Download Perspectives in Diabetes Insulin Resistance or Insulin Deficiency

Perspectives in Diabetes
Insulin Resistance or Insulin Deficiency
Which Is the Primary Cause of NIDDM?
Simeon. I. Taylor, Domenico Accili, and Yumi Imai
E
xtensive investigations of the pathophysiology of
non-insulin-dependent diabetes mellitus (NIDDM)
have identified two defects in endocrine function:
insulin resistance and insulin deficiency. Despite
general agreement that both defects are present in most
patients with established NIDDM, many authorities have
debated the question of which defect is the primary cause of
NIDDM. Many interesting physiological studies have been
conducted in an effort to address the following questions:
Which defect can be detected earliest in the course of the
disease? Which defect is more important in the pathogenesis
of NIDDM? These clinical investigations have provided valuable insights into the pathophysiology of NIDDM. However,
like many productive scientific investigations, they have
raised as many questions as they have answered. Fortunately, after years of spirited debate, methods are becoming
available that are likely t o resolve the controversy. Genetic
factors contribute importantly to the predisposition to develop NIDDM. Nevertheless, abundant evidence suggests
that environmental factors (e.g., nutrition, physical exercise,
etc.) may also modulate the expression of the diabetic
phenotype. (Such interactions between genetics and the
environment are commonly observed in many genetic
diseases. For example, patients with mild forms of
glucose&-phosphate dehydrogenase deficiency are usually
asymptomatic unless they are exposed to environmental
stresses [e.g., administration of certain drugs, infections,
etc.].) Inasmuch as NIDDM is a genetic disease, the identity
of the cause of the disease is encrypted in the sequence of
nucleotides in the patients' DNA. To learn the secret of the
disease, we need to decipher the code. With the development
of powerl:ul methods of molecular genetic analysis, the time
is rapidly approaching when identification of the primary
genetic defects that render an individual susceptible to
NIDDM will be possible. In this perspective, we review the
evidence supporting the balanced view that both insulin
resistance and insulin deficiency contribute to the pathogen-
Rom the D~abetesBranch, National Institute of Diabetes and Digestive and Kidney
Diseases, Nar.ional Institutes of Health, Bethesda, Maryland.
Address correspondence and reprint requests to Dr. S i e o n I. Taylor, National
Institutes of Health, Building 10, Room 8S-239, Bethesda, MD 20892.
NIDDM, non-insulin-dependent diabetes meIlitus; OGTT, oral glucose tolerance
test; IGT, impaired glucose tolerance; IDDM, insulin-dependent diabetes mellitus;
FSIVGTT, frequently sampled intravenous glucose tolerance test; WGTT, intravenous glucose tolerance test; FPG, fasting plasma glucose.
DIABETES, VOL. 43, JUNE 1994
esis of NIDDM but that the relative importance of each factor
may vary from patient to patient. Before attempting to
discuss the more controversial areas, we will begin by
reviewing the points about which there is general agreement.
INSULIN RESISTANCE AND INSULIN DEFICIENCY IN
PATIENTS WITH ESTABLISHED HYPERGLYCEMLA
Insulin resistance. Insulin is a pluripotent hormone that
elicits multiple biological responses. Among its important
biological actions, insulin accelerates glucose transport in
muscle and adipose tissue, regulates the activities of intracellular enzymes, and regulates the transcription of selected
genes. Insulin resistance is a pathological condition in which
there is a shift in the dose-response curve such that the
magnitude of the biological response to insulin is decreased
(1). The impaired response to insulin may be observed either
over the entire range of insulin concentrations or only at low
concentrations of the hormone. Two types of evidence
support the conclusion that patients with NIDDM are resistant to the biological actions of insulin. First, patients with
NIDDM have a diminished response to exogenously administered insulin. Sophisticated methods have been developed
to measure insulin action in vivo, e.g., euglycemic insulin
clamps (2) and minimal model analysis of frequently sampled intravenous glucose tolerance tests (FSIVGTTs) (3).
These methods have documented that all the major target
tissues are resistant to the biological actions of insulin. For
example, insulin is impaired in its ability to promote glucose
utilization by skeletal muscle, t o inhibit glucose production
in liver, and t o inhibit lipolysis in adipose tissue (4,5).
The second line of evidence is based on the observation
that patients with NIDDM are resistant to the action of
i athe fastendogenously secreted insulin. H y p e r i n ~ ~ n e min
ing state is one of the laboratory abnormalities observed
relatively early in the natural history of NIDDM. Both crosssectional and longitudinal studies have demonstrated that
patients are hyperinsulinemic even before the plasma glucose has become elevated t o the point where it satisfies the
diagnostic criteria for diabetes (4-9). For example, in patients with impaired glucose tolerance (IGT) (a group of
patients at increased risk of developing NIDDM in the
future), plasma insulin levels are elevated throughout the
course of an oral glucose tolerance test (OGTT) (Fig. 1) (10).
The fact that the hyperinsulinemia does not induce hypoglycemia demonstrates that the patient is resistant to the
hypoglycemic action of endogenous insulin secreted by the
pancreas.
500
NIDDM (FPG ,150
mg%)
M (FPG 4 5 0 mg%)
Time (hr)
early in the natural history of NIDDM (4-9). However,
plasma insulin levels usually decline later in the course of the
disease, around the time when a patient develops overt
NIDDM. Indeed, the progressive deterioration of pancreatic
insulin secretion has been implicated as the proximate cause
of the progressive increase in plasma glucose levels. (According to the hypothesis that NIDDM is a genetic disease, it
is appropriate to consider the natural history of NIDDM as
beginning early in life, even from the time of conception.
Thus, the development of overt diabetes is a relatively late
event in the natural history of the disease.) Thus, by the time
patients have developed fasting hyperglycemia, demonstration of impaired insulin secretion is usually straightforward.
For example, plasma insulin levels are decreased throughout
the course of an OGTT in patients with NIDDM associated
with a fasting plasma glucose (FPG) >8.3 mM (150 mgldl)
(Fig. 1). Furthermore, a marked decrease in the first phase of
insulin secretion occurs in response to intravenous glucose
(12). Similarly,sophisticated tests of p-cell function based on
deconvolution analysis of the kinetics of C-peptide turnover
in the plasma also demonstrate that insulin secretion is
reduced in patients with NIDDM (11).
OVERVIEW OF THE AREAS OF CONTROVERSY
IGT
Time (hr)
FIG. 1. OGTT in patients with IGT and NIDDM. OGlTs were carried out
in four groups of individuals: normal individuals (a), patients with IGT
(o), patients with NIDDM and FPG 4 . 3 mM (150 mg/dl) ( o ) , and
patients with NIDDM and FPG 3 . 3 mM (150 mg/dl) (B). The graphs
were drawn using data obtained from Reaven e t al. (10).
Insulin deficiency. Pancreatic insulin secretion is subject
to regulation by multiple factors. Although the concentration
of glucose in the plasma is the most important regulator of
insulin secretion, other regulatory influences are important
as well (e.g., amino acids, circulating hormones, neurotransmitters, paracrine factors). Insulin deficiency is defined as a
pathological condition in which there is an inappropriate
decrease in the rate at which the p-cell secretes insulin. Most
commonly, normal ranges for the concentration of insulin in
plasma are defined as a function of the concentration of
glucose in plasma. Nevertheless, because insulin secretion is
a dynamic process, the levels of insulin in plasma are not
constant, but vary from minute to minute throughout the day.
Thus, subtle defects in p-cell function may possibly manifest
as abnormalities in the rate at which insulin concentrations
change as a function of time (11,12).
As discussed above, most patients are hyperinsulinemic
It is reassuring that there is considerable agreement about
the description of the pathophysiology of patients with
severe hyperglycemia-the patients in whom the defects are
most severe and, therefore, most easily quantitated. Much of
the controversy relates to investigations of prediabetic patients. By definition, these are individuals who are not yet
diabetic, but are destined to develop NIDDM in the future.
Thus, these studies have the potential to identify defects that
occur early in the course of the natural history of the disease,
even before the time that patients develop hyperglycemia. It
seems reasonable to postulate that the primary cause(s) of
NIDDM must appear early in the natural history, before the
onset of overt hyperglycemia. Although this approach may
seem straightforward, it is bedeviled by experimental difficulties that have engendered much of the disagreement and
controversy.
Identification of prediabetic individuals. Strictly speaking, prediabetes is a retrospective diagnosis that can be made
only after the patient has actually developed overt diabetes.
Thus, in an optimal experimental design, it would be desirable to identify a cohort of nondiabetic individuals and study
them prospectively. At the end of the study, the individuals
who ultimately developed diabetes would be labeled retrospectively as prediabetic. Even in this type of idealized study,
the diagnosis of "normal" is conditional; one cannot be
certain that apparently nondiabetic individuals would not
have developed NIDDM had they been followed for a longer
time.
Because a population-based prospective study of this type
requires a prohibitive amount of resources, most investigators have limited the scope of the study to obtain data in a
more reasonable time frame. Accordingly, study subjects
have been drawn from groups at high risk of developing
NIDDM-e.g., Pima Indians (8,9), Mexican Americans (13),
or offspring of two parents with NIDDM (6,7,14). These
individuals have such a high risk of developing NIDDM that
it has been possible to conduct tnie prospective studies. On
the other hand, there is no guarantee that these groups are
representative of the total universe of patients with NIDDM.
DIABETES, VOL. 43, JTTNE 1994
Another approach has been to study first-degree relatives
of patients with NIDDM (15-18). This group includes many
individuals who are destined ultimately to develop NIDDM.
However, because most studies of first-degree relatives have
not been long-term prospective studies, these studies are
usually limited by one of two problems. In some studies,
first-degree relatives of patients with NIDDM are compared
with normal individuals without any family history of diabetes (15-18). In this study design, neither group is homogeneous. Although the relatives of patients with NIDDM are at
increased risk of developing NIDDM, the risk is considerably
<loo%; furthermore, the control group almost certainly
contains;some prediabetic individuals. The inability to obtain
homogeneous groups tends to blur the distinctions between
prediabetic and normal individuals. An alternative study
design is to compare the group of first-degree relatives with
IGT to the group of first-degree relatives with normal glucose
tolerance (18). However, by the time patients have developed IG'I', the investigator can no longer be certain that any
physiological defect is primary rather than a secondary
consequence of the acquired metabolic abnormality.
Vicious cycle of insulin resistance and insulin denciency. It is essentially impossible to isolate insulin deficiency from insulin resistance. For example, in insulindependent diabetes mellitus (IDDM), it is well accepted that
the primary defect is insulin deficiency caused by autoimmune destruction of pancreatic P-cells (19). Nevertheless,
even in IDDM, chronic insulin deficiency renders the target
tissues resistant to the acute actions of insulin. Similarly, in
patients with NIDDM, the insulin deficiency exacerbates the
severity of the underlying insulin resistance (20). In fact,
aggressive replacement therapy with insulin can markedly
increase insulin action in vivo (20). Conversely, just as
insulin deficiency can cause insulin resistance, insulin resistance can lead to insulin deficiency. To the extent that insulin
resistance can lead to chronic hyperglycemia, this can impair
p-cell function as a result of glucose toxicity (21). In short,
there is a vicious cycle involving insulin resistance and
insulin deficiency. Thus, when both insulin resistance and
insulin deficiency are present, it is difficult to know whether
both abnormalities are independent primary defects, or
whether one defect is secondary to the other. In an effort to
circumvent this problem, Porte and collaborators (14) have
defined a relationship between parameters of insulin secretion as a function of parameters of insulin sensitivity. Using
this functional relationship, they concluded that offspring of
two parents with NIDDM have a defect in insulin secretion
relative to their observed insulin sensitivity when compared
with a matched group of normal individuals without a family
history of diabetes (14). Thus, they concluded that the
genetic predisposition to develop NIDDM is caused by a
defect in the ability of the P-cell to secrete insulin. In
contrast, Martin et al. (7) conducted prospective studies on a
similar population-the
offspring of two parents with
NIDDM. In this larger study, insulin resistance and hyperinsulinemia were the most powerful predictors of future
development of NIDDM. Indeed, even when first-phase insulin secretion was stratified according to the quintile of insulin
senstivity, Martin et al. (7) did not observe a decrease in
first-phase insulin secretion among the offspring who later
developed NIDDM. Although these two studies differed with
respect to their detailed methodology, whether these differences are sufficient t o account for the diametrically opposed
DIABETES, VOL. 43, JUNE 1994
conclusions is not clear. Nevertheless, the discrepancies
illustrate the difficulties in obtaining definitive data in this
area.
Difficulty in designing relevant tests of physiological
function
Insulin action. Two tests are commonly used to measure
insulin action in vivo: the euglycemic insulin clamp (2) and
minimal model analysis of FSIVGTTs (3). While each approach has its advocates, convincing data are available that
validate the use of both tests to identify physiological
abnormalities that predict the future development of
NIDDM. In prospective studies of Pima Indians, the euglycemic insulin clamp provided measurements of peripheral
glucose utilization in the presence of maximally effective
insulin concentrations. The risk of future development of
NIDDM was primarily related to the severity of the insulin
resistance (8,9,22). Similarly, Martin et al. (7) used the
FSIVGTT to measure insulin sensitivity in a prospective
study of offspring of two parents with NIDDM. This study
confirmed that insulin resistance was the best predictor of
future risk of developing NIDDM.
Insulin dmciency. Tests of P-cell function are more problematic. The IVGTT is among the most commonly used tests.
First-phase insulin secretion (measured during the first 10
min of the test) is markedly impaired in patients with
established NIDDM (12). The response to other secretagogues is more difficult to measure because their effectiveness is modulated by the ambient level of plasma glucose
(12). When all individuals are studied at comparable levels of
glucose in plasma, patients with NIDDM also have diminished insulin secretion in response to other secretagogues
such as arginine and P-adrenergic agonists (12). Polonsky et
al. (11) used a more physiological test in which they measured the rate of insulin secretion during a 24-h period,
during which time the individual was eating normal meals
and doing relatively normal physical activities. These investigations confirmed the conclusion that NIDDM is associated
with a defect in insulin secretion (11). However, in apparent
conflict with the data obtained with the IVGTT (12), firstphase insulin secretion appeared to be relatively normal,
while second phase insulin secretion was the locus of the
major defect (11).
Moreover, as summarized above, studies of prediabetic
individuals are even more confusing. Most studies have
demonstrated that prediabetic individuals are hyperinsulinemic (7,9), but some studies have suggested the existence of
impaired insulin secretion (15-17). Several sophisticated
approaches have suggested the existence of subtle abnormalities in p-cell function early in the course of the disease,
even before the development of overt diabetes. For example,
in normal individuals there are rapid oscillations (with a
periodicity of -10 min) in the level of insulin in plasma.
O'Rahilly et al. (16) reported that these rapid oscillations are
absent in first-degree relatives of patients with NIDDM.
These observations may provide a marker for a defect in
P-cell function that occurs very early in the natural history of
NIDDM. In a similar effort to identify subtle defects in p-cell
function, several investigators have analyzed the nature of
immunoreactive insulin in plasma. This approach has led to
the conclusion that the percentage of proinsulin-like component in the plasma of patients with NIDDM is increased
(23,24). In conclusion, although the data are not definitive,
several lines of evidence suggest that subtle defects in p-cell
TABLE 1
Defined genetic loci at which mutations have been reported as primary causes of NIDDM
Genetic locus
Insulin
Insulin receptor
Glucokinase
Insulin receptor substrate-1
Mitochondria1 DNA
Pathophysiological defect
References
Impaired insulin secretion (insulin molecule with decreased
bioactivity)
Insulin resistance (defect in first step of insulin action)
Impaired insulin secretion (defect in glucose-sensing
mechanism of @-cell)
Insulin resistance (? defect in one branch of pathway of insulin
action within the target cell)
? Impaired insulin secretion
function may be detected before the development of overt
diabetes and hyperglycemia.
NIDDM is a syndrome of multiple diseases with differe n t causes. In recent years, it has become obvious that the
syndrome of NIDDM is not a single disease, but a collection
of multiple diseases with d i e r e n t causes. For example,
specific mutations have been identified in a small percentage
of patients with unusual variants of NIDDM (Table I).
Mutations in some genes (e.g., insulin receptor, insulin
receptor substrate-1) appear to cause insulin resistance
(25-27), and mutations in other genes (e.g., insulin, glucokinase) impair p-cell function (28-31). However, specific mutations have not yet been identified in the majority of patients
with NIDDM. In addition, there appears to be another source
of diversity. Especially in populations with a high prevalence
of IDDM (e.g., in Scandinavia), some patients who appear to
have NIDDM may actually have a mild form of autoimmune
disease causing partial destruction of pancreatic p-cells
(3234). In some patients, this may eventually progress to
IDDM. Nevertheless, insulin deficiency seems likely to be the
primary pathophysiological defect in NIDDM caused by
autoimmune destruction of pancreatic p-cells. Obviously,
with this degree of diversity, it is hardly surprising that
clinical investigators have not reached agreement as to the
identity of the primary cause of NIDDM.
LESSONS FROM MOLECULAR GENETICS
Molecular genetics provides an opportunity to identify mutations in specific genes that are responsible for causing
disease. So far, several genes have been identified as the
locus of mutations that cause syndromes associated with
non-insulin-dependent forms of diabetes (Table 1). Because
the nature of the mutation is known precisely, there can be
little doubt as to the causal role of the genetic defect in the
pathogenesis of the disease in these patients. These genetic
defects can viewed a s primary causes of diabetes. (The term
primary is appropriate in the sense that the presence of the
mutation is not secondary to some other cause of diabetes.)
Nevertheless, because the common form of NIDDM is likely
to have polygenic inheritance, an individual with NIDDM is
likely to have mutations in more than one gene. In that sense,
there may be more than one primary cause of NIDDM, even
in an individual patient. Thus, these patients provide illustrations of what is possible. Is it possible for a patient to
become diabetic as the result of insulin resistance in the
absence of insulin deficiency? Is it possible for mild insulin
deficiency to cause diabetes in the absence of insulin resistance?
Insulinresistance can cause diabetes. Numerous patients have
been reported t o develop diabetes as a result of mutations in
the insulin receptor gene (25). Not only are these patients
severely resistant to insulin, but they generally have striking
elevations of plasma insulin (e.g., fasting plasma insulin
>I00 ~Ulml).Thus, these patients provide unambiguous
evidence that insulin resistance can be a sufficient cause of
diabetes despite supranormal levels of insulin. Moreover,
these patients have many clinical characteristics that resemble the common forms of diabetes-including a predisposition to develop such chronic complications as retinopathy,
nephropathy, and neuropathy. Nevertheless, it is equally
striking that many of these severely insulin resistant patients
with mutations in the insulin receptor gene are not diabetic
(25). Moreover, even among those patients who ultimately
become diabetic, the diabetes is not necessarily present
during childhood. Because her medical history is particularly
instructive in this regard, we will briefly summarize the case
of one patient @atient A-5) with the syndrome of type A
insulin resistance caused by a homozygous missense mutation in the insulin receptor gene. When she was 8 years old,
her fasting plasma insulin level was extremely high (-900
pU/ml) although her FPG level was within normal limits (35).
However, by the time she was 17 years of age, her FPG had
risen to 12.3 mM (221 mgldl) and her fasting plasma insulin
had fallen to 350 pU/ml (36). At this time, therapy with
insulin was instituted, and she required in excess of 2,000 U
per day of insulin to regulate her plasma glucose. Thus, even
in this severely insulin resistant patient, her pancreas was
able to provide sufficient insulin to prevent diabetes for
nearly two decades. Furthermore, even at the time she
became diabetic, she was hardly insulin deficient given her
fasting plasma insulin of 350 ~ U l m l .Nevertheless, it is
tempting to speculate that the development of diabetes was
precipitated by the relative decline in her pancreatic function. Clearly, knowing the cause of the deterioration of her
p-cell function in late adolescence would be of interest.
Diabetes caused by insulin deficiency. IDDM provides the
clearest example that severe insulin deficiency can cause
diabetes. Furthermore, at least two genetic diseases provide
evidence that partial impairment of p-cell function can
contribute to the cause of a non-insulin-dependent form of
diabetes: mutations in the insulin gene (28) and maturityonset type diabetes of the young caused by mutations in the
glucokinase gene (29-31). Mutations in the insulin gene lead
to the synthesis of an insulin molecule with impaired biological activity. Mutations in the glucokinase gene impair insulin
secretion by compromising the function of the glucosesensing mechanism in the p-cell. Thus far, mutations in the
insulin and glucokinase genes have only been identified in
the heterozygous state; homozygotes have not been identified. The presence of a normal allele in all affected individuals permits preservation of -50% of normal function.
Accordingly, patients with mutations in either of these genes
DIABETES, VOL 43, JUNE 1994
are at risk of developing a mild form of NIDDM. However,
there is only incomplete penetrance of the phenotype of
overt diabetes. For example, only half of individuals with
mutations in the glucokinase gene are diabetic (30). Moreover, the metabolic abnormality appears not to be progressive, i.e., the prevalence of diabetes appears not to increase
with age. What determines which patients with mutations in
the insulin or glucokinase genes will become diabetic is not
clear. Nevertheless, susceptibility to develop diabetes may
be modulated by other genetic factors, e.g., other genes that
affect either insulin sensitivity or p-cell function. Furthermore, it is virtually certain that environmental factors (e.g.,
nutrition and physical exercise) can modulate the expression
of the diabetic phenotype.
CONCLUSIONS
A large body of evidence demonstrates thatboth insulin resistance
and insulir~deficiencycontribute to the pathogenesis of NIDDM. In
selected cases, mutations in single genes have been identjfied as
the cause of diabetes. These patients demonshate the fact that,
when the clefect is severe, a selective defect in either insulin action
or in insulin secretion is sufficient to cause diabetes. However, in
most patients with the common form of NIDDM, the primary
causes of the disease have not been idenaed at a molecular level.
Nevertheless, there is general agreement that the majority of
patients with NIDDM are insulin resistant, and that the develop
ment of insulin resistance is an early event in the natural h k b r y of
the disease. Indeed, insulin resistance is probably the single best
predictor of the future development of NIDDM in populations at
high risk of developing the disease (7-9). Furthermore, several
lines of evidence strongly suggest that genetic factors contribute
importantly to determining an individual's sensitivity to insulin,
and that iredin resistance contributes as a cause of NIDDM in
most patients.
In addition, there is general agreement that insulin secretion is impaired in most patients with overt NIDDM
(1 1,12,16). However, whether the defect in insulin secretion
develops early in the disease remains controversial. In addition, the most recent studies have suggested that impaired
insulin secretion is not a powerful predictor of future development of NIDDM (7,8). On the other hand, these epidemiological studies do not definitively address the question of
whether an independent genetic defect may lead to impaired
p-cell function. Nevertheless, many insulin-resistant individuals may secrete sufficient insulin to prevent the development of NIDDM for many years. How, then, can one explain
the fact that p-cell function deteriorates in the patients who
ultimately develop NIDDM? Although not proven, genetic
factors seem likely to be the primary determinants of impaired insulin secretion in these individuals. Fortunately, one
can be opt;imistic that future molecular genetic studies will
eventually resolve this debate by precisely identifying the
primary causes of NIDDM at a molecular level.
ACKNOWLEDGMENTS
We gratefully acknowledge a post-doctoral fellowship grant
awarded to Y.I. by the Juvenile Diabetes Foundation International.
In addition, we thank Dr. Marc Reitman for helpful discussion and critical reading of the manuscript.
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DIABETES, VOL. 43, JUNE 1994