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-Cell Function as Explanations for Metabolic Diversity1 ,2
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and
*
Department of Veterans Affairs, Puget Sound Health Care System and
**
Harborview Medical Center, Seattle, WA 98108; and
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80267
3To whom correspondence should be addressed. E-mail: skahn{at}u.washington.edu.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRelationship between body fat...Insulin sensitivity as a...Defective {beta}-cell function...SUMMARYREFERENCES |
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-cell function. Thus, we have learned that
although insulin resistance is usually associated with obesity, even
lean subjects can be insulin resistant due to the accumulation of
visceral fat. Insulin sensitivity and -cell function are also
intimately linked. The hyperbolic relationship between these two
parameters explains why insulin-resistant individuals have markedly
enhanced insulin responses, whereas subjects who are insulin sensitive
exhibit very low responses. Failure to take into account this
relationship will lead to erroneous conclusions. By accounting for this
important interaction, it has been clearly demonstrated that subjects
at high risk of developing type 2 diabetes (older individuals, women
with a history of gestational diabetes or polycystic ovary syndrome,
subjects with impaired glucose tolerance and first-degree relatives
of individuals with type 2 diabetes) have impaired -cell function.
Furthermore, the progression from normal glucose tolerance to impaired
glucose tolerance and type 2 diabetes is associated with declining
insulin secretion.
KEY WORDS: • obesity • intra-abdominal fat • impaired glucose tolerance • gestational diabetes • polycystic ovary syndrome
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRelationship between body fat...Insulin sensitivity as a...Defective {beta}-cell function...SUMMARYREFERENCES |
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. This increase in the prevalence of
obesity appears to be associated with an increased prevalence of risk
factors for cardiovascular disease and type 2 diabetes, including
hypertension and reduced glucose tolerance. Although coronary artery
disease and dyslipidemia are also common, their incidence is declining
in part due to improved treatment, which includes nutritional and
exercise interventions (2)
.
One component of the work examining the pathogenesis of states of
altered lipid, glucose and blood pressure regulation has focused on the
potential role of insulin resistance. Recognition that these are
associated with insulin resistance has led to the description of what
is now known as the metabolic syndrome, insulin resistance syndrome or
Syndrome X (3)
. Although it has been demonstrated
conclusively that obesity is associated with insulin resistance, the
importance of the pattern of body fat distribution to the insulin
resistance that characterizes this syndrome has been less well studied.
It is our thesis and that of others that it is likely that a central
pattern of body fat distribution is a major cause of insulin resistance
and may explain the heterogeneity observed when examining insulin
sensitivity in different population groups.
The pathogenesis of complex diseases such as type 2 diabetes, familial
combined hyperlipidemia, hypertension and polycystic ovary syndrome
that are commonly associated with insulin resistance frequently
requires the presence of at least one other factor. Type 2 diabetes is
one of the best examples because hyperglycemia is clearly the result of
the interaction of defects in both insulin sensitivity and -cell
function (4)
. In trying to discern the pathogenesis of
this disease process, it has become clear that when one of these two
critical factors is considered alone, erroneous conclusions may be
drawn. Thus, with the realization that insulin sensitivity is a major
determinant of the degree of -cell function and that interpretation
of -cell function must be done in the light of the prevailing degree
of insulin sensitivity (5
,6)
, it has become clear that
defects in islet -cell function are absolutely critical to the
development of type 2 diabetes. Furthermore, with the use of this
approach, it has been demonstrated that defects in -cell function
are present long before the diagnostic criterion for diabetes has been
met (7
8
9
10
11
12
13
14)
.
In this review, we will address a number of these issues, highlighting
possible reasons for metabolic diversity. First, the importance of body
composition and body fat distribution to insulin sensitivity will be
examined. Second, the effect of insulin sensitivity on -cell
function and delineation of the nature of this relationship will be
discussed. Finally, knowledge of this relationship between insulin
sensitivity and -cell function will be used to highlight the
importance of alterations in insulin secretion on glucose tolerance in
states of health and disease.
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Relationship between body fat distribution and insulin sensitivity |
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TOPABSTRACTINTRODUCTIONRelationship between body fat...Insulin sensitivity as a...Defective {beta}-cell function...SUMMARYREFERENCES |
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,16)
. Studies examining this issue
have concluded that the obesity-associated defect in insulin
sensitivity is the result of both pre- and postreceptor abnormalities
(17)
. However, even with the tremendous advances in
molecular biology and the identification of many of the molecules
involved in the insulin signaling cascade (18)
, the
mechanism(s) underlying this abnormality remains unclear.
The search for the elusive genetic or environmental factor(s)
responsible for insulin resistance is ongoing, and the body of work
that has been conducted to examine the role of body adiposity and fat
distribution on insulin sensitivity has also grown. Unfortunately, many
investigators studying metabolic diseases have simply used body mass
index (BMI) as a measure of relative body size or obesity and attempted
to match groups for this variable, without considering that BMI does
not account for the fact that people with similar BMI may have widely
varying distribution of their adipose tissue. This is critical because
as discussed a little later, it appears that central adiposity is a
more important determinant of insulin sensitivity than body size alone.
Thus, when we examined the relationship between insulin sensitivity and
BMI in a group of 93 healthy subjects <45 y old, we found that these
two variables are not simply linearly related (6)
. Rather,
as illustrated in Figure 1
, even individuals who would be considered to be lean (BMI < 25
kg/m2) had a broad range of insulin sensitivity
with some of these apparently lean subjects having insulin sensitivity
values that were as low as those observed in individuals who would be
considered to be obese and insulin resistant.
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, age
(20
,21)
, acute exercise (22)
, physical
fitness (23)
, dietary nutrients (24)
,
medications (25
,26)
and body fat distribution
(27
28
29
30
31)
. However, when one considers a group of healthy
subjects in a population, genetic mutations associated with insulin
resistance are rare. For instance, in a cohort of markedly
insulin-resistant individuals, two different dominant negative
mutations of the peroxisome proliferator activating receptor-
could
explain <4% of these cases of extreme insulin resistance
(19)
. Thus, a genetic alteration that would explain a
large number of the "garden variety" cases of insulin resistance
seems unlikely. When considering what appear on the surface to be
factors that are not genetically determined, aging is associated with
declining insulin sensitivity (20
,21)
, whereas exercise
appears to have both acute and chronic effects to improve insulin
sensitivity (22
,23)
. However, it should be recognized that
even the long-term effect of exercise training on insulin
sensitivity is relatively short lived, waning significantly within a
few days of stopping regular exercise (22
,32)
. The effect
of dietary constituents on insulin sensitivity appears to be age
related in part because aging is associated with a decline in the
body’s responsiveness to carbohydrate (24
,33)
. Thus,
consumption of the typical Western diet, which contains an increased
proportion of dietary fat and lower amounts of carbohydrate, tends to
promote a reduction in insulin sensitivity. This effect of dietary
constituents has been shown to be reversible when dietary carbohydrate
is increased for periods as short as 3 d (33)
.
Finally, in addition to their desired effects, a number of medications
including corticosteroids (25)
and nicotinic acid
(26)
produce insulin resistance, a fact that should be
borne in mind when using these agents. However, even when age is
considered in studies of insulin sensitivity in populations, there is
still a large residual variation, and diet and exercise appear to be
minor contributors.
Thus, it is becoming abundantly clear that the pattern of body fat
distribution is a major determinant of the residual variation of
insulin sensitivity. Accumulation of body fat centrally is associated
with insulin resistance, whereas distribution of body fat in a
peripheral pattern is less metabolically important from the standpoint
of impairing insulin action. However, although it is clear that central
adiposity is of greater importance metabolically
(28
,34
,35)
, there is still debate about which of the
central depots is more important. Although many groups, including our
own, have championed the role of the intra-abdominal depot
(27
28
29)
, others have proposed that it is central
subcutaneous fat accumulation that is the critical determinant of
reduced insulin sensitivity (30
,36)
.
In our studies using computerized tomography scan–based measures, we
have found that subjects with increased visceral or intra-abdominal
fat are more insulin resistant than those who have increased quantities
of centrally located subcutaneous fat. In our initial work in a small
cohort of Japanese Americans, we demonstrated that BMI was not
associated with insulin sensitivity but that the quantity of
intra-abdominal fat was strongly related to the minimal
model–derived measure of insulin sensitivity (29)
(Fig. 2
). However, this study was hampered in part by the small size of the
cohort. Thus, we have undertaken another study from which preliminary
data are now available (37)
. We have now examined >200
men and women who were middle aged and apparently healthy and confirmed
that intra-abdominal fat was the strongest predictor of insulin
sensitivity. Although subcutaneous fat was also related to insulin
sensitivity, this effect was much less than that seen with
intra-abdominal fat. Further analyses of these data revealed three
additional interesting points. First, the relationship between central
body fat distribution and insulin sensitivity was not a simple linear
function but was best represented by a complex nonlinear relationship.
Second, gender does not appear to affect the relationship between the
quantity of intra-abdominal fat and insulin sensitivity. Third, the
individual data demonstrated a large degree of overlap in the amount of
intra-abdominal fat between insulin resistant individuals with low
and high BMI. Interestingly, the two subjects with the most
intra-abdominal fat were equally insulin resistant but one had a
low and the other a high BMI.
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,38)
. However, this
intervention was also associated with the loss of peripheral fat and is
complicated by the effect of exercise per se to improve insulin
sensitivity (22)
. On the other hand, the results of our
weight loss study that are not confounded by any exercise effect
strongly suggest that intra-abdominal fat is critical. In a cohort
of 21 older men, we found that a 3-mo weight loss program was
associated with an average 10-lb (
4.5 kg; 10%) weight loss, of
which 80% was fat. This decrease in fat mass was associated with a
24% reduction in intra-abdominal fat area, a 58% improvement in
insulin sensitivity and the development of a less atherogenic lipid
profile (39)
. Similar findings of the effect of weight
loss on body fat distribution and insulin sensitivity were recently
reported by Goodpaster et al. (31)
. In summary, one of the most important factors determining insulin sensitivity in apparently healthy subjects is body fat distribution. Subjects judged to be lean by BMI criteria may be very insulin resistant if they have centrally distributed body fat. Although the issue of which of the central depots is the most important is still being debated and how these fat depots may predict this reduction in whole body insulin sensitivity is also unclear, it is apparent that marked variability in these parameters occurs in healthy subjects and may contribute to differences in disease risk among these individuals.
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Insulin sensitivity as a modulator of -cell function
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TOPABSTRACTINTRODUCTIONRelationship between body fat...Insulin sensitivity as a...Defective {beta}-cell function...SUMMARYREFERENCES |
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-cell is a complex event, which is modulated by a number of
different variables including the nature of the secretagogue, the
quantity of the secretagogue administered, the route of administration
of the stimulus, the prevailing glucose level at the time of
administration of the stimulus and finally, the prevailing degree of
insulin sensitivity (6
,40)
. When considering these
factors, it is clear that matching of these variables is essential when
assessing insulin secretion in healthy subjects and those with states
of reduced glucose tolerance; failure to do so can result in erroneous
conclusions.
The importance of the first four factors has become better understood
over the last two decades, whereas the importance of insulin
sensitivity as a determinant of the magnitude of the insulin response
had been less well studied. In fact, although it was well recognized
that obesity and its associated insulin resistance were associated with
hyperinsulinemia, both in the basal state and after stimulation of the
-cell with glucose and nonglucose secretagogues (16
, 41
42
43)
, the nature of this regulation was not determined until
more recently (6)
. With the application of measures of
insulin sensitivity, it appears that it is not obesity per se that is
responsible for the greater insulin responses, but that variations in
insulin sensitivity are responsible for modulating -cell function.
Thus, subjects with reduced insulin sensitivity have increased
responses to glucose and nonglucose secretagogues. On the other hand,
insulin responses are small when insulin sensitivity is high.
We have quantified the relationship between different measures of
-cell function and insulin sensitivity by assessing these two
variables in a large cohort of healthy subjects <45 y old
(6)
. As postulated by Bergman et al. (44)
, we
found that the relationship between insulin sensitivity and secretion
is nonlinear and best described by a hyperbolic function. The nature of
this relationship implies that the product of insulin sensitivity and
-cell function, often called the disposition index, is a constant
for a given degree of glucose tolerance. This hyperbolic relationship
exists whether -cell function is examined in response to glucose
(Fig. 3
) or nonglucose stimulation. Furthermore, these variations in insulin
release in response to changes in insulin sensitivity are the result of
changes in the secretory capacity of the -cell (6
,26)
.
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-cell and the peripheral tissues. Thus,
for glucose tolerance to remain constant when insulin sensitivity
varies, a proportionate and reciprocal alteration in insulin output has
to occur. This can best be visualized by examining another component of
the analysis that we performed. In this same large cohort of healthy
subjects, we determined the percentiles for the relationship between
insulin sensitivity and -cell function. The mean relationship was
represented as the 50th percentile. Enhanced -cell responses for the
degree of insulin sensitivity are represented by percentiles above the
50th, whereas reduced responses are represented below the 50th
percentile (Fig. 3)
. It would then be predicted that for glucose
tolerance to remain constant, the percentile ranking must remain
identical when insulin sensitivity changes. Thus, if insulin secretion
does not change appropriately, glucose tolerance will differ.
Whether this regulation of -cell function is governed by a central
neural process or is the result of a humoral metabolic signal, such as
free fatty acids, arising in the peripheral tissues, is unclear.
However, it is clear that this adaptive increase in insulin secretion
in response to the development of insulin resistance can occur
relatively quickly as demonstrated by an enhancement of insulin release
after only 2 wk of nicotinic acid–induced experimental insulin
resistance in young healthy subjects (26)
. Because the
disposition index declined, it appears that it may take longer for
complete adaptation to occur. Furthermore, although insulin secretion
increased in this study, this incomplete compensation was associated
with a mild deterioration of glucose tolerance, supporting the
importance of the feedback loop. However, it is also apparent from
other studies that complete adaptation can occur. Such complete
adaptation was demonstrated in a study of a group of older subjects who
underwent a 6-mo program of intensive exercise training
(23)
. In these subjects, a 36% improvement in insulin
sensitivity was balanced by a reciprocal 30% reduction in -cell
function, resulting in no change in either intravenous or oral glucose
tolerance. Thus, the -cells of older subjects appeared to adapt
almost perfectly to the increase in insulin sensitivity, aiming to
defend the state of reduced glucose tolerance.
The hyperbolic nature of the relationship between insulin sensitivity
and insulin secretion that we originally described in a cohort of
apparently healthy subjects has now also been demonstrated to be
present in a large group of Danish subjects (45)
and in a
cohort of Pima Indians (46)
. The nature of this
relationship also has important implications for the estimation of
-cell function in humans. Because differences in insulin sensitivity
must be balanced by reciprocal changes in -cell function in order to
maintain glucose tolerance, it is apparent that although insulin
responses may be identical in two groups of subjects, if insulin
sensitivity is not the same, then glucose tolerance will also differ
between the two groups. On the basis of the concept that -cell
function should be assessed relative to insulin sensitivity, subjects
with type 2 diabetes, those at risk for developing the disease and
those who progress from a state of normal glucose tolerance to
hyperglycemia have all been shown to have poorer -cell function than
controls with normal glucose tolerance (7
8
9
10
11
12
,14
47
,48)
.
This issue is discussed in the following section.
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Defective -cell function as a precursor to the development of
type 2 diabetes mellitus
|
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TOPABSTRACTINTRODUCTIONRelationship between body fat...Insulin sensitivity as a...Defective {beta}-cell function...SUMMARYREFERENCES |
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-cell function, studies of
groups of subjects at high risk of progression to type 2 diabetes have
demonstrated the importance of impaired -cell function to the
pathogenesis of hyperglycemia. In these high risk subjects, reduced
-cell function is evident at a time when the fasting plasma glucose
concentration is still well within the normal range. A selection of
these studies is illustrated in Figures 4
and
5
and described in greater detail below.
|
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, type 2 diabetes represents the extreme of defects
in both insulin sensitivity and -cell function. Most patients with
type 2 diabetes have insulin resistance as well as a markedly reduced
insulin response to glucose (47)
. Moreover,
cross-sectional studies have demonstrated that high risk groups
represent a spectrum of abnormalities with some having severe
reductions in insulin sensitivity, others severe defects in -cell
function, and most having abnormalities in both.
It is well recognized that older subjects have an increased risk of
developing type 2 diabetes. In many instances, these subjects have
greater impairments in postprandial than fasting glucose. This
observation is explained by the association of aging with reductions in
both insulin sensitivity and secretion (21)
; as
illustrated in Figure 4
, the magnitude of the -cell defect in these
apparently healthy nondiabetic subjects is quite profound so that they
fall below the 5th percentile for persons aged 18–45 y
(23)
. Two syndromes in women, namely, gestational diabetes
and polycystic ovary syndrome, are known to place them at increased
risk of progressing to type 2 diabetes. At a time when they are not
pregnant and have normal fasting plasma glucose levels, women with a
history of hyperglycemia during a previous pregnancy can be
demonstrated to have reduced -cell function (7
8
9)
.
Although these women do exhibit an insulin response to glucose, they
are insulin resistant; in the presence of this resistance, they should,
if anything, have enhanced insulin release. Thus, the magnitude of the
impairment in -cell function can be shown to be quite severe when
the relationship between insulin sensitivity and insulin secretion is
considered (Fig. 4)
. The importance of defective insulin secretion as a
risk factor for diabetes was highlighted in a report of -cell
function in women with polycystic ovary syndrome and a family history
of type 2 diabetes (10)
. Similar to the women with a
history of gestational diabetes, these women demonstrated markedly
reduced glucose-stimulated insulin responses, especially when these
responses were assessed relative to their degree of insulin sensitivity
(Fig. 4)
. Another state that is well recognized to be a precursor to
type 2 diabetes is impaired glucose tolerance (50)
.
Although there has been debate about the relative importance of insulin
resistance and -cell dysfunction in the development of this state of
altered glucose metabolism, it is clear from an analysis using these
percentile plots that these individuals are insulin resistant; in fact,
they are as insulin resistant as the subjects with type 2 diabetes, but
they also have a marked impairment in their ability to release insulin
[(14)
; (Fig. 4)
]. The last set of cross-sectional
data was obtained in a group of healthy, nondiabetic, first-degree
relatives of individuals with type 2 diabetes. As illustrated in Figure 5
, individual subjects in this group exhibited broad ranges of insulin
sensitivity and insulin secretion. However, when these two parameters
are assessed in conjunction, it is apparent that many of them have
markedly reduced -cell function relative to their degree of insulin
sensitivity such that their percentile ranking is in the lower range
regardless of their absolute -cell function measurement, presumably
contributing to their high risk of subsequently developing type 2
diabetes (48)
.
The relevance and applicability of examining -cell function in
concert with insulin sensitivity have been further highlighted by some
recently reported longitudinal data obtained in Pima Indians
[(46)
; Figure 6
]. In this 5-y longitudinal follow-up study, a group of 48 subjects
was evaluated. At baseline, all had normal glucose tolerance. Of the
cohort, 17 subjects progressed from normal to impaired to diabetic
glucose tolerance, whereas 31 had normal glucose tolerance throughout.
As illustrated, at the first time point at which these subjects were
studied, those individuals who subsequently progressed already
manifested a reduction in -cell function compared with the
nonprogressors, despite the fact that at the time of this initial
evaluation they still had normal glucose tolerance. When followed over
time, the individuals who did not progress had small declines in
insulin sensitivity, which were matched by an appropriate increase in
insulin secretion; thus, this group followed their isotolerance line.
In contrast, the group of progressors had a similar small decline in
insulin sensitivity but rather than being compensated by increased
-cell function, insulin secretion declined progressively so that
these individuals deviated further and further from their starting
point and developed diabetes.
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-cell function can be
demonstrated to be a feature in many, if not perhaps the majority of
subjects at high risk of subsequently developing type 2 diabetes.
Interpretation of -cell function in the context of the degree of
insulin sensitivity is critical to defining the importance of defects
in -cell secretory function to progressive impairments of glucose
tolerance. |
SUMMARY |
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TOPABSTRACTINTRODUCTIONRelationship between body fat...Insulin sensitivity as a...Defective {beta}-cell function...SUMMARYREFERENCES |
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-cell function in the pathogenesis of metabolic disease processes
including type 2 diabetes has progressed in recent years. The new
understanding of the relationships between body fat distribution and
insulin sensitivity, and insulin sensitivity and -cell function has
explained some of the observed diversity in metabolic parameters by
clarifying how adiposity contributes to insulin resistance and has
reemphasized the importance of -cell dysfunction to hyperglycemia.
Ultimately, this information should allow us to develop approaches that
may change these parameters appropriately to improve human health.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by National Institutes of Health grants DK-02654, DK-17047, DK-31170, DK-35816, AG-06581, AG-08673, HL-30086 and RR-37 and the Medical Research Service of the Department of Veterans Affairs.
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