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Special Features |
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108
Address all correspondence and requests for reprints to: Steven E. Kahn M.B., Ch.B., Veterans Affairs Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, Washington 98108. E-mail: skahn{at}u.washington.edu
The pathogenesis of type 2 diabetes is complex and in most instances clearly requires defects in both ß-cell function and insulin sensitivity (1). Together, these abnormalities result in increased rates of glucose release by the liver and kidney as well as decreased clearance from the circulation (2, 3). For the last decade, a great deal of attention has been directed at further understanding the role of insulin resistance as an important contributor to the development and maintenance of the hyperglycemia of type 2 diabetes. During this same period, the well described vital role of the pancreatic islet, and specifically the ß-cell, in this process has been largely neglected.
Perhaps one of the most striking and sobering findings of the United Kingdom Prospective Diabetes Study (UKPDS) was the reaffirmation of the clinically recognized progressive nature of type 2 diabetes (4). Every day clinicians all over the world find themselves struggling to maintain good glycemic control in subjects with type 2 diabetes, and the results of this study clearly confirm that, even with the use of algorithmic approaches aimed at maintaining superb glucose control, it is very difficult to maintain individuals at the desired levels of glycemia. In fact, in the UKPDS after 9 yr only 25% of the subjects in the intensive treatment arm were achieving a HbA1c less than 7% with monotherapy alone (5). When one examines the outcome in the different groups based on their initial assignment, this goal was attained in 8% of subjects given dietary therapy, 13% receiving metformin, 24% taking sulfonylureas, and 42% of individuals using insulin. The reason(s) for the progressive deterioration in glycemic control observed in the UKPDS have been addressed using the Homeostasis Model Assessment (HOMA). This model provides a simple approach for estimating insulin sensitivity and ß-cell function and lends itself to use in large studies such as the UKPDS. With this approach, the UKPDS has clearly demonstrated that the progressive nature of diabetes in this cohort of individuals with recently diagnosed type 2 diabetes is an ongoing decline in ß-cell function without a change in insulin sensitivity (6, 7). It is of interest that a similar observation was made in the Belfast diet intervention study in which the progressive deterioration of glycemic control was associated with a progressive deterioration of ß-cell function without a change in insulin sensitivity (8). However, when using simple approaches such as HOMA, one does not necessarily gain insights into what may be the characteristics and underlying pathology responsible for the observed changes.
This Clinical Review focuses on the role of the ß-cell in the pathogenesis of type 2 diabetes. The recent evidence documenting support for the existence of this defect well before the diagnostic criteria for diabetes are attained will be discussed. Finally, while as yet we do not understand all the possible mechanisms responsible for these functional alterations, a synopsis of the information that is being gathered and will likely bear on our success at treating this relentless metabolic disorder will be provided.
The nature of ß-cell dysfunction in type 2 diabetes
It is well accepted that for hyperglycemia to exist in type 2 diabetes, ß-cell dysfunction has to be present. This alteration is manifest in a number of different ways including reductions in insulin release in response to glucose (9, 10, 11) and nonglucose secretagogues (12, 13, 14, 15), changes in pulsatile (16) and oscillatory insulin secretion (17), an abnormality in the efficiency of proinsulin to insulin conversion (18, 19, 20, 21, 22, 23, 24), and reduced release of islet amyloid polypeptide (IAPP), also known as amylin (25, 26, 27).
Reductions in insulin release can be demonstrated in individuals with
type 2 diabetes following oral glucose loading (Refs. 9, 10, 27 and 28 ; Fig. 1A
).
In these individuals, the absolute responses occurring early (typically
within 30 min) after administration of glucose are reduced whereas
those that are observed later in the test may be greater due to the
fact that lack of early insulin secretion leads to hyperglycemia later
in the test (9, 10). The nature of the relationship
between this early phase insulin response and glucose tolerance has
been demonstrated to be nonlinear in nature (Ref. 27 ; Fig. 1B). Thus, small decreases in this early response can have dramatic
effects on the later glucose excursion in subjects with diabetes
whereas larger changes may have a smaller effect in individuals with
normal glucose tolerance. Although it can be demonstrated that type 2
diabetes is associated with a reduction in early insulin release as a
measure of ß-cell function, the different secretory functions
involved in this process cannot be discerned from this simple test.
Thus, delineation of the different components of ß-cell function has
been addressed primarily using iv testing.
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Besides its ability to directly stimulate insulin release, glucose also
modulates the ß-cell’s response to other secretagogues. The iv
administration of a nonglucose secretagogue such as the amino acid
arginine (15), peptides such as secretin
(37), the ß-adrenergic agonist isoproterenol
(37), and sulfonylureas such as tolbutamide
(38) is associated with an acute insulin response. When
the same quantity of the nonglucose secretagogue is injected in the
presence of an elevated glucose level, the magnitude of the response is
increased (14, 15). This effect of glucose to enhance the
insulin response to these other secretagogues is termed glucose
potentiation (14, 39). The magnitude of these responses is
"normal" in age and obesity-matched healthy and type 2 diabetic
subjects. However, when the glucose levels are matched, these responses
are clearly diminished in type 2 diabetes (14). When a
full dose-effect curve from 100–600 mg/dl glucose is performed, it has
been demonstrated that the maximum secretory capacity of the ß cell
is diminished whereas its half-maximum or sensitivity to glucose is
unchanged (15). The severity of this reduction in ß-cell
secretory capacity is related to the fasting glucose level in an
inverse, nonlinear manner (Ref. 40 ; Fig. 2). The nature of this relationship
suggests that, as with many other endocrine organs, a significant
proportion (50–75%) of the secretory capacity of the cell is lost by
the time fasting hyperglycemia develops. However, because fasting
hyperglycemia is a relatively late event in the pathogenesis of
diabetes and ß-cell dysfunction is progressive, lesser reductions in
ß-cell secretory capacity will be associated with reduced glucose
tolerance before fasting hyperglycemia is manifest. Such a postulate is
supported by the UKPDS in which ß-cell function was reduced some 50%
at the time of diagnosis of fasting hyperglycemia (6, 7).
The finding of a reduction in ß-cell secretory capacity has
implications for possible mechanisms responsible for the loss of
ß-cell function in type 2 diabetes as a reduction in secretory
capacity has been associated with experimental, generalized reductions
in islet mass (41, 42).
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Two other components related to ß-cell function are worthy of mention as they are both disturbed in type 2 diabetes. The first relates to the insulin biosynthetic process. Insulin production requires the cleavage of insulin out of its larger precursor peptide proinsulin, resulting in the formation of insulin and C-peptide. This process occurs within the secretory granule while it transits the ß-cell and matures and involves the action of two endoproteases, PC1/3 and PC2 (50, 51, 52). When the contents of the granule are acutely released in response to ß-cell stimulation, in healthy subjects about 2% of all insulin-like immunoreactivity is composed of intact proinsulin and its cleavage intermediate des-31,32-split proinsulin (19, 24), suggesting that under normal conditions proinsulin to insulin processing is incomplete. In type 2 diabetes, the efficiency by which the cell processes proinsulin is reduced. Thus, in hyperglycemic individuals, following acute stimulation the proportion of proinsulin-like molecules is increased to between 5% and 8% (19, 24). In contrast to the findings examining acutely released products, in the fasting state, the proportion of circulating proinsulin-like molecules is approximately 15% in healthy subjects and is increased 2- to 3-fold in subjects with type 2 diabetes (18, 19, 20, 21, 22, 23, 24). These increased proportions in the basal state are due to the slower metabolic clearance rate of proinsulin-related peptides (53). The degree of elevation in proinsulin-like molecules is linearly related to the degree of hyperglycemia suggesting that the proportion of proinsulin is a marker of the magnitude of ß-cell dysfunction (22, 40). The basis for this disproportionate increase in the release of proinsulin-like molecules in type 2 diabetes is still not understood. Two different hypotheses have been proposed. One suggests that this inefficiency represents a primary defect in ß-cell function (54), whereas the other proposes that increased secretory demand results in the release of a less mature ß-cell granule at a time when proinsulin to insulin conversion is incomplete (55).
The second interesting component relates to the description in 1987 of a new ß-cell peptide. This 37 amino acid peptide, designated IAPP, was isolated from the amyloid deposits that are commonly found in the islets of subjects with type 2 diabetes (56, 57). IAPP has been colocalized with insulin in the ß-cell secretory granule (58) and, therefore, is secreted along with insulin in response to glucose and other stimuli (59). In keeping with its cosecretion with insulin, release of IAPP is diminished in individuals with type 2 diabetes (25, 26, 27). Studies examining whether IAPP can induce insulin resistance or impair ß-cell function have produced variable and nonconclusive results (60, 61, 62). The native peptide has however been demonstrated to slow gastric emptying and, thus, delay glucose absorption (63). Whether deficient IAPP release contributes to the pathophysiology observed in the diabetes disease process is still unclear.
Thus, it is clear that ß-cell dysfunction exists in individuals with type 2 diabetes. This dysfunction is global involving a number of different measures of the functional integrity of the ß-cell. Furthermore, the degree of ß-cell dysfunction is related to degree of hyperglycemia, suggesting that if hyperglycemia and ß-cell dysfunction are present at the time of diagnosis, dysfunction must also be present before the fasting and/or 2-h glucose levels reaching the diagnostic cutpoints for diabetes. Supporting evidence for this is presented next.
ß-cell dysfunction is present before the development of type 2 diabetes
Data from the UKPDS suggests that the onset of the ß-cell dysfunction associated with diabetes occurs well before the development of hyperglycemia, and may commence many years before diagnosis of the disease (7). However, this suggestion is based on an extrapolation of findings in subjects with established type 2 diabetes. While this concept is gaining support, it has not been a universally accepted idea. Thus, although there is no doubt that defects in ß-cell function exist in all subjects with hyperglycemia, when this abnormality begins and what factors may be responsible for producing this change has been a subject of great debate. Part of the failure to recognize the existence of defects in ß-cell function early in the course of the development of diabetes has been related to the failure to consider that the systems involved in glucose regulation cannot always be assessed in isolation. Recent advances in our understanding of the modulating effect of insulin sensitivity on ß-cell function have brought a new understanding and therefore a new interpretation to the assessments of insulin release in individuals at risk of developing type 2 diabetes.
Insulin sensitivity has long been recognized to be an important factor
determining the magnitude of the insulin response to ß-cell
stimulation (64, 65). Thus, when ß-cell function is
assessed, obese individuals who are insulin resistant manifest greater
responses than age-matched lean subjects (10, 12, 66, 67, 68).
The concept that a feedback loop between the insulin-sensitive tissues
and the ß cell exists and determines this adaptive response was first
advanced by Bergman et al. (69) and confirmed
by us in humans (65). The nature of this relationship is
such that insulin sensitivity and ß-cell function are inversely and
proportionally related so that the product of these two parameters is
always a constant (Fig. 3). This constant
is referred to as the disposition index (70). Our
understanding of the nature of this relationship has also highlighted
the fact that if two individuals have identical absolute insulin
responses, the only way their ß-cell function can be considered to be
similar is if they have identical insulin sensitivity. Conversely, if
these same individuals differ in terms of insulin sensitivity, it has
to be concluded that their ß-cell function differs.
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and 5). Using this approach, we have found
that the vast majority of individuals who have two first-degree
relatives with type 2 diabetes fall below the mean (50th percentile)
for the relationship between insulin sensitivity and insulin secretion,
in keeping with their high-risk status (unpublished observation). In
keeping with the observations in first-degree relatives and the fact
that type 2 diabetes is an inherited, polygenic syndrome, it is
interesting to note that a recent study examining the heritability of
ß-cell function, assessed in relation to insulin sensitivity
(SI x AIRglucose), demonstrated a heritability of
67% in 120 subjects who had either impaired or normal glucose
tolerance and 70% when only the 94 normal glucose tolerant individuals
were examined (82). Interestingly, in this same study,
when AIRglucose was considered alone, it could not be shown to be an
inherited phenotype (82). Thus, it would seem that
attempts to identify ß-cell defects contributing to typical type 2
diabetes are likely to be more successful if they take into account the
modulating effect of insulin sensitivity on ß-cell function.
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). Seventeen of these individuals
progressed from normal glucose tolerance through impaired glucose
tolerance to diabetes. In the subjects who progressed to hyperglycemia,
insulin secretion declined progressively by 78% whereas insulin
sensitivity declined by 14%. In the 31 individuals who did not develop
diabetes, a similar 11% decrease in insulin sensitivity was associated
with a 30% increase, rather than a decrease, in insulin secretion.
Examination of the data obtained in these two groups at baseline
provides another interesting observation. At their initial assessment,
when all subjects had normal glucose tolerance, those subjects who
comprised the group that subsequently progressed to diabetes had
ß-cell function that was markedly decreased for their degree of
insulin resistance compared with those subjects who did not progress
over time. In fact, at the time of this baseline assessment, these
individuals fell below the 95th confidence interval for the
relationship between insulin sensitivity and insulin secretion, in
keeping with the existence of a severe impairment of ß-cell function
(Fig. 6). With the concept of a hyperbolic relationship between insulin
sensitivity and ß-cell function in mind, reexamination of data from
other studies of high-risk subjects with normal glucose tolerance would
suggest that the conclusions in those papers regarding ß-cell
function may, in fact, be erroneous given the lack of a difference in
insulin levels despite the presence of insulin resistance in high-risk
subjects (84, 85, 86, 87, 88, 89, 90).
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If progressive ß-cell dysfunction is likely to be an important component in the pathogenesis of type 2 diabetes, it would be anticipated that other changes in ß-cell function may also be present before the development of fasting hyperglycemia. A disproportionate elevation in proinsulin levels has been demonstrated in individuals who typically have reductions in glucose-stimulated insulin secretion such as individuals with impaired glucose tolerance (34, 95), and such an alteration in proinsulin levels can be found at baseline in subjects who progress to type 2 diabetes over a 5-yr follow-up period (Ref. 96 ; S. Haffner, personal communication). As would be anticipated for scenarios that represent milder alterations in ß-cell function, the magnitude of these changes is intermediate between those in healthy subjects and those with diabetes. These data suggest that alterations in the efficiency of proinsulin to insulin processing probably occur before the time of clinical diagnosis.
In keeping with the changes in insulin secretion, the release of IAPP is also diminished in groups of subjects with impaired glucose tolerance (26, 27). The known colocalization of IAPP with insulin in the same secretory granules (58) and the corelease of these two peptides (27, 59, 97, 98) suggests that insulin sensitivity is likely to also be an important modulator of IAPP secretion and plasma levels. We have shown this to be the case (99), and using this information, we have recently been able to demonstrate that IAPP release is diminished in first-degree relatives of individuals with type 2 diabetes, when considered in light of the prevailing degree of insulin sensitivity (100). However, while IAPP release is reduced, it does not seem to provide any additional information beyond that obtained with insulin as a marker of ß-cell function.
In summary, examination of a number of different parameters of ß-cell
function highlight that it is reduced well before the onset of
hyperglycemia and that this seems to be a generalized event. The effect
of this progressive decline in ß-cell function is a transition from
normal glucose tolerance through impaired glucose tolerance to diabetes
(Fig. 7). The mechanism(s) that underlies
this change and the progressive decline in this measure is the subject
of a great deal of research.
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A number of different hypotheses have been advanced as explanations for the development of ß-cell dysfunction in type 2 diabetes. These include ß-cell exhaustion due to the increased secretory demand arising from insulin resistance (101), desensitization of the ß-cell due to the elevations in glucose (102, 103), lipotoxicity (104), and a reduction in ß-cell mass, the latter possibly due to amyloid deposition (105, 106). The argument made for the existence of a ß-cell defect in high-risk subjects and the progression thereof would suggest that these alterations should also be present before the clinical diagnosis of diabetes. What evidence then supports one or more of these possibilities?
It is well accepted that under normal circumstances insulin resistance increases the secretory function of the ß-cell (64, 65). This increase in the need for insulin biosynthesis and release has led to the suggestion that over a prolonged period of time, the increasing demand associated with increasing resistance will result in "exhaustion" of the ß cell so that it will ultimately fail (101). There are a number of observations that would tend to argue against this as a primary mechanism involved in the pathogenesis of type 2 diabetes. First, insulin resistance is common, occurring in nearly all obese subjects (65, 68, 107). However, even though diabetes is more prevalent in obese subjects, only a small proportion of obese individuals ultimately develop diabetes (108). Second, the recent longitudinal data from the Pima Indians highlights the fact that ß-cell function is enhanced in apparently healthy subjects as insulin resistance progresses (83). Third, induction of short-term experimental insulin resistance with nicotinic acid is associated with an adaptive increase in ß-cell function manifest as increased insulin release and a decrease in the proportion of proinsulin in plasma (109, 110). Therefore, it would seem that a failure to adequately adapt to insulin resistance may be due to a genetically programmed ß-cell abnormality associated with an inability of the normal ß-cell to adapt to insulin resistance and increased secretory demand thus uncovering a defect in ß-cell function. On the other hand, the ß-cells in those without such a genetic lesion would adapt and prevent the development of hyperglycemia.
Glucose has been suggested to not only be a ß-cell stimulant but to also potentially modify ß-cell function in a deleterious manner. This concept is known as "glucose toxicity" or "glucose desensitization" (102, 103). It has been demonstrated in vitro when islets or ß-cell lines have been exposed to increased glucose concentrations (103) and in vivo in animal models in which ß-cell mass has been surgically reduced (111) or glucose levels have been dramatically increased by administration of a continuous glucose infusion (112). All these instances have been associated with reductions in insulin secretion in response to typical secretagogues including glucose itself. In vitro, the increased glucose levels have been associated with a reduction in the expression of the insulin and PDX-1 genes (113), the latter the gene responsible for regulation of ß-cell replication (114). Balancing these findings are observations in humans that would suggest that glucose toxicity may not be a primary factor in the loss of ß-cell function observed in individuals as they progress from a state of high risk to fasting hyperglycemia or possibly even in the early stages of diabetes. Thus, in apparently healthy human subjects, the continuous infusion of glucose for periods of up to 42 h is not associated with a decrease in insulin release but rather has been shown to increase the first- and second-phase insulin responses to iv glucose (115, 116) and to enhance the potentiating effect of glucose on insulin secretion (117). The same intervention in individuals with type 2 diabetes does not result in these changes suggesting that prior prolonged exposure to hyperglycemia may deleteriously impact this adaptive response (118). It is of interest that the glucose levels attained in these studies in healthy subjects were equivalent to or exceeded those that have been shown to be associated with the loss of the first-phase response in subjects at high risk of developing the disease (11). In addition to the findings regarding stimulated secretion, infusion of glucose has been demonstrated to produce changes that suggest that the efficiency of proinsulin processing is enhanced (119). This latter finding is of interest as it has been demonstrated that the enzymes responsible for proinsulin to insulin conversion within the ß-cell are up-regulated by exposure to glucose (120, 121). Whether this functional change does not occur in the presence of diabetes is unknown. Finally, the findings in the UKPDS would suggest that in the early stages of diabetes, glucose is unlikely to be a critical factor in determining the progression of ß-cell dysfunction. This suggestion comes from the observations made in the group who received intensive therapy. In these individuals, glucose control was normalized the first year after commencement of the intervention, based on the reduction of the hemoglobin A1c level into the normal range. Despite this "normalization" of glucose levels and continuation of the therapy that had achieved this level of control, the disease progressed so that over time hyperglycemia returned and worsened (4). Based then on these series of observations, it would seem that glucose may be a factor in reducing ß-cell dysfunction in type 2 diabetes but that this effect is likely to occur later rather than earlier, and may well contribute to ß-cell dysfunction once this secretory abnormality is present.
While we routinely use glucose as the substrate we evaluate when
managing diabetes clinically, the disease is a global metabolic
disorder that is also characterized by changes in fat and protein
metabolism. Thus, it is of interest that recent data obtained in animal
models of diabetes have suggested the possibility that changes in lipid
metabolism may contribute to the development of ß-cell dysfunction
(104). In fact, morphological studies of pancreas samples
from rodent models of diabetes have demonstrated the accumulation of
triglyceride within islets (122). Whereas it has been
demonstrated that lipid accumulates in ß-cells in humans and that
this accumulation is increased in older subjects (123),
studies of this morphological change have not been reported in humans
with type 2 diabetes. Because it is unclear whether it is a causative
factor in the development of ß-cell dysfunction, this morphological
change should be evaluated to determine whether it occurs in human
diabetes and, if so, how frequently. In contrast to conditions that
likely lead to the development of glucose toxicity, Westernization and
the accompanying increase in dietary fat intake may contribute to
alterations in ß-cell function (124). Although human
studies have not examined this effect of fat in a systematic way,
studies examining the effect of differences in carbohydrate intake
provide indirect support as they involved a reciprocal alteration in
the proportion of calories derived from fat. In these studies, the
increase in dietary carbohydrate (and decrease in dietary fat) resulted
in improved glucose tolerance as a result of an increase in insulin
secretion and an improvement in insulin sensitivity in older subjects
(125, 126) and individuals with type 2 diabetes
(127). More rigorous examination of the effects of
increased dietary fat intake and/or altered fat metabolism on ß-cell
function has been performed in mice (128) and dogs
(129, 130). In both species, ingestion of a high-fat diet
was associated with reductions in insulin release determined in
vitro (128) and in vivo (129, 130). In the canine studies, insulin sensitivity declines as the
dogs become obese but when ß-cell function declines, glucose
tolerance deteriorates (129, 130). What mechanism(s)
underlies this effect of dietary fat has not been established. As the
development of obesity commonly results in an accumulation of
intra-abdominal fat that appears to be a metabolically active fat depot
(131), it is possible that factors emanating from fat may
be the critical mediator. One candidate is free fatty acids, the
fluctuations of which are known to be critical for the maintenance of
ß-cell function. However, chronic increases of this nutrient may have
a deleterious effect on the ß-cell (132, 133, 134). This
adverse effect seems not only to result in a decline in insulin release
but may also have an effect to reduce the efficiency of proinsulin to
insulin conversion within the ß-cell (133, 134). Recent
data would suggest that for fatty acids to have a deleterious effect on
ß-cell function and for esterification to occur so that neutral
lipids can accumulate in the islet, hyperglycemia may also need to be
present (135). These data are somewhat in contrast with
those from Boden et al. (136) who failed to
observe a deleterious effect of fatty acids on insulin secretion during
a 48-h infusion of lipids along with heparin in humans. Whether or not
it turns out that fatty acids are critical, other candidate molecules
derived from adipose tissue may also play a role. These would include
leptin that is released largely from sc fat and the cytokine TNF-
,
both of which have been suggested to decrease ß-cell function
in vitro (137, 138, 139, 140, 141).
The potential importance of reduced ß-cell mass to explain impaired maximal secretory capacity for insulin secretion has also been raised by a number of studies that have shown that this measure is reduced in individuals with type 2 diabetes (142, 143, 144). However, this reduction in mass cannot explain the entire pattern of functional changes observed in type 2 diabetes. The etiology of this mass reduction may be multifactorial. It is possible that an increase in programmed cell death, known as apoptosis, may occur as a result of the deranged metabolic state such as elevation in glucose and free fatty acids (145, 146). The observation of amyloid deposits a century ago provides another plausible mechanism to explain a portion of the reduced ß-cell mass (106, 147). The relationship between these amyloid deposits and glucose metabolism has been difficult to examine in humans, but has been studied in animal models. In nonhuman primates, it has been shown that the accumulation of islet amyloid is associated with a progressive reduction in both insulin secretion and glucose tolerance (148). In this study, the development of fasting hyperglycemia was a late event and only occurred after there was marked amyloid deposition. This finding suggests that if amyloid related ß-cell mass reduction is the only abnormality contributing to a disturbance in glucose metabolism, a marked degree of mass loss must exist for fasting hyperglycemia to occur. However, because of the multifactorial nature of type 2 diabetes, such a large degree of ß-cell mass reduction is not likely to be necessary in type 2 diabetes. To better study this phenomenon of islet mass reduction by amyloid, transgenic mice bearing the amyloidogenic human IAPP gene have been produced (149, 150, 151). Using these models, we and others have been able to demonstrate that islet amyloidogenesis occurs in mice fed a diet containing increased dietary fat (149), is increased in female mice that are estrogen deficient following oophorectomy (152), is not necessarily increased by hyperglycemia (153), but is associated with reduced ß-cell function and the development of hyperglycemia as amyloid deposition increases (150, 151). These findings are applicable to the clinical syndrome of type 2 diabetes in that the prevalence of the disease is increased in populations consuming diets containing increased quantities of fat (124, 154) and may be reduced by postmenopausal estrogen therapy (155). Finally, in addition to being the amyloidogenic precursor for the large, light microscopy visible amyloid deposits associated with islet mass reduction, IAPP has been shown to form amyloid fibrils that are not identifiable by light microscopy (156). These fibrils have been demonstrated to be toxic to these cells in vitro, thereby resulting in death by apoptosis (157, 158). Thus, the formation of the fibrils themselves may have deleterious effects on ß-cell function before their coalescing to form amyloid deposits visible by light microscopy.
Thus, whereas a large body of work has been performed to try and better
understand the pathogenesis of the impairments of ß-cell function in
type 2 diabetes, the exact mechanism(s) responsible is still not
clearly defined. Rather, it would seem that the deterioration in
ß-cell function is multifactorial and multiplicative with the
contribution possibly varying from individual to individual. As an
example, a model for an interaction of dietary fat, glucose and islet
amyloid is illustrated in Fig. 8. In this
model, in individuals who are genetically determined to be at risk of
developing type 2 diabetes, a prolonged increase in dietary fat intake
induces ß-cell dysfunction. This reduction in function results in
reduced insulin secretion that in turn results in the development of
hyperglycemia. This alteration in ß-cell function also involves
changes in the manner in which the ß-cell handles the amyloidogenic
precursor IAPP and allows islet amyloidogenesis to occur. As these
deposits progressively increase, they replace ß-cell mass further
aggravating the ability of the islet to produce and secrete insulin.
The existence of sustained hyperglycemia in these individuals with
impaired ß-cell function further aggravates ß-cell function as a
result of "glucose toxicity." Because the disease is progressive,
it is likely that these effects feed forward aggravating the clinical
syndrome and in most individuals requiring increases in therapy aimed
at reducing hyperglycemia.
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Because it is now becoming apparent that the relentless decline in ß-cell function commences well before the clinical diagnosis of diabetes is made, future approaches to the therapy of the disease have to include attempts at prevention. While we may be fortunate to find a means for doing so before the pathogenesis of this process is fully unraveled, our chances of achieving this goal will be enhanced by gaining a better understanding of the genetic alterations and the metabolic process(es) that underlies this progressive ß-cell dysfunction.
As discussed, there are a number of possible mechanisms responsible for the development of the ß-cell dysfunction of type 2 diabetes. The concept that hyperglycemia and elevated free fatty acids contribute to ß-cell dysfunction would imply that aggressive control of these parameters should result in improved insulin release and could prevent progression. However, based on the UKPDS in which the intensive policy group underwent aggressive glucose control, ß-cell function continued to decline. Whether control of lipids would produce similar or different results is subject to determination. As the deposition of islet amyloid would be predicted to result in an ongoing loss of ß-cell mass, it is possible that a small nidus of amyloid could be sufficient to explain the early progressive failure of ß-cell function observed in type 2 diabetes. Therefore, inhibition of the amyloidogenic process may well require the development of inhibitors that prevent the binding of secreted IAPP to formed fibrils, well before large amounts of amyloid are visible by light microscopy.
Finally, a few recent observations related to peroxisome
proliferator-activated receptor-
raise some interesting
possibilities. The discovery of resistin, a peptide that is produced
and secreted by adipocytes and is capable of inducing insulin
resistance in rodents (159), opens additional avenues for
research. It is possible that differences in the release of this
peptide may mediate changes in ß-cell function. If so, whether these
will result in an increase or a decrease in insulin output remains to
be determined. In addition, recent reports of a potential effect of
thiazolidinediones to preserve ß-cell function in animal models of
diabetes (160, 161) provides the impetus for clinical
testing of the interesting possibility that the use of these agents may
slow the progressive decline in ß-cell function observed in type 2
diabetes.
Conclusions
Hyperglycemia has conclusively been demonstrated to be an important contributing factor in the development of the ravaging complications of type 2 diabetes. The challenge to attain and maintain normoglycemia is compounded by the progressive nature of the disease that in large part seems to be due to a continuous decline in ß-cell function that starts many years before diagnosis. Whereas a greater number of therapeutic options are available for lowering plasma glucose, none have been shown to reliably slow the progressive loss of ß-cell function. Thus, the future is filled with many challenges that will surely involve genetic, physiological, and pharmacological approaches that likely will have to focus early on the ß-cell to be beneficial.
Acknowledgments
I thank the faculty, collaborators, fellows, and technicians who have helped direct my thinking and thus contributed in no small measure to this manuscript.
Footnotes
This work was supported by NIH Grants DK-02654, DK-17047, DK-50703, and RR-37; the Medical Research Service of the Department of Veterans Affairs; and the American Diabetes Association.
Abbreviations: HOMA, Homeostasis Model Assessment; IAPP, islet amyloid polypeptide; UKPDS, United Kingdom Prospective Diabetes Study.
Received February 5, 2001.
Accepted April 12, 2001.
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 Z. Zhao, C. Zhao, X. H. Zhang, F. Zheng, W. Cai, H. Vlassara, and Z. A. Ma Advanced Glycation End Products Inhibit Glucose-Stimulated Insulin Secretion through Nitric Oxide-Dependent Inhibition of Cytochrome c Oxidase and Adenosine Triphosphate Synthesis Endocrinology, June 1, 2009; 150(6): 2569 - 2576. [Abstract] [Full Text] [PDF]
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 Z. Wang and D. C. Thurmond Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins J. Cell Sci., April 1, 2009; 122(7): 893 - 903. [Abstract] [Full Text] [PDF]
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 N. Balcazar, A. Sathyamurthy, L. Elghazi, A. Gould, A. Weiss, I. Shiojima, K. Walsh, and E. Bernal-Mizrachi mTORC1 Activation Regulates {beta}-Cell Mass and Proliferation by Modulation of Cyclin D2 Synthesis and Stability J. Biol. Chem., March 20, 2009; 284(12): 7832 - 7842. [Abstract] [Full Text] [PDF]
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 D. A. D'Alessio, A. M. Denney, L. M. Hermiller, R. L. Prigeon, J. M. Martin, W. G. Tharp, M. L. Saylan, Y. He, B. E. Dunning, J. E. Foley, et al. Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 81 - 88. [Abstract] [Full Text] [PDF]
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 T. H. Inge, G. Miyano, J. Bean, M. Helmrath, A. Courcoulas, C. M. Harmon, M. K. Chen, K. Wilson, S. R. Daniels, V. F. Garcia, et al. Reversal of Type 2 Diabetes Mellitus and Improvements in Cardiovascular Risk Factors After Surgical Weight Loss in Adolescents Pediatrics, January 1, 2009; 123(1): 214 - 222. [Abstract] [Full Text] [PDF]
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 A. De Gaetano, T. Hardy, B. Beck, E. Abu-Raddad, P. Palumbo, J. Bue-Valleskey, and N. Porksen Mathematical models of diabetes progression Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1462 - E1479. [Abstract] [Full Text] [PDF]
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 V. A Fonseca Defining and characterising the progression of type 2 diabetes The British Journal of Diabetes & Vascular Disease, November 1, 2008; 8(2_suppl): S3 - S9. [Abstract] [PDF]
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K. K. Ong, B. Diderholm, G. Salzano, D. Wingate, I. A. Hughes, J. MacDougall, C. L. Acerini, and D. B. Dunger Pregnancy Insulin, Glucose, and BMI Contribute to Birth Outcomes in Nondiabetic Mothers Diabetes Care, November 1, 2008; 31(11): 2193 - 2197. [Abstract] [Full Text] [PDF]
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 M. I. Goran, C. Lane, C. Toledo-Corral, and M. J. Weigensberg Persistence of Pre-Diabetes in Overweight and Obese Hispanic Children: Association With Progressive Insulin Resistance, Poor {beta}-Cell Function, and Increasing Visceral Fat Diabetes, November 1, 2008; 57(11): 3007 - 3012. [Abstract] [Full Text] [PDF]
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 A. R. Gosmanov and G. E. Umpierrez A Patient with Diabetes, Hepatitis C Virus Infection, and Hemochromatosis Gene Mutation Clin. Diabetes, October 1, 2008; 26(4): 174 - 176. [Full Text] [PDF]
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T. Kimura, Y. Kaneko, S. Yamada, H. Ishihara, T. Senda, A. Iwamatsu, and I. Niki The GDP-dependent Rab27a effector coronin 3 controls endocytosis of secretory membrane in insulin-secreting cell lines J. Cell Sci., September 15, 2008; 121(18): 3092 - 3098. [Abstract] [Full Text] [PDF]
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T. Kato, H. Shimano, T. Yamamoto, M. Ishikawa, S. Kumadaki, T. Matsuzaka, Y. Nakagawa, N. Yahagi, M. Nakakuki, A. H. Hasty, et al. Palmitate Impairs and Eicosapentaenoate Restores Insulin Secretion Through Regulation of SREBP-1c in Pancreatic Islets Diabetes, September 1, 2008; 57(9): 2382 - 2392. [Abstract] [Full Text] [PDF]
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M. A. Abdul-Ghani, M. Matsuda, R. Jani, C. P. Jenkinson, D. K. Coletta, K. Kaku, and R. A. DeFronzo The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E401 - E406. [Abstract] [Full Text] [PDF]
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 L. Rachdi, N. Balcazar, F. Osorio-Duque, L. Elghazi, A. Weiss, A. Gould, K. J. Chang-Chen, M. J. Gambello, and E. Bernal-Mizrachi Disruption of Tsc2 in pancreatic {beta} cells induces {beta} cell mass expansion and improved glucose tolerance in a TORC1-dependent manner PNAS, July 8, 2008; 105(27): 9250 - 9255. [Abstract] [Full Text] [PDF]
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G. Nijpels, W. Boorsma, J. M. Dekker, F. Hoeksema, P. J. Kostense, L. M. Bouter, and R. J. Heine Absence of an Acute Insulin Response Predicts Onset of Type 2 Diabetes in a Caucasian Population with Impaired Glucose Tolerance J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2633 - 2638. [Abstract] [Full Text] [PDF]
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 M. Salehi, B. A. Aulinger, and D. A. D'Alessio Targeting {beta}-Cell Mass in Type 2 Diabetes: Promise and Limitations of New Drugs Based on Incretins Endocr. Rev., May 1, 2008; 29(3): 367 - 379. [Abstract] [Full Text] [PDF]
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D. L. Eizirik, A. K. Cardozo, and M. Cnop The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus Endocr. Rev., February 1, 2008; 29(1): 42 - 61. [Abstract] [Full Text] [PDF]
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 T. O. Kilpelainen, T. A. Lakka, D. E. Laaksonen, O. Laukkanen, J. Lindstrom, J. G. Eriksson, T. T. Valle, H. Hamalainen, S. Aunola, P. Ilanne-Parikka, et al. Physical activity modifies the effect of SNPs in the SLC2A2 (GLUT2) and ABCC8 (SUR1) genes on the risk of developing type 2 diabetes Physiol Genomics, October 19, 2007; 31(2): 264 - 272. [Abstract] [Full Text] [PDF]
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B. J. Goldstein, M. N. Feinglos, J. K. Lunceford, J. Johnson, D. E. Williams-Herman, and for the Sitagliptin 036 Study Group Effect of Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin on Glycemic Control in Patients With Type 2 Diabetes Diabetes Care, August 1, 2007; 30(8): 1979 - 1987. [Abstract] [Full Text] [PDF]
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A. Gastaldelli, E. Ferrannini, Y. Miyazaki, M. Matsuda, A. Mari, and R. A. DeFronzo Thiazolidinediones improve beta-cell function in type 2 diabetic patients Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E871 - E883. [Abstract] [Full Text] [PDF]
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G. E. Umpierrez Ketosis-Prone Type 2 Diabetes: Time to revise the classification of diabetes Diabetes Care, December 1, 2006; 29(12): 2755 - 2757. [Full Text] [PDF]
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 W. S. Shim, S. K. Kim, H. J. Kim, E. S. Kang, C. W. Ahn, S. K. Lim, H. C. Lee, and B. S. Cha Decrement of postprandial insulin secretion determines the progressive nature of type-2 diabetes. Eur. J. Endocrinol., October 1, 2006; 155(4): 615 - 622. [Abstract] [Full Text] [PDF]
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M. S. Kirkman, R. R. Shankar, S. Shankar, C. Shen, E. Brizendine, A. Baron, and J. McGill Treating postprandial hyperglycemia does not appear to delay progression of early type 2 diabetes: the early diabetes intervention program. Diabetes Care, September 1, 2006; 29(9): 2095 - 2101. [Abstract] [Full Text] [PDF]
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F. Bacha, R. Saad, N. Gungor, and S. A. Arslanian Are Obesity-Related Metabolic Risk Factors Modulated by the Degree of Insulin Resistance in Adolescents? Diabetes Care, July 1, 2006; 29(7): 1599 - 1604. [Abstract] [Full Text] [PDF]
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S.-H. Ihm, I. Matsumoto, T. Sawada, M. Nakano, H. J. Zhang, J. D. Ansite, D. E.R. Sutherland, and B. J. Hering Effect of donor age on function of isolated human islets. Diabetes, May 1, 2006; 55(5): 1361 - 1368. [Abstract] [Full Text] [PDF]
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 G. E. Umpierrez, D. Smiley, and A. E. Kitabchi Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med, March 7, 2006; 144(5): 350 - 357. [Abstract] [Full Text] [PDF]
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S. Fatrai, L. Elghazi, N. Balcazar, C. Cras-Meneur, I. Krits, H. Kiyokawa, and E. Bernal-Mizrachi Akt Induces {beta}-Cell Proliferation by Regulating Cyclin D1, Cyclin D2, and p21 Levels and Cyclin-Dependent Kinase-4 Activity Diabetes, February 1, 2006; 55(2): 318 - 325. [Abstract] [Full Text] [PDF]
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D. A. Elder, R. L. Prigeon, R. P. Wadwa, L. M. Dolan, and D. A. D'Alessio {beta}-Cell Function, Insulin Sensitivity, and Glucose Tolerance in Obese Diabetic and Nondiabetic Adolescents and Young Adults J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 185 - 191. [Abstract] [Full Text] [PDF]
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J. P. Palmer, C. S. Hampe, H. Chiu, A. Goel, and B. M. Brooks-Worrell Is Latent Autoimmune Diabetes in Adults Distinct From Type 1 Diabetes or Just Type 1 Diabetes at an Older Age? Diabetes, December 1, 2005; 54(suppl_2): S62 - S67. [Abstract] [Full Text] [PDF]
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Y.-P. Zhou, A. Madjidi, M. E. Wilson, D. A. Nothhelfer, J. H. Johnson, J. F. Palma, A. Schweitzer, C. Burant, J. E. Blume, and J. D. Johnson Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats Diabetes, September 1, 2005; 54(9): 2612 - 2619. [Abstract] [Full Text] [PDF]
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L. S. Cozma, S. D. Luzio, G. J. Dunseath, P. M. Underwood, and D. R. Owens {beta}-Cell Response During a Meal Test: A comparative study of incremental doses of repaglinide in type 2 diabetic patients Diabetes Care, May 1, 2005; 28(5): 1001 - 1007. [Abstract] [Full Text] [PDF]
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 C. L. Winter, J. S. Lange, M. G. Davis, G. S. Gerwe, T. R. Downs, K. G. Peters, and B. Kasibhatla A Nonspecific Phosphotyrosine Phosphatase Inhibitor, Bis(maltolato)oxovanadium(IV), Improves Glucose Tolerance and Prevents Diabetes in Zucker Diabetic Fatty Rats Experimental Biology and Medicine, March 1, 2005; 230(3): 207 - 216. [Abstract] [Full Text] [PDF]
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M. H. Tan, A. Baksi, B. Krahulec, P. Kubalski, A. Stankiewicz, R. Urquhart, G. Edwards, D. Johns, and for the GLAL Study Group Comparison of Pioglitazone and Gliclazide in Sustaining Glycemic Control Over 2 Years in Patients With Type 2 Diabetes Diabetes Care, March 1, 2005; 28(3): 544 - 550. [Abstract] [Full Text] [PDF]
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N. Gungor, F. Bacha, R. Saad, J. Janosky, and S. Arslanian Youth Type 2 Diabetes: Insulin resistance, {beta}-cell failure, or both? Diabetes Care, March 1, 2005; 28(3): 638 - 644. [Abstract] [Full Text] [PDF]
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 A. H. Minn, H. Lan, M. E. Rabaglia, D. M. Harlan, B. A. Peculis, A. D. Attie, and A. Shalev Increased Insulin Translation from an Insulin Splice-Variant Overexpressed in Diabetes, Obesity, and Insulin Resistance Mol. Endocrinol., March 1, 2005; 19(3): 794 - 803. [Abstract] [Full Text] [PDF]
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S. Del Guerra, R. Lupi, L. Marselli, M. Masini, M. Bugliani, S. Sbrana, S. Torri, M. Pollera, U. Boggi, F. Mosca, et al. Functional and Molecular Defects of Pancreatic Islets in Human Type 2 Diabetes Diabetes, March 1, 2005; 54(3): 727 - 735. [Abstract] [Full Text] [PDF]
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M. Ohsugi, C. Cras-Meneur, Y. Zhou, E. Bernal-Mizrachi, J. D. Johnson, D. S. Luciani, K. S. Polonsky, and M. A. Permutt Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion J. Biol. Chem., February 11, 2005; 280(6): 4992 - 5003. [Abstract] [Full Text] [PDF]
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 C. J. Rhodes Type 2 Diabetes-a Matter of {beta}-Cell Life and Death? Science, January 21, 2005; 307(5708): 380 - 384. [Abstract] [Full Text] [PDF]
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 E. M Vivian, S. V Olarte, and A. M Gutierrez Insulin Strategies for Type 2 Diabetes Mellitus Ann. Pharmacother., November 1, 2004; 38(11): 1916 - 1923. [Abstract] [Full Text] [PDF]
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A. Caumo and L. Luzi First-phase insulin secretion: does it exist in real life? Considerations on shape and function Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E371 - E385. [Abstract] [Full Text] [PDF]
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P. E. MacDonald, J. W. Joseph, D. Yau, J. Diao, Z. Asghar, F. Dai, G. Y. Oudit, M. M. Patel, P. H. Backx, and M. B. Wheeler Impaired Glucose-Stimulated Insulin Secretion, Enhanced Intraperitoneal Insulin Tolerance, and Increased {beta}-Cell Mass in Mice Lacking the p110{gamma} Isoform of Phosphoinositide 3-Kinase Endocrinology, September 1, 2004; 145(9): 4078 - 4083. [Abstract] [Full Text] [PDF]
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R. L. Hull, G. T. Westermark, P. Westermark, and S. E. Kahn Islet Amyloid: A Critical Entity in the Pathogenesis of Type 2 Diabetes J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3629 - 3643. [Abstract] [Full Text] [PDF]
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M. K Jayapaul and M. Walker Review: Mechanisms contributing to the development of type 2 diabetes The British Journal of Diabetes & Vascular Disease, July 1, 2004; 4(4): 227 - 231. [Abstract] [PDF]
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A. Duttaroy, C. L. Zimliki, D. Gautam, Y. Cui, D. Mears, and J. Wess Muscarinic Stimulation of Pancreatic Insulin and Glucagon Release Is Abolished in M3 Muscarinic Acetylcholine Receptor-Deficient Mice Diabetes, July 1, 2004; 53(7): 1714 - 1720. [Abstract] [Full Text] [PDF]
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E. Bonora, S. Kiechl, J. Willeit, F. Oberhollenzer, G. Egger, J. B. Meigs, R. C. Bonadonna, and M. Muggeo Population-Based Incidence Rates and Risk Factors for Type 2 Diabetes in White Individuals: The Bruneck Study Diabetes, July 1, 2004; 53(7): 1782 - 1789. [Abstract] [Full Text] [PDF]
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S. Deng, M. Vatamaniuk, X. Huang, N. Doliba, M.-M. Lian, A. Frank, E. Velidedeoglu, N. M. Desai, B. Koeberlein, B. Wolf, et al. Structural and Functional Abnormalities in the Islets Isolated From Type 2 Diabetic Subjects Diabetes, March 1, 2004; 53(3): 624 - 632. [Abstract] [Full Text] [PDF]
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C. Dos Santos, D. Fallin, C. Le Stunff, S. LeFur, and P. Bougneres INS VNTR is a QTL for the insulin response to oral glucose in obese children Physiol Genomics, February 13, 2004; 16(3): 309 - 313. [Abstract] [Full Text] [PDF]
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H. Bays, L. Mandarino, and R. A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 463 - 478. [Full Text] [PDF]
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M. I. Goran, R. N. Bergman, Q. Avila, M. Watkins, G. D. C. Ball, G. Q. Shaibi, M. J. Weigensberg, and M. L. Cruz Impaired Glucose Tolerance and Reduced {beta}-Cell Function in Overweight Latino Children with a Positive Family History for Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 207 - 212. [Abstract] [Full Text] [PDF]
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I. Niki, T. Niwa, W. Yu, D. Budzko, T. Miki, and T. Senda Ca2+ Influx Does Not Trigger Glucose-Induced Traffic of the Insulin Granules and Alteration of Their Distribution Experimental Biology and Medicine, November 1, 2003; 228(10): 1218 - 1226. [Abstract] [Full Text] [PDF]
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D. M. Eddy and L. Schlessinger Archimedes: A trial-validated model of diabetes Diabetes Care, November 1, 2003; 26(11): 3093 - 3101. [Abstract] [Full Text] [PDF]
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H. Larsson, G. Berglund, and B. Ahren Insulin Sensitivity, Insulin Secretion, and Glucose Tolerance Versus Intima-Media Thickness in Nondiabetic Postmenopausal Women J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4791 - 4797. [Abstract] [Full Text] [PDF]
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E. V. Polyzogopoulou, F. Kalfarentzos, A. G. Vagenakis, and T. K. Alexandrides Restoration of Euglycemia and Normal Acute Insulin Response to Glucose in Obese Subjects With Type 2 Diabetes Following Bariatric Surgery Diabetes, May 1, 2003; 52(5): 1098 - 1103. [Abstract] [Full Text] [PDF]
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 A. Bagust and S. Beale Deteriorating beta-cell function in type 2 diabetes: a long-term model QJM, April 1, 2003; 96(4): 281 - 288. [Abstract] [Full Text] [PDF]
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 J. E. Gerich Contributions of Insulin-Resistance and Insulin-Secretory Defects to the Pathogenesis of Type 2 Diabetes Mellitus Mayo Clin. Proc., April 1, 2003; 78(4): 447 - 456. [Abstract] [PDF]
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K. Yaekura, R. Julyan, B. L. Wicksteed, L. B. Hays, C. Alarcon, S. Sommers, V. Poitout, D. G. Baskin, Y. Wang, L. H. Philipson, et al. Insulin Secretory Deficiency and Glucose Intolerance in Rab3A Null Mice J. Biol. Chem., March 7, 2003; 278(11): 9715 - 9721. [Abstract] [Full Text] [PDF]
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B. Ahren and O. Thorsson Increased Insulin Sensitivity Is Associated with Reduced Insulin and Glucagon Secretion and Increased Insulin Clearance in Man J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1264 - 1270. [Abstract] [Full Text] [PDF]
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M. Guldstrand, B. Ahren, and U. Adamson Improved beta -cell function after standardized weight reduction in severely obese subjects Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E557 - E565. [Abstract] [Full Text] [PDF]
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R. L. Hull, S. Andrikopoulos, C. B. Verchere, J. Vidal, F. Wang, M. Cnop, R. L. Prigeon, and S. E. Kahn Increased Dietary Fat Promotes Islet Amyloid Formation and {beta}-Cell Secretory Dysfunction in a Transgenic Mouse Model of Islet Amyloid Diabetes, February 1, 2003; 52(2): 372 - 379. [Abstract] [Full Text] [PDF]
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R. A Defronzo Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1_suppl): S24 - S40. [Abstract] [PDF]
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M. I. Goran, R. N. Bergman, M. L. Cruz, and R. Watanabe Insulin Resistance and Associated Compensatory Responses in African-American and Hispanic Children Diabetes Care, December 1, 2002; 25(12): 2184 - 2190. [Abstract] [Full Text] [PDF]
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A. Ando, T. Yatagai, K. Rokkaku, S. Nagasaka, S.-e Ishikawa, and S. Ishibashi Obesity Is a Critical Risk Factor for Worsening of Glucose Tolerance in a Family With the Mutant Insulin Receptor Diabetes Care, August 1, 2002; 25(8): 1484 - 1485. [Full Text]
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C. C. Jensen, M. Cnop, R. L. Hull, W. Y. Fujimoto, S. E. Kahn, and the American Diabetes Association GENNID Study Gro {beta}-Cell Function Is a Major Contributor to Oral Glucose Tolerance in High-Risk Relatives of Four Ethnic Groups in the U.S. Diabetes, July 1, 2002; 51(7): 2170 - 2178. [Abstract] [Full Text] [PDF]
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K. L. Herbst and I. B. Hirsch Insulin Strategies for Primary Care Providers Clin. Diabetes, January 1, 2002; 20(1): 11 - 17. [Abstract] [Full Text] [PDF]
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| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
IRI/
), impaired glucose tolerance (
), and type 2 diabetes
(
) are indicated. The relationship between these variables is
nonlinear with an r2 value of 0.38 (P
< 0.0001). [Reproduced with permission from S. E. Kahn et
al.: Diabetes 47:640–645, 1998 (
). There is a
broad range of ß-cell secretory capacity in the healthy subjects due
to large differences in insulin sensitivity, whereas in the subjects
with type 2 diabetes the range is narrower as a manifestation of the
impaired islet function. The nonlinear relationship between these two
parameters (r = -0.76; P < 0.0001)
demonstrates that the degree of ß-cell function is a determinant of
the fasting glucose level. In subjects with type 2 diabetes, ß-cell
secretory capacity is reduced by approximately 75% when the fasting
glucose level increases. [Adapted from Ref. 
