presence of
a family history resulted in more severe deteriorations in lipids, especially in fasting trigrycerides (interaction P = 0.075).
No interaction between indices of obesity and a family history was observed.
Conclusions. Our findings suggest that elderty diabetic men with a family history of diabetes represent a different
subgroup than elderly men without such a history, characterized by larger deteriorations in indices for beta-cell function
and higher triglyceride levels.
Keywords: diabetes mellitus, non-insulin-dependent, family history, glucose tolerance, Insulin, lipoproteins, obesity
It is well established that non-insulin-dependent (Type
2) diabetes mellitus (NIDDM) is a heterogeneous
syndrome with both environmental and genetic factors
contributing to its aetiology.' Whether insulin resistance or a defect in insulin secretion from the pancreatic
beta-cell is the primary defect in the development of
NIDDM may also depend on genetic background, but
conflicting results have been reported.2 In genetically
susceptible individuals a defect in insulin-secretion,3
insulin resistance4-5, or both 6 ' 7 were mentioned as the
earliest lesion in the development of NIDDM.
Several studies suggest that, besides heredity, obesity
and fat distribution are strongly related to diabetes
risk. 8 "" Recently, some studies reported that these factors interact with each other, and suggest that the effect
of obesity is less in subjects with a family history of
diabetes. In subjects with a family history of diabetes
there seems to be no difference in obesity level and fat
distribution between subjects with normal glucose
tolerance and impaired glucose tolerance.12-13 Osei
et al. found indices of obesity could not predict insulin
responses in relatives of diabetic subjects.14
• Department of Chronic Disease and Environmental Epidemiology,
National Institute of Public Health and Environmental Protection,
PO Box 1, NL-3720 BA Billhoven, The Netherlands.
• • Department of Epidemiology and Public Health, Wageningen
Agricultural University, Wageningen, The Netherlands.
f
Division of Public Health Research, National Institute of Public
Health and Environmental Protection, Bilthoven, The Netherlands.
Lipid metabolism is probably involved in the
aetiology of NIDDM.2 Plasma insulin levels and insulin
resistance are correlated with plasma lipoprotein levels,
e.g. elevated triglycerides and reduced high-densitylipoprotein (HDL) cholesterol levels. 13 It is not clear to
what extent these associations depend on genetic susceptibility and are modified by a positive family history
of diabetes. 1416
394
FAMILIAL AND NON-FAMIUAL DIABETES MELLITUS
Therefore, the aim of the present study was to determine whether a family history of diabetes modifies the
association of obesity, glucose metabolism and plasma
lipoproteins, with NIDDM. This issue was studied in a
population-based study of elderly men with a relatively
high prevalence of diabetes mellitus.
SUBJECTS AND METHODS
Subjects
The Zutphen Elderly Study is a longitudinal study on
risk factors for chronic diseases.17 It represents a continuation of the Zutphen Study, the Dutch contribution
to the Seven Countries Study.18 In 1985, 1266 men born
between 1900 and 1920 and living in Zutphen for at
least 5 years were invited for the examinations, of
which 939 men agreed to participate. This group formed
the cohort of the Zutphen Elderly Study. In 1990, 718
of these men were still alive and invited for the followup survey, of which 560 attended. For the analyses presented in this paper known diabetic men using insulin
(n = 8) were excluded because of suspicion of insulindependent (Type 1) diabetes mellitus (IDDM) or Late
Autoimmune Diabetes Mellitus in Adults (LADA).19
For 468 men (aged 69-90 years) data on family history
and glucose tolerance were available and used in
analyses.
Study Protocol
An anthropometric examination took place with subjects dressed in underwear only. Height was measured
to the nearest 0.5 cm with a microtoise. Body weight
was recorded to the nearest 0.5 kg. Body mass index
(BMI) was defined as weight/height2 (kgAn2). Triceps
and subscapular skinfold thickness were measured
twice to the nearest mm, at the right side of the body,
using a Harpenden calliper. Triceps skinfold was measured midway between the acromion and the olecranon,
whereas subscapular skinfold was taken just below the
tip of the scapula. The ratio of subscapular to triceps
skinfold thickness (skinfold ratio) was used as an index
of body fat distribution.
A 75 g oral glucose tolerance test (OGTT) was carried out in the morning, after an overnight fast. Known
diabetic subjects treated with oral hypoglycaemic agents (n = 23) were excluded from the test
for ethical reasons. Before the test, a fasting blood
sample was taken and thereafter two more samples 1
and 2 hours after the glucose load. Samples were
collected in tubes with sodium fluoride. Plasma glucose was determined using the hexokinase method.20
Serum insulin was measured using a radioimmuneassay (Pharmacia Diagnostics, Uppsala, Sweden), and
395
within- and between-run coefficients of variation
ranged from 6 to 7%. Fasting serum C-peptide levels
were determined using a I25 I RIA Kit (Incstar Corp.,
Minnesota, USA). The within-run coefficient of
variation was 6.5% and the between-run coefficient of
variation was 14%. Glucose and insulin areas under the
OGTT-curve (AUC) were calculated using the
trapezoidal method. Subjects were classified according
to WHO criteria as subjects with normal glucose
tolerance (fasting glucose <7.8 mmol/1 and 2-h glucose
<8.7 mmol/1), impaired glucose tolerance (IGT, fasting
glucose <7.8 mmol/1 and 2-h glucose 8.7-11.1 mmol/1),
or diabetes mellitus (fasting glucose 3*7.8 mmol/1
and/or 2-h glucose 2=11.1 mmol/1).21 The latter group
also included diabetic subjects who were excluded from
the OGTT.
Triglycerides were determined enzymatically using
a test kit (Boehringer, Mannheim)22 in serum collected
in the fasting state. The HDL-lipoproteins were isolated
according to the method of Warnick et al.23 Non-fasting
total serum cholesterol and HDL-cholesterol were
determined enzymatically using a CHOD-PAP monotestkit (Boehringer, Mannheim) as described elsewhere.24'25 Low-density-lipoprotein (LDL) cholesterol
levels were calculated using the Friedewald equation.26
In the 1985 survey participants were asked whether
or not a first degree relative (i.e. father, mother, sibling
or child) was diabetic. If this was the case, a family
history of diabetes was considered to be present.
Statistical Analyses
Analyses were carried out on ranked values because
other transformations did not improve normality of the
data. Differences between the three groups (normal
glucose tolerance, impaired glucose tolerance and
diabetes mellitus) were tested by analyses of variance.
Subjects with normal glucose tolerance were compared
to diabetic subjects using the Wilcoxon rank-sum test
for independent samples, separately for subjects with
and subjects without a family history of diabetes. Subjects with impaired glucose tolerance (n = 47) were excluded from these analyses because of small numbers.
Adjusted means of the ranked values were determined
by analysis of covariance, and differences between men
with normal glucose tolerance and diabetic men were
calculated. To transform the differences back to original
units, adjusted means were substituted in regression
lines relating normal to the ranked values. Interactions
of family history of diabetes with other determinants
for diabetes in the association with diabetes prevalence
were calculated using logistic regression. All analyses
were carried out with the Statistical Analysis System
(SAS version 6.07, SAS Institute, Cary, NC, USA).
396
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
TABLE 1 Selected characteristics of elderly men with normal glucose tolerance, impaired glucose tolerance and diabetes mellilus: The
Zutphen Elderly Study
Normal glucose tolerance
n = 353
Age (years)
Body mass index (kg/m2)
Triceps skinfold (mm)
Subscapular skinfold (mm)
Skinfold ratio
Family history of diabetes (%)
75.8
25.4
12.1
16.8
1.44
6.8
Impaired glucose tolerance
n-47
± 4.4
± 3.0
±4.4
±5.8
±0.37
77.8
26.6
13 8
19.7
1.49
8.5
±5.1*
± 4.0*
±5.3*
±6.8*
±0.38
Diabetes mellitus
n = 68
75.4 ± 4.4f
26.1 ±3.0
12.2 ±4.2
19.4 ± 6.6'
1.64 ±0.49'
22.1«
Data are presented as mean ± SD.
* P < 0.05, * P < 0.01, • P < 0.001 versus men with normal glucose tolerance.
' P < 0.01 versus men with impaired glucose tolerance.
P-values < 0.05 were considered statistically significant. Interaction terms were considered to be significant at P < 0.1, as recommended by Rothman.27
RESULTS
According to WHO criteria 353 men (75.4%) had normal glucose tolerance, while 47 men (10.0%) showed
impaired glucose tolerance and 68 men (14.5%) had
NIDDM. Of the diabetic men, 57% were newly diagnosed by the OGTT. Men with impaired glucose tolerance were older than both men with normal glucose
tolerance and diabetes (Table 1). Both diabetic men and
men with impaired glucose tolerance were more obese
than subjects with normal glucose tolerance, as demonstrated by differences in BMI and subscapular skinfold
thickness. Men with diabetes had a more centralized
body fat distribution compared to both other groups, but
the difference only reached significance compared to
men with normal glucose tolerance. Adjustment for age
did not alter these results.
A family history of diabetes occurred three times
more often in diabetic men than in men with normal
glucose tolerance (odds ratio [OR] 3.9, 95% confidence
interval [CI] : 1.9-7.9), and additional analyses showed
that this difference was independent of age, BMI, and
skinfold ratio. The occurrence of a family history was
comparable in known (24.1%) and newly diagnosed
diabetic men (20.5%). The presence of a family history
of diabetes in men with impaired glucose tolerance was
comparable to those with normal glucose tolerance.
The duration from time of clinical diagnosis to time
of study did not differ significantly between diabetic
men with (4.6 ± 7.8 years) and without a family history
(3.4 ± 6.4 years). Further results concerning separate
analyses for men with and men without a family history
of diabetes are shown in Tables 2, 3 and 4. In men
without a family history, obesity was weakly associated
with diabetes prevalence. For subscapular skinfold
thickness and the skinfold ratio this association was
statistically significant (P < 0.05), but not for BMI or
triceps skinfold (Table 2). In men with a family history
of diabetes, no significant differences in BMI, triceps
and subscapular measures were found between diabetic
and non-diabetic subjects (P > 0.05). The difference in
skinfold ratio was larger than in men without a family
history (P < 0.05). Interaction terms between family
history of diabetes and indices of obesity and body fat
distribution were not statistically significant (P > 0.1).
In both diabetic men with and without a family history of diabetes, fasting glucose and the area under the
glucose curve were elevated when compared to nondiabetic men (Table 3). In contrast, fasting insulin and
C-peptide levels were elevated, suggesting insulin
resistance, in diabetic men without a family history, but
not in diabetic men with a family history of diabetes
(Table 3). Interaction terms were, however, not significant (P > 0.1). The adjusted ratio of fasting insulin
to fasting glucose as well as the adjusted ratio AUC
insulin to AUC glucose during the OGTT were reduced
in diabetic men without a family history (-0.25 and
-18.8, respectively). Among diabetic men with a family
history, the reduction of the ratio of fasting insulin to
fasting glucose was stronger (-0.56) and the reduction
in the ratio of insulin to glucose during the OGTT
was larger (-26.6, interaction P = 0.06). As shown in
Figures 1 and 2 glucose curves during OGTT according
to diabetes status were similar (Figure 1), while insulin
curves were different for men with and without a family
history (Figure 2). The larger impairment in insulin
secretion relative to the glucose levels suggests that
beta-cell function was more impaired in diabetic men
397
FAMILIAL AND NON-FAMIUAL DIABETES MELLITUS
TABLE 2 Selected characteristics of elderly men with normal glucose tolerance and diabetes mellitus according to family history of
diabetes: The Zutphen Elderly Study
Normal glucose tolerance
Diabetes mellitus
Difference
crude
adjusted*
Without a family history
Age (years)
Body mass index (kg/m2)
Triceps skinfold (mm)
Subscapular skinfold (mm)
Skinfold ratio
n = 329
75.7 ± 4.3
25.4 ± 3.0
12.1 ±4.5
16.9 ± 5.9
1.45 ±0.38
n = 53
75.5 ±4.7
26.1 ± 3 . 0
15.5 ±4.3
19.5 ±6.1
1.60 ±0.39
-02
0.7
3.4
2.6'
0.15*
—
0.8
0.4
2.4*
0.13'
With a family history
Age (years)
Body mass index (kg/m2)
Triceps skinfold (mm)
Subscapular skinfold (mm)
Skinfold ratio
n = 24
77.2 ± 5.6
25.3 ± 2.6
12.3 ±4.4
16.3 ±4.6
1.36 ±0.31
n = 15
75.1 ±3.5
25.8 ± 3.2
11.3 ±3.7
19.4 ± 8 3
1.80 ±0.74
-2.1
05
-1.0
3.1
0.44*
0.5
-0.9
2.1
0 26*
Data we presented as mean ± SD.
* Adjusted for age, *P < 0.05, '/> < 0.01. No significant interactions with family history were found.
TABLE 3 Characteristics of glucose metabolism in elderly men with normal glucose tolerance and diabetes mellitus according to family
history of diabetes: The Zutphen Elderly Study
Normal glucose tolerance
Difference
Diabetes mellitus
crude
adjusted*
Without a family history
Fasting glucose (mmol/1)
Fasting insulin (pmol/1)
Fasting C-peptide (nmol/1)
Insulin/glucose
C-peptide/insulin (x 100)
AUC glucose (mol/l.min)1
AUC insulin (nmol/1.min)"
AUC insulin/AUC glucose1
n = 329
5.6 ± 0.5
64.3 ± 28.6
0.69 ± 0.27
1.58 ±0.66
3.43 ± 1.15
0.84 ±0.16
37.33 ± 16.87
44.51 ± 19.27
n = 53
8.7 ± 3.2
91.8 ±57.8
0 92 ± 0.53
1.61 ± 1.15
3.27 ± 1.02
1.55 ±0.28
38.55 ± 2 4 91
26.15 ± 17.90
3.1'
27.5'
0.23'
0.03
-0.16
0.71'
1.22
18.36'
1.3'
13.1'
0.101
-0.25'
-0.18
0.45'
-3.23
-18.80'
With a family history
Fasting glucose (mmol/1)
Fasting insulin (pmol/1)
Fasting C-peptide (nmol/1)
Insulin/glucose
C-peptide/insulin
AUC glucose (mol/l.min)"
AUC insulin (nmol/1.min)1
AUC insulin/AUC glucose1
n = 24
5.6 ± 0.6
62.6 ± 18.3
0.71 ±0.18
1.58 ±0.47
361 ± 1.16
0.87 ±0.16
36.84± 11.10
43.23 ± 12.75
n - 15
9.1 ± 2 . 5
71.8 ±34.3
0.81 ±0.24
1.18 ±0.59
3.81 ± 1.20
1.56 ±0.32
31.37 ± 11.22
20.56 ± 7.60
3.5'
9.2
0.10
-0.40*
0.20
0.69'
-5.47
22.67'
1.7'
1.7
0.06
-0.56*
0.00
0.44'
-8.25
-26.59'
Data are presented as mean ± SD.
• Adjusted for age, BMI and skinfold ratio.
1
n •= 36 in diabetic men without and n = 9 in diabetic men with a family history.
AUC: Area under the oral glucose tolerance test curve.
• P < 0.05, *P < 0.01, '/> < 0.001. Interaction with family history is significant (P = 0.061) for AUC insulin/AUC glucose.
398
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
20 r
600r
500
15
400
o
o
a.
10
300
200
100
60
120
Time (min)
60
120
Time (min)
FIGURE 1 Glucose levels (mean ± SE) during oral
glucose tolerance test (OGTT) among men with normal
glucose tolerance and diabetes according to family
history of diabetes (The Zutphen Elderly Study)
FIGURE 2 Insulin levels (mean ± SE) during oral glucose
tolerance test (OGTT) among men with normal glucose
tolerance and diabetes according to family history of
diabetes (The Zutphen Elderly Study)
with a family history than in diabetic men without a
family history. The ratio of C-peptide to insulin, an
index of hepatic insulin clearance, was normal in diabetic men with a family history, but reduced, albeit not
significantly, in diabetic men without a family history.
In both diabetic men with and without a family history fasting triglyceride levels were elevated and HDLcholesterol levels were reduced (Table 4). Adjustment
for age, obesity level and body fat distribution did not
alter these results. The deteriorations seemed more
serious in diabetic men with a family history. This was
confirmed by the interaction of family history of
diabetes in the association between serum triglyceride
levels and diabetes prevalence (P = 0.075). For
the other lipid variables no interaction was observed
(P>0.\).
in individuals without a family history impaired hepatic
insulin clearance and insulin resistance seemed to
contribute to glucose intolerance. In diabetic men with
a family history, the disturbances in lipoprotein profile, as often seen in diabetic individuals,15 were more
severe than in diabetic men without a family history.
This effect was especially clear for triglycerides. Associations of indices of obesity and body fat distribution did not differ according to family history of
diabetes.
The men who participated in this study were 70 years
and over. The prevalence of diabetes is therefore relatively high. We cannot exclude selective loss of subjects, due to death or non-cooperation because of health
problems. However, associations of family history,
obesity and lipoprotein levels with diabetes prevalence
were as expected, l ' 2-8 ~"' 15 ' 16 suggesting that the influence on the results was probably small. If diabetic
patients with a less severe state of the disease have
survived, this would have resulted in a dilution of the
observed differences in glucose and lipid metabolism.
A family history of diabetes occurred three times
more often in diabetic men than in non-diabetic
men. This suggests the presence of genetic factors in
the development of NIDDM, as presented earlier. ll - 28 ' 29
DISCUSSION
The results of the present study show that a family
history of diabetes interacts with characteristics of
glucose metabolism and triglycerides in explaining
its association with NIDDM. In diabetic individuals
with a family history of diabetes there were indications for impaired pancreatic beta-cell function, while
399
FAMILIAL AND NON-FAMIUAL DIABETES MELUTUS
TABLE 4 Upids and lipoproteins in elderly men with normal glucose tolerance and diabetes mellitus according to family history of
diabetes: The Zutphen Elderly Study
Normal glucose tolerance
Diabetes mellitus
Difference
crude
adjusted
Without • family history
Triglycerides (mmol/1)
Total cholesterol (mmol/1)
LDL-cholesterol (mmol/1)
HDL-cbolesterol (mmol/1)
n = 329
1.39 ±0.75
6.09 ± 1.07
4.28 ± 0.97
1.17 ±0.30
n = 53
1.70 ±0.79
6.11 ± 1.20
4.30 ± 1.08
1.04 ±0.25
0.31*
0.02
0.02
-0.13 f
0.23*
0.01
0.01
-0.09*
With a family history
Triglycerides (mmol/1)
Total cholesterol (mmol/1)
LDL-cholesterol (mmol/1)
HDL-cholesterol (mmol/1)
n = 24
1.19 ±0.43
6.09 ± 0.96
4.31 ±0.94
1.24 ±0.30
n = 15
1.86 ±0.72
6.52 ± 1.09
4.59 ± 1.07
1.08 ±0.21
0 67 f
0.43
0 28
-0.16
0.60*
0.08
0 02
-0.18
Data are presented as mean ± SD.
• Adjusted for age, BMI and sldnfold ratio
* P < 0.05,' P < 0.01. Interaction with family history is significant (/> = 0.075) for triglycerides.
It is likely that men have been misclassified with
respect to family history. Since, as is shown in this
study, 57% of diabetic patients are not diagnosed, it is
likely that subjects did not know whether or not a
relative was diabetic. Some additional, but probably
small, misclassification might have occurred from
the lag time between the interview where family
history was recorded (1985) and the determination
of the diabetes status in 1990. If a better index for
genetic susceptibility was used, reducing misclassification of family history, the association with diabetes prevalence would probably have been stronger.
The relationship between diabetes prevalence and
family history of diabetes might proceed from
the fact that individuals with diabetic relatives are
diagnosed more often than subjects without diabetic relatives. In our population, however, the percentage of men with a family history was comparable
in known and newly diagnosed diabetic men. This
suggests a true association between family history
and non-insulin-dependent diabetes in the present
study.
Type of family history (maternal, paternal or from a
sib) might influence obesity level and diabetes prevalence. Two studies showed that maternal family history
is more strongly related to both.30-31 In the present
study, however, no differences in obesity level, fat distribution, nor in insulin or glucose levels were found
according to type of family history. Therefore no discrimination was made between different types of family
history of diabetes.
In our study, both diabetic men with and without a
family history had a higher BMI than men with normal
glucose tolerance, but these differences were not statistically significant. However, diabetic men had significantly higher values for subscapular skinfold thickness
and skinfold ratio. These findings have been shown
before,32 and confirm that body fat distribution is associated with glucose tolerance33"36 and might play a
role in the aetiology of NIDDM.32 The differences in
skinfolds between diabetic men and men with normal
glucose tolerance were similar for the groups with and
without a family history. In a study on 157 Japanese
American men Fujimoto e/a/. 12 did not find differences
in overweight and fat distribution between diabetic and
non-diabetic subjects among individuals with a family
history of diabetes, whereas large differences in the
group without a family history were observed. In our
study such clear interaction between obesity and family
history was not seen. This may be caused by a different
genetic background (Caucasians) or an older age. Diabetic subjects are known to lose weight, either by the
disease itself or by therapy, and this might have influenced our results. The body fat index studied might also
affect the outcome. In a study on female relatives of
black NIDDM patients Osei et al.u were not able to
show an association between BMI and glucose and
insulin levels, whereas they observed a positive association with subscapular skinfold thickness, both in the
relatives and in a control group. These findings indicate
that effect modification by family history may depend
on the body fat index studied.
400
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Our data suggest that, although measured indirectly,
beta-cell function was markedly impaired in diabetic
men with a family history, and less in men without a
family history of diabetes. Assuming the two-step mechanism for the development of NIDDM, with insulin
resistance leading to beta-cell exhaustion and glucose
toxicity,1 it may be argued that the diabetic men with
a positive family history in our study represent a subgroup of diabetic individuals with a more severe state
of the disease. This seems, however, an unlikely explanation since the proportion of men with newly
diagnosed diabetes and duration from time of clinical
diagnosis was similar in the group with and without a
family history. Furthermore, adjustment for the time
since diagnosis did not alter the results.
O'Rahilly et al} demonstrated that impaired betacell function was the primary defect in the development
of familial diabetes. Others, however, suggest that insulin resistance is the primary defect in subjects with
a family history.14'37 Although our study is crosssectional in design, and employed a standard OGTT,
instead of more sophisticated euglycaemic clamps, 38
the Findings seem to support the hypothesis that
reduced beta-cell function is an important feature of
familial diabetes, whereas insulin resistance, indicated
by elevated fasting insulin levels,39 seems to be more
important in diabetic individuals without a family history. This is also suggested by a study from Lemieux
et a/.13 which compared 39 non-diabetic men with and
without a family history, and observed lower fasting
insulin levels in those with a family history. In our
study, however, the suggestion of the impact of betacell function in familial diabetes mostly results from
findings in diabetic men: those with a family history
have a more reduced insulin response. This might be
due to the fact that our study population consisted of
older subjects. The men with a true genetic susceptibility may already have developed diabetes during the
course of their life, and therefore differences in
normoglycaemic men with and men without a family
history were small.
We observed that triglyceride levels were higher in
men with diabetes than in men with normal glucose
tolerance. The increase was most pronounced in
diabetic men with a family history of diabetes. Haffner
et al.16 observed higher lipid levels in relatives of
diabetic patients, but Osei et al. could not confirm this
finding in a small study among relatives of black
NIDDM patients.14 Elevated triglyceride levels may
result from an increased production or decreased clearance of VLDL. Insulin stimulates triglyceride production, 40 but this seems no explanation why in this study
higher levels of triglycerides are found in diabetic men
with a family history, since they produce less insulin,
than the men without a family history. Another explanation may be the suppressive effect of insulin on VLDL
secretion.41 In diabetic subjects the hepatic sensitivity
to the suppressive effect of insulin might be impaired.13142 A third potential explanation may refer to
the effect of lipoprotein lipase polymorphism on
VLDL-triglyceride levels43 and a subsequently impaired
insulin action.44-45 Patients with familial combined
hyperlipidaemia show partial lipoprotein lipase deficiency,46 and lipid and glucose metabolism seem to be
linked in these patients.47 The difference in triglyceride
elevation between diabetic men with and without a
family history might therefore be explained by a more
severe defect in insulin action in the group with a family history or an additive genetic effect in lipoprotein
lipase in the group with a family history of diabetes.
In conclusion, our findings suggest that elderly
diabetic men who have a family history of diabetes
represent a different subgroup in comparison to elderly
diabetic men who do not have such a history, characterized by larger deteriorations in beta-cell function and
higher triglyceride levels. No interaction between
indices of body fatness and a family history of diabetes
was found.
ACKNOWLEDGEMENTS
We are indebted to the fieldwork team in Zutphen, especially to Dr B P M Bloemberg, for co-ordinating the
survey, to Dr E B Bosschieter and Mrs A H ThomassenGijsbers; to the Laboratory of Clinical Chemistry and
Haematology of the Nieuwe Spitaal hospital in
Zutphen; to the Laboratory of the Unit of Teratology,
Endocrinology and Perinatal Screening of the RIVM
(Dr G Loeber and Mr L Elvers) for the insulin and
C-peptide analyses; and to Dr E G Schouten of the Dept
of Epidemiology and Public Health, Agricultural
University, Wageningen, for his comments. This study
is presented in abstract form in TSG 1994;4:17 (in
Dutch).
REFERENCES
'Zimmet P. Non-insulin-dependent (Type 2) diabetes mellitus:
Does it really exist? Diabetic Med 1989; 6: 728-35.
2
Reaven G M. Insulin secretion and insulin action in non-insulindependent diabetes mellitus: which defect is primary?
Diabetes Care 1984; 7(Suppl. 1): 17-24.
3
O'Rahilly S P, Nugent Z, Rudenski A S et al. Beta-cell
dysfunction, rather than insulin insensitivity, is the primary
defect in familial Type 2 diabetes. Lancet 1986; II: 360-63.
4
Haffner S M, Stem M P, Hazuda H P, Mitchell B D, Patterson
J K. Increased insulin concentrations in nondiabetic
offspring of diabetic parents. N Engl J Med 1988; 319:
1297-301.
FAMILIAL AND NON-FAMILIAL DIABETES MELLITUS
5
Martin B C, Warram J H, Krolewski A S, Bergman R N,
Soeldner J S, Kahn C R. Role of glucose and insulin
resistance in development of type 2 diabetes mellitus:
results of a 25-year follow-up study. Lancet 1992; 340:
925-29.
'Eriksson J, Franssila-Kallunki A, Ekstrand A et al. Early metabolic defects in persons at increased risk for non-insulindependent diabetes mellitus. N Engl J Med 1989; 321:
7
Lillioja S, Mott D M, Spraul M et al. Insulin resistance and
insulin secretory dysfunction as precursors of non-insulindependent diabetes mellitus. N Engl J Med 1993; 329:
1988-92.
'Colditz G A, Willet W C, Stampfer M J et al. Weight as a nsk
factor for clinical diabetes in women. Am J Epidemiol
1990; 132: 501-13.
9
Knowler W C, Petutt D J, Savage P J, Bennett P H. Diabetes
incidence in Pima indians; contributions of obesity and
parental diabetes. Am J Epidemiol 1981; 113: 144-56.
10
Kuzuya T, Matsuda A. Family histories of diabetes among
Japanese patients with Type 1 (insulin dependent) and
Type 2 (non-insulin-dependent) diabetes. Diabetologia
1982; 22: 372-74.
" Morris R D, Rimm D L, Hartz A J, Kalkhoff R K, Rimm A A.
Obesity and heredity in the etiology of non-insulindependent diabetes mellitus in 32,662 adult white women.
Am J Epidemiol 1989; 130: 112-21.
12
l3
Fujimoto W Y, Leonetti D L, Newell-Morris L, Shuman W P,
Wahl P W. Relationship of absence or presence of a family
history of diabetes to body weight and body fat distribution
in Type 2 diabetes. Int J Obes 1991; 15: 111-20.
Lemieux S, Despres J-P, Nadeau A, Prud'homme D, Tremblay
A, Bouchard C. Heterogeneous glycaemic and insulinaemic responses to oral glucose in non-diabetic men: interactions between duration of obesity, body fat distribution
and family history of diabetes mellitus. Diabetologia 1992;
35: 653-59.
14
Osei K, Cottrell D A, Bossetti B. Relationships of obesity
indices to serum insulin and lipoproteins in relatives of
black patients with non-insulin-dependent diabetes mellitus
(NIDDM). Int J Obes 1991; 15:441-51.
13
Howard B V. Lipoprotein metabolism in diabetes mellitus.
J Ltpid Res 1987; 28: 613-28.
16
Haffner S M, Stem M P, Hazuda H P, Mitchell B D, Patterson
J K, Ferrannini E. Parental history of diabetes is associated
with increased cardiovascular risk factors. Arteriosclerosis
1989; 9: 928-33.
l7
Hertog M G L, Feskens E J M, Hollman P C H, Katan M B,
Kromhout D. Dietary flavonoids and the risk of coronary
heart disease (The Zutphen Elderly Study). Lancet 1993;
342: 1007-11.
"Keys A, Aravanis C, Blackburn H. Epidemiological studies
related to coronary heart disease: characteristics of men
aged 40-59 in seven countries. Ada Med Scan 1966; 460
(Suppl.): 1-392.
"Zimmet P Z, Tuomi T, Mackay I R et al. Latent Autoimmune
Diabetes Mellitus in Adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and
prediction of insulin dependency. Diabetic Med 1993; 11:
299-303.
^Richterich R, Dauwalder H. Zur bestimmung der plasmaglucosekonzentration mit der hexokinase-glucose-6-phosphatdehydrogenase-methode. Schweiz Med Wochenschr 1971;
101:615-18.
401
21
World Health Organization. Diabetes Mellitus. Report of a WHO
Study Group. WHO Technical Report Series 727. WHO,
Geneva, 1985.
22
Sullivan D R, Kruijswijk Z , W e s t C E , K o h l m e i e r M , Katan
M B . Determination of serum triglycendes by an enzymatic
method not affected by free glycerol. Clin Chem 1985; 31:
1227-28.
23
Wamick G R, Benderson J, Albers J J. Dextran sulfate-Mg2+
precipitation procedure for quantitation of high density
lipoprotein cholesterol. Clin Chem 1982; 28: 1379-88.
24
Siedel J, Schlumberger H, Klose S, Ziegenhorn J, Wahlefeld
A W. Improved reagent for the enzymatic determination
of serum cholesterol. J Clin Chem Clin Biochem 1981; 19:
838-39.
"StShler F, Gruber W, Stinshoff K, Raschlau P. Eine pnuisgerechte enzymatische cholesterin-bestimmung. Med Lab
1977; 30: 29-37.
26
Friedewald W T, Levy R I, Frednckson D S. Estimation of the
concentration of low-density lipoprotein cholesterol in
plasma without use of the preparative ultracentrifugation.
Clin Chem 1972; 18: 499-502.
"Rothman K J, Greenland S, Walker A M. Concepts of interaction. Am J Epidemiol 1980; 112: 467-70.
^Elbein S C, Maxwell T M, Schumacher C. Insulin and glucose
levels and prevalence of glucose intolerance in pedigrees with multiple diabetic siblings. Diabetes 1991; 40:
1024-32.
29
Stem M P, Gonzalez C, Mitchell B D, Villalpando E, Haffner
S M, Hazuda H P. Genetic and environmental determinants
of Type II diabetes in Mexico City and San Antonio.
Diabetes 1989; 41: 484-92.
^Alcolado J C, Alcolado R. Importance of maternal history of
non-insulin-dependent diabetic patients. Br Med J 1991;
302: 1178-80.
31
Lapidus L, Lissner L, Bengtsson C, Smith U. Family history of
diabetes in relation to different types of obesity and change
of obesity during 12-yr period. Diabetes Care 1992; 15:
1455-58.
32
Feskens E J M , K r o m h o u t D . C a r d i o v a s c u l a r risk factors a n d
the 25-year diabetes incidence in middle-aged men. The
Zutphen Study. Am J Epidemiol 1989; 130: 1101-08.
33
Feskens E J M , K r o m h o u t D . Effects of body fatness and its
development over a ten-year period on glucose tolerance in
euglycaemic men: the Zutphen Study. Int J Epidemiol 1989;
18: 368-73.
^Freedman D S, Srinivasan S R, Harsha D W, Webber L S,
Berenson L S. Relation of body fat distribution to hyperinsulinemia in children and adolescents: The Bogalusa
Heart Study. Am J Clin Nutr 1987; 46: 403-10.
33
Harlan L C, Harlan W R, Landis J R, Goldstein N G. Factors associated with glucose tolerance in U.S. adults. Am J Epidemiol
1987; 126: 674-84.
36
Newell-Morris L L, Treder R P, Shuman W P, Fujimoto W Y.
Fatness, fat distribution, and glucose tolerance in secondgeneration Japanese American (Nisei) men. Am J Clin Nutr
1989; 50: 9-18.
37
Groop L C, Bonadonna R C, DelPrato S et al. Glucose and free
fatty acid metabolism in non-insulin-dependent diabetes
mellitus. Evidence for multiple sites of insulin resistance.
J Clin Invest 1989; 84: 205-13.
38
Groop L C, Widen E, Ferrannini E. Insulin resistance and insulin
deficiency in the pathogenesis of Type 2 (non-insulindependent) diabetes mellitus: errors of metabolism or of
methods? Diabetologia 1993; 36: 1326-31.
402
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
" H o l l e n b e c k C B, Chen N, Chen Y D 1, Reaven G M. Relationship between the plasma insulin response to oral glucose
and insulin-stimulated glucose utilisation in normal subjects. Diabetes 1984; 33: 460-63.
40
Reaven G M, Chen Y-D. Role of insulin in regulation of lipoprotein metabolism in diabetes. Diabetes Metab Rev 1988;
4: 639-52.
41
Byrne C D, Wang T W, Hales C N. Control of Hep G2-cell triacylglycerol and apolipoprotein B synthesis and secretion
by polyunsaturated non-esterified fatty acids and insulin.
BiochemJ 1992; 288: 101-07.
4J
Gibbons G F. Assembly and secretion of hepatic very-lowdensity lipoprotein. Biochem J 1990; 268: 1-13.
43
Peacock R E, Hamsten A, Nilsson-Ehle P, Humphries S E. Associations between lipoprotein lipase gene polymorphism and
plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and agematched healthy individuals from Sweden. Atherosclerosis
1992; 97: 171-85.
" B i e g e r W P, Michel G, Barwich D, Biehl K, Wirth A. Diminished insulin receptors on monocytes and erythrocytes in
hypertriglyceridemia. Metabolism 1984; 3 3 : 982-87.
43
Yki-JBrvinen H, Taskinen M-R. Interrelationships among
insulin's antilipolytic and glucoregulatory effects and
plasma triglycerides in non-diabetic and diabetic patients
with endogenous hypertriglyceridemia. Diabetes 1988; 37:
1271-78.
46
Babirak S P, Iverius P H, Fujimoto W Y, Brunzell J D. Detection
and characterization of the heterozygote state for lipoprotein lipase deficiency. Arteriosclerosis 1989; 9: 326-34.
47
Cabezas M C, de Bruin T W A, de Valk H W, Shoulders C C.
Jansen H, Erkelens W. Impaired fatty acid metabolism in
familial combined hyperlipidaemia: a mechanism associating hepatic apolipoprotein B overproduction and insulin
resistance. J Clin Invest 1993; 92: 160-68.
(Revised version received September 1995)