The Importance of ß-Cell Failure in the Development and Progression of Type 2 Diabetes
Steven E. Kahn
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.
When glucose is administered iv, the dynamics of insulin release
comprise two phases: first and second. The first-phase response peaks
within 25 min following glucose administration and lasts
approximately 10 min. This response is thought to represent the release
of a pool of secretory granules that is present in close proximity to
the ß-cell plasma membrane (29, 30, 31). The second-phase
response commences shortly after glucose administration and is more
prolonged being maintained for the period that the glucose level is
elevated. This second-phase response is believed to represent in large
part the release of secretory granules that are being mobilized within
the ß-cell for release (29, 30, 31) and includes many
granules that contain newly synthesized insulin (32, 33).
In individuals with type 2 diabetes both these responses are
diminished. In fact, the lack of a first-phase response is a sine
quo non for diabetes and is absent in all individuals who are
hyperglycemic (9, 11, 34). Of interest, but of unknown
cause, is the observation that the first-phase response may in fact be
negative in subjects with marked elevations of fasting glucose
(35). The second-phase response may seem relatively normal
in subjects with type 2 diabetes early on. However, this apparently
normal response occurs at the expense of hyperglycemia so that when
subjects are matched for the degree of glucose elevation, it is clear
that the second-phase insulin response is also reduced in subjects with
type 2 diabetes (15, 34, 36).
Besides its ability to directly stimulate insulin release, glucose also
modulates the ß-cells 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 100600 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 (5075%) 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).

View larger version (12K):
[in this window]
[in a new window]
|
Figure 2. Relationship between ß-cell secretory capacity
(AIRmax) and fasting plasma glucose in 9 subjects with type 2 diabetes
() and 10 subjects with normal glucose tolerance ( ). 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. 40 .]
|
|
Using frequent sampling over prolonged periods of time, it has been
clearly demonstrated that insulin release can occur in both a pulsatile
and an oscillatory manner. In healthy subjects, pulses in insulin
release occur spontaneously every 810 min (43). The
origin of these pulses seems to be intrinsic to the islet as isolated
islets in culture still demonstrate the presence of these pulses
despite the fact that they lack their neural connection
(44). In subjects with type 2 diabetes, this pulsatile
pattern of insulin release is disrupted (45). The loss of
these pulses may also play an important role in the development of a
portion of the insulin resistance of the disease as delivery of insulin
as a continuous infusion is associated with impaired insulin action,
that does not occur when insulin is administered in a pulsatile pattern
(46, 47). It is also of interest that these rapid pulses
are superimposed on larger oscillations in insulin release. These
prolonged oscillations have a phase of approximately 120 min and can
also be made to oscillate in concert with a variable rate iv infusion
of glucose administered with a similar periodicity (48, 49). It is uncertain what regulates these longer oscillations
but it is possible that these are related to a signal arising outside
the islet. These natural oscillations and the ability of glucose to
entrain them have both been demonstrated to be defective in subjects
with type 2 diabetes (17, 49).
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.

View larger version (18K):
[in this window]
[in a new window]
|
Figure 3. Relationship between insulin sensitivity and
ß-cell function quantified as the first-phase insulin response
(AIRglucose) in 93 (55 males and 38 females) apparently healthy,
nondiabetic subjects under the age of 45 yr. The cohort demonstrates a
broad range of insulin sensitivity and ß-cell function. The
solid line depicts the best-fit relationship (50th
percentile) whereas the broken lines represent the 5th,
25th, 75th, and 95th percentiles. The relationship is best described by
a hyperbolic function so that any change in insulin sensitivity is
balanced by a reciprocal and proportionate change in ß-cell function.
[Reproduced with permission from S. E. Kahn et
al.: Diabetes 42:16631672, 1993 (65 ).]
|
|
Based on this concept of a feedback loop and the need to consider the
magnitude of insulin responses in the face of the prevailing degree of
insulin sensitivity, it has become evident that subjects who are at
high risk of developing type 2 diabetes have diminished ß-cell
function at a time when many of them still have normal glucose
tolerance. Thus, first- degree relatives of individuals with type 2
diabetes (71, 72, 73), women with a history of either
gestational diabetes (74, 75, 76) or polycystic ovarian
disease (71, 77), older subjects (78, 79, 80),
and individuals with impaired glucose tolerance (81) can
all be demonstrated to have a reduced first-phase insulin response to
iv glucose administration (Figs. 4
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.

View larger version (18K):
[in this window]
[in a new window]
|
Figure 4. Percentile lines for the relationship between
insulin sensitivity (SI) and the first-phase insulin
response (AIRglucose) based on data from 93 normal subjects
(65 ). Mean data from six other studies are plotted. The 10
subjects with type 2 diabetes are insulin resistant and have markedly
impaired insulin secretion (162 ). Thirteen healthy older
subjects demonstrate that aging is associated with insulin resistance
and a reduction in ß-cell function (79 ). Reduced
ß-cell function is also manifest in 8 women with a history of
gestational diabetes (GDM) (74 ), 11 women with polycystic
ovarian disease (PCO), and a family history of type 2 diabetes
(71 ), 21 subjects with impaired glucose tolerance (IGT)
(81 ), and in 14 subjects with a first-degree relative with
type 2 diabetes mellitus (72 ). The reduction in ß-cell
function in these latter three groups is compatible with their high
risk of subsequently developing type 2 diabetes. [Reproduced with
permission from J. Vidal and S. E. Kahn: Genetics of
Diabetes Mellitus (edited by W. L. Lowe, Jr.), Kluwer,
Stamford, CT, 2001, pp 109131 (163 ).]
|
|

View larger version (17K):
[in this window]
[in a new window]
|
Figure 5. Individual measurements of insulin sensitivity and
ß-cell function in a group of first-degree relatives of subjects with
type 2 diabetes from three different families indicated by different
symbols. These individuals were studied when their
fasting glucose levels were normal and exhibit broad ranges of both
SI and AIRglucose. When these two parameters are assessed
together, it is apparent that some individuals have well-preserved
ß-cell function while others have markedly deficient responses and,
thus, would be predicted to be at very high risk of progressing on to
develop hyperglycemia. [Reproduced with permission from S. E.
Kahn: Diabetes Rev 4:372389, 1996 (72 ).]
|
|
A recent longitudinal study in Pima Indians did examine both these
variables taking into account the known hyperbolic relationship between
insulin sensitivity and ß-cell function (83). In the
study in this very high-risk population, 48 subjects with normal
glucose tolerance were followed for an average of 5 yr with multiple
measures being performed over this period (Fig. 6
). 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).

View larger version (21K):
[in this window]
[in a new window]
|
Figure 6. Changes in ß-cell function measured as the acute
insulin response to glucose (AIR) relative to changes in insulin
sensitivity measured by the clamp technique at a low insulin
concentration (M-low). These measurements were made in 11 Pima Indians
in whom glucose tolerance deteriorated from normal glucose tolerance
(NGT) to impaired glucose tolerance (IGT) to diabetes (DIA)
(progressors), and in 23 subjects who maintained normal glucose
tolerance (NGT) throughout (nonprogressors). The lines
represent the prediction line and the lower and upper limits of the
95% confidence interval of the regression between the AIR and M-low as
determined from a population of 277 Pima Indians with normal glucose
tolerance. [Reproduced with permission from C. Weyer et
al.: J Clin Invest 104:787794, 1999
(83 ).]
|
|
In addition to the first-phase insulin response, reductions in ß-cell
function have also been demonstrated in other studies that have used a
variety of different approaches (16, 27, 49, 71, 75, 91, 92, 93, 94). However, in the absence of measurements of insulin
sensitivity, not all the studies have come to the same conclusion.
Nevertheless, when one tallies all the studies, it does seem that
reductions in the early phase insulin response to oral glucose
(27, 91, 92), second-phase insulin secretion in response
to iv glucose (93), glucose potentiation of ß-cell
function (94), pulsatile insulin secretion
(16), oscillatory insulin release (49, 71, 75), and the ability of glucose to entrain insulin secretion
(49, 71, 75) are all present in subjects who would be
predicted to be at very high risk of subsequently developing type 2
diabetes. The subject groups from whom these conclusions have been
drawn include those typically thought to be at high risk such as
first-degree relatives, women with a history of gestational diabetes or
polycystic ovarian disease and individuals with impaired glucose
tolerance.
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.

View larger version (14K):
[in this window]
[in a new window]
|
Figure 7. Model for the relationship between progressive
ß-cell dysfunction and deterioration of glucose tolerance. As
ß-cell function declines, glucose tolerance deteriorates so that the
criteria for impaired fasting glucose and/or impaired glucose tolerance
are reached. Subsequently, with a further loss of ß-cell function,
diabetes develops based on either or both the fasting and 2-h glucose
levels.
|
|
Potential mechanisms for the progressive ß-cell failure in the
pathogenesis and progression of type 2 diabetes
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.

View larger version (14K):
[in this window]
[in a new window]
|
Figure 8. Model of the interaction of genetics and the
environment to produce ß-cell dysfunction, amyloid, and
hyperglycemia. For diabetes to develop, a genetic ß-cell lesion(s)
must exist. Consumption of a diet containing increased amounts of fat
in conjunction with this genetic defect results in the development of
ß-cell dysfunction. This dysfunction is associated with an alteration
in insulin secretion so that hyperglycemia develops. In addition,
ß-cell dysfunction is associated with the development of amyloid
fibrils that contain islet amyloid polypeptide (IAPP). Progressive
amyloid deposition results in a loss of ß cells, further reducing
insulin release and aggravating hyperglycemia. Formation of amyloid
fibrils is also associated with an impairment of ß-cell function. In
addition, the presence of hyperglycemia may further aggravate ß-cell
function by desensitizing the ß cell.
|
|
The future for preventing the progressive ß-cell failure of type
2 diabetes
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.
References
-
Kahn SE, Porte Jr D 1996 Pathophysiology of
type II diabetes mellitus. In: Porte Jr D, Sherwin RS, eds. Diabetes
mellitus. Stamford, CT: Appleton and Lange; 487512
-
Best JD, Judzewitsch RG, Pfeifer MA, Beard JC, Halter
JB, Porte Jr D 1982 The effect of chronic sulfonylurea therapy on
hepatic glucose production in non-insulin-dependent diabetes. Diabetes 31:333338[Abstract]
-
Kolterman OG, Gray RS, Shapiro G, Scarlett JA,
Griffin J, Olefsky JM 1984 The acute and chronic effects of
sulfonylurea therapy in type II diabetic subjects. Diabetes 33:346354[Abstract]
-
UK Prospective Diabetes Study (UKPDS) Group 1998 Intensive blood- glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet 352:837853[CrossRef][Medline]
-
Turner RC, Cull CA, Frighi V, Holman RR 1999 Glycemic control with diet, sulfonylurea, metformin, or insulin in
patients with type 2 diabetes mellitus: progressive requirement for
multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS)
Group. JAMA 281:20052012[Abstract/Free Full Text]
-
Matthews DR, Cull CA, Stratton IM, Holman RR, Turner
RC 1998 UKPDS 26: sulphonylurea failure in non-insulin-dependent
diabetic patients over six years. UK Prospective Diabetes Study (UKPDS)
Group. Diabetes Med 15: 297303
-
Holman RR 1998 Assessing the potential for
alpha-glucosidase inhibitors in prediabetic states. Diabetes Res Clin
Pract 40(Suppl):S21S25
-
Levy J, Atkinson AB, Bell PM, McCance DR, Hadden
DR 1998 ß-cell deterioration determines the onset and rate of
progression of secondary dietary failure in type 2 diabetes mellitus:
the 10-year follow-up of the Belfast Diet Study. Diabetes Med 15:290296[CrossRef][Medline]
-
Perley MJ, Kipnis DM 1967 Plasma insulin
responses to oral and intravenous glucose: studies in normal and
diabetic subjects. J Clin Invest 46:19541962[Medline]
-
Bagdade JD, Bierman EL, Porte Jr D 1967 The
significance of basal insulin levels in the evaluation of the insulin
response to glucose in diabetic and nondiabetic subjects. J Clin
Invest 46:15491557[Medline]
-
Brunzell JD, Robertson RP, Lerner RL, et al. 1976 Relationships between fasting plasma glucose levels and insulin
secretion during intravenous glucose tolerance tests. J Clin
Endocrinol Metab 42:222229[Abstract]
-
Perley M, Kipnis DM 1966 Plasma insulin responses
to glucose and tolbutamide of normal weight and obese diabetic and
nondiabetic subjects. Diabetes 15:867874[Medline]
-
Robertson RP, Halter JB, Porte Jr D 1976 A role
for
-adrenergic receptors in abnormal insulin secretion in diabetes
mellitus. J Clin Invest 57:791795[Medline]
-
Halter JB, Graf RJ, Porte Jr D 1979 Potentiation
of insulin secretory responses by plasma glucose levels in man:
evidence that hyperglycemia in diabetes compensates for impaired
glucose potentiation. J Clin Endocrinol Metab 48:946954[Medline]
-
Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte Jr
D 1984 Diminished B cell secretory capacity in patients with
noninsulin-dependent diabetes mellitus. J Clin Invest 74:13181328[Medline]
-
ORahilly S, Turner RC, Matthews DR 1988 Impaired pulsatile secretion of insulin in relatives of patients
with non-insulin-dependent diabetes. N Engl J Med 318:12251230[Abstract]
-
Polonsky KS, Given BD, Hirsch LJ, et al. 1988 Abnormal patterns of insulin secretion in non-insulin-dependent
diabetes mellitus. N Engl J Med 318:12311239[Abstract]
-
Mako ME, Starr JI, Rubenstein AH 1977 Circulating
proinsulin in patients with maturity-onset diabetes. Am J Med 63:865869[Medline]
-
Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ,
Porte Jr D 1987 Disproportionate elevation of immunoreactive
proinsulin in type 2 (non- insulin-dependent) diabetes mellitus and
experimental insulin resistance. Diabetologia 30:698702[Medline]
-
Yoshioka N, Kuzuya T, Matsuda A, Taniguchi M, Iwamoto
Y 1988 Serum proinsulin levels at fasting and after oral glucose
load in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 31:355360[Medline]
-
Temple RC, Clark PMS, Nagi DK, Schneider AE, Yudkin
JS, Hales CN 1990 Radioimmunoassay may overestimate insulin in
non-insulin-dependent diabetics. Clin Endocrinol 32:689693[Medline]
-
Saad MF, Kahn SE, Nelson RG, et al. 1990 Disproportionately elevated proinsulin in Pima Indians with
noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 70:12471253[Abstract]
-
Kahn SE, Leonetti DL, Prigeon RL, Bergstrom RW,
Fujimoto WY 1995 Relationship of proinsulin and insulin with
noninsulin-dependent diabetes mellitus and coronary heart disease in
Japanese American men: impact of obesity. J Clin Endocrinol Metab 80:13991406[Abstract]
-
Kahn SE, Halban PA 1997 Release of incompletely
processed proinsulin is the cause of the disproportionate
proinsulinemia of NIDDM. Diabetes 46:17251732[Abstract]
-
Ludvik B, Lell B, Hartter E, Schnack C, Prager R 1991 Decrease of stimulated amylin release precedes impairment of
insulin secretion in type II diabetes. Diabetes 40:16151619[Abstract]
-
Enoki S, Mitsukawa T, Takemura J, et al. 1992 Plasma islet amyloid polypeptide levels in obesity, impaired glucose
tolerance and non-insulin-dependent diabetes mellitus. Diabetes Res
Clin Pract 15:97102[Medline]
-
Kahn SE, Verchere CB, Andrikopoulos S, et al. 1998 Reduced amylin release is a characteristic of impaired glucose
tolerance and type 2 diabetes in Japanese Americans. Diabetes 47:640645[Abstract]
-
Yalow RS, Berson SA 1960 Plasma insulin
concentrations in nondiabetic and early diabetic subjects:
determinations by a new sensitive immunoassay technic. Diabetes 9:254260
-
Pupo AA, Wajchenberg BL, Schnaider J 1966 Carbohydrate metabolism in hyperadrenocorticism. Diabetes 15:2429[Medline]
-
Grodsky GM 1989 A new phase of insulin secretion:
how will it contribute to our understanding of ß-cell function? Diabetes 38:673678[Abstract]
-
Daniel S, Noda M, Straub SG, Sharp GW 1999 Identification of the docked granule pool responsible for the first
phase of glucose-stimulated insulin secretion. Diabetes 48:16861690[Abstract]
-
Rhodes CJ, Halban PA 1987 Newly synthesized
proinsulin/insulin and stored insulin are released from pancreatic B
cells predominantly via a regulated, rather than a constitutive,
pathway. J Cell Biol 105:145153[Abstract]
-
Sizonenko S, Irminger JC, Buhler L, Deng S, Morel P,
Halban PA 1993 Kinetics of proinsulin conversion in human islets. Diabetes 42:933936[Abstract]
-
Porte Jr D 1991 ß-cells in type II diabetes
mellitus. Diabetes 40:166180[Abstract]
-
Metz SA, Halter JB, Robertson RP 1979 Paradoxical
inhibition of insulin secretion by glucose in human diabetes mellitus. J Clin Endocrinol Metab 48:827835[Medline]
-
Polonsky KS, Sturis J, Bell GI 1996 Non-insulin-dependent diabetes mellitusa genetically programmed
failure of the beta cell to compensate for insulin resistance. N
Engl J Med 334:777783[Free Full Text]
-
Halter JB, Porte Jr D 1978 Mechanisms of impaired
acute insulin release in adult onset diabetes: studies with
isoproterenol and secretin. J Clin Endocrinol Metab 46:952960[Abstract]
-
Varsano-Aharon N, Echemendia E, Yalow RS, Berson
SA 1970 Early insulin responses to glucose and to tolbutamide in
maturity-onset diabetes. Metabolism 19:409417[Medline]
-
Cerasi E 1975 Potentiation of insulin release by
glucose in man. II. Role of the insulin response, and enhancement of
stimuli other than glucose. Acta Endocrinol (Copenh) 79:502510[Medline]
-
Røder ME, Porte Jr D, Kahn SE 1998 Disproportionately elevated proinsulin levels reflect the degree of
impaired B-cell secretory capacity in patients with non-insulin
dependent diabetes mellitus. J Clin Endocrinol Metab 83:604608[Abstract/Free Full Text]
-
Leahy JL, Bonner-Weir S, Weir GC 1984 Abnormal
glucose regulation of insulin secretion in models of reduced B-cell
mass. Diabetes 33:667673[Abstract]
-
Ward WK, Wallum BJ, Beard JC, Taborsky Jr GJ, Porte Jr
D 1988 Reduction of glycemic potentiation: a sensitive indicator
of ß-cell loss in partially pancreatectomized dogs. Diabetes 37:723729[Abstract]
-
Matthews DR, Lang DA, Burnett MA, Turner RC 1983 Control of pulsatile insulin secretion in man. Diabetologia 24:231237[Medline]
-
Bergstrom RW, Fujimoto WY, Teller DC, De Haen C 1989 Oscillatory insulin secretion in perifused isolated rat islets.
Am J Physiol 257:E479E485
-
Lang DA, Matthews DR, Burnett M, Turner RC 1981 Brief, irregular oscillations of basal plasma insulin and glucose
concentrations in diabetic man. Diabetes 30:435439[Abstract]
-
Matthews DR, Naylor BA, Jones RG, Ward GM, Turner
RC 1983 Pulsatile insulin has greater hypoglycemic effect than
continuous delivery. Diabetes 32:617621[Abstract]
-
Ward GM, Walters JM, Aitken PM, Best JD, Alford
FP 1990 Effects of prolonged pulsatile hyperinsulinemia in humans.
Enhancement of insulin sensitivity. Diabetes 39:501507[Abstract]
-
Polonsky KS, Given BD, Van Cauter E 1988 Twenty-four-hour profiles and patterns of insulin secretion in normal
and obese subjects. J Clin Invest 81:442448[Medline]
-
OMeara NM, Sturis J, Van Cauter E, Polonsky KS 1993 Lack of control by glucose of ultradian insulin secretory
oscillations in impaired glucose tolerance and in non-insulin-dependent
diabetes mellitus. J Clin Invest 92:262271[Medline]
-
Halban PA 1991 Structural domains and molecular
lifestyles of insulin and its precursors in the pancreatic ß cell. Diabetologia 34:767778[Medline]
-
Smeekens SP, Steiner DF 1990 Identification of a
human insulinoma cDNA encoding a novel mammalian protein structurally
related to the yeast dibasic processing protease Kex2. J Biol Chem 265:29973000[Abstract/Free Full Text]
-
Smeekens SP, Avruch AS, LaMendola J, Chan SJ, Steiner
DF 1991 Identification of a cDNA encoding a second putative
prohormone convertase related to PC2 in AtT20 cells and islets of
Langerhans. Proc Natl Acad Sci USA 88:340344[Abstract]
-
Glauber HS, Henry RR, Wallace P, et al. 1987 The
effects of biosynthetic human proinsulin on carbohydrate metabolism in
non-insulin-dependent diabetes mellitus. N Engl J Med 316:443449[Abstract]
-
Porte Jr D, Kahn SE 1989 Hyperproinsulinemia and
amyloid in NIDDM: clues to etiology of islet ß-cell dysfunction? Diabetes 38:13331336[Abstract]
-
Rhodes CJ, Alarcon C 1994 What ß-cell defect
could lead to hyperproinsulinemia in NIDDM? Some clues from recent
advances made in understanding the proinsulin-processing mechanism. Diabetes 43:511517[Abstract]
-
Westermark P, Wernstedt C, Wilander E, Hayden DW,
OBrien TD, Johnson KH 1987 Amyloid fibrils in human insulinoma
and islets of Langerhans of the diabetic cat are derived from a
neuropeptide-like protein also present in normal islets. Proc Natl Acad
Sci USA 84:38813885[Abstract]
-
Cooper GJS, Willis AC, Clark A, Turner RC, Sim RB,
Reid KBM 1987 Purification and characterization of a peptide from
amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci
USA 84:86288632[Abstract]
-
Lukinius A, Wilander E, Westermark GT, Engstrom U,
Westermark P 1989 Co-localization of islet amyloid polypeptide and
insulin in the B cell secretory granules of the human pancreatic
islets. Diabetologia 32:240244[Medline]
-
Kahn SE, DAlessio DA, Schwartz MW, et al. 1990 Evidence of cosecretion of islet amyloid polypeptide and insulin by
ß-cells. Diabetes 39:634638[Abstract]
-
Leighton B, Cooper GJS 1988 Pancreatic amylin and
calcitonin gene-related peptide cause resistance to insulin in skeletal
muscle in vitro. Nature 335: 632635
-
Silvestre RA, Peiro E, Degano P, Miralles P, Marco
J 1990 Inhibitory effect of rat amylin on the insulin responses to
glucose and arginine in the perfused rat pancreas. Regul Pept 31:2331[CrossRef][Medline]
-
Cooper GJS, Day AJ, Willis AC, Roberts AN, Reid KBM,
Leighton B 1989 Amylin and the amylin gene: structure, function
and relationship to islet amyloid and to diabetes mellitus. Biochim
Biophys Acta 1014:247258[CrossRef][Medline]
-
Young AA, Gedulin B, Vine W, Percy A, Rink TJ 1995 Gastric emptying is accelerated in diabetic BB rats and is slowed
by subcutaneous injections of amylin. Diabetologia 38:642648[CrossRef][Medline]
-
Olefsky J, Farquhar JW, Reaven G 1973 Relationship between fasting plasma insulin level and resistance to
insulin-mediated glucose uptake in normal and diabetic subjects. Diabetes 22:507513[Medline]
-
Kahn SE, Prigeon RL, McCulloch DK, et al. 1993 Quantification of the relationship between insulin sensitivity and
B-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42:16631672[Abstract]
-
Bagdade JD, Porte Jr D, Brunzell JD, Bierman EL 1974 Basal and stimulated hyperinsulinism: reversible metabolic
sequelae of obesity. J Lab Clin Med 83:563569[Medline]
-
Polonsky KS, Given BD, Hirsch L, et al. 1988 Quantitative study of insulin secretion and clearance in normal and
obese subjects. J Clin Invest 81:435441[Medline]
-
Beard JC, Ward WK, Halter JB, Wallum BJ, Porte Jr
D 1987 Relationship of islet function to insulin action in human
obesity. J Clin Endocrinol Metab 65:5964[Abstract]
-
Bergman RN, Phillips LS, Cobelli C 1981 Physiologic evaluation of factors controlling glucose tolerance in man:
measurement of insulin sensitivity and ß-cell glucose sensitivity
from the response to intravenous glucose. J Clin Invest 68:14561467[Medline]
-
Bergman RN 1989 Toward physiological
understanding of glucose tolerance: minimal-model approach. Diabetes 38:15121527[Abstract]
-
Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield
RL, Polonsky KS 1995 Insulin secretory defects in polycystic ovary
syndrome. Relationship to insulin sensitivity and family history of
non-insulin-dependent diabetes mellitus. J Clin Invest 96:520527[Medline]
-
Kahn SE 1996 Regulation of B-cell function
in vivo: from health to disease. Diabetes Rev 4:372389
-
Elbein SC, Wegner K, Kahn SE 2000 Reduced
ß-cell compensation to the insulin resistance associated with obesity
in members of Caucasian familial type 2 diabetic kindreds. Diabetes
Care 23:221227[Abstract]
-
Ward WK, Johnston CLW, Beard JC, Benedetti TJ, Halter
JB, Porte Jr D 1985 Insulin resistance and impaired insulin
secretion in subjects with histories of gestational diabetes mellitus. Diabetes 34:861869[Abstract]
-
Ryan EA, Imes S, Liu D, et al. 1995 Defects in
insulin secretion and action in women with a history of gestational
diabetes. Diabetes 44:506512[Abstract]
-
Buchanan TA, Xiang AH, Kjos SL, Trigo E, Lee WP,
Peters RK 1999 Antepartum predictors of the development of type 2
diabetes in Latino women 1126 months after pregnancies complicated by
gestational diabetes. Diabetes 48:24302436[Abstract]
-
Dunaif A, Finegood DT 1996 ß-Cell dysfunction
independent of obesity and glucose intolerance in the polycystic ovary
syndrome. J Clin Endocrinol Metab 81:942947[Abstract]
-
Chen M, Bergman RN, Pacini G, Porte Jr D 1985 Pathogenesis of age-related glucose intolerance in man: insulin
resistance and decreased ß-cell function. J Clin Endocrinol
Metab 60:1320[Abstract]
-
Kahn SE, Larson VG, Beard JC, et al. 1990 Effect
of exercise on insulin action, glucose tolerance and insulin secretion
in aging. Am J Physiol 258:E937E943
-
Kahn SE, Larson VG, Schwartz RS, et al. 1992 Exercise training delineates the importance of B-cell dysfunction to
the glucose intolerance of human aging. J Clin Endocrinol Metab 74:13361342[Abstract]
-
Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS 1997 Treatment with the oral antidiabetic agent troglitazone improves
beta cell responses to glucose in subjects with impaired glucose
tolerance. J Clin Invest 100:530537[Abstract/Free Full Text]
-
Elbein SC, Hasstedt SJ, Wegner K, Kahn SE 1999 Heritability of pancreatic beta-cell function among nondiabetic members
of Caucasian familial type 2 diabetic kindreds. J Clin Endocrinol
Metab 84:13981403[Abstract/Free Full Text]
-
Weyer C, Bogardus C, Mott DM, Pratley RE 1999 The
natural history of insulin secretory dysfunction and insulin resistance
in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104:787794[Abstract/Free Full Text]
-
Haffner S, Stern M, Hazuda H, Mitchell B, Patterson
J 1988 Increased insulin concentrations in nondiabetic offspring
of diabetic parents. N Engl J Med 319:12971301[Abstract]
-
Lillioja S, Mott DM, Howard BV, et al. 1988 Impaired glucose tolerance as a disorder of insulin action.
Longitudinal and cross-sectional studies in Pima Indians. N Engl
J Med 318:12171225[Abstract]
-
Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn
CR 1990 Slow glucose removal rate and hyperinsulinemia precede the
development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909915[Medline]
-
Martin BL, Warram JH, Krolewski AS, Bergman RN,
Soeldner JS, Kahn CR 1992 Role of glucose and insulin resistance
in development of type 2 diabetes mellitus: results of a 25-year
follow-up study. Lancet 340:925929[Medline]
-
Eriksson J, Franssila Kallunki A, Ekstrand A, et
al. 1989 Early metabolic defects in persons at increased risk for
non-insulin-dependent diabetes mellitus. N Engl J Med 321:337343[Abstract]
-
Lillioja S, Mott DM, Spraul M, et al. 1993 Insulin resistance and insulin secretory dysfunction as precursors of
non-insulin-dependent diabetes mellitus. Prospective studies of Pima
Indians. N Engl J Med 329:19881992[Abstract/Free Full Text]
-
Ferrannini E 1998 Insulin resistance versus
insulin deficiency in non-insulin-dependent diabetes mellitus: problems
and prospects. Endocr Rev 19:477490[Abstract/Free Full Text]
-
Chen K-W, Boyko EJ, Bergstrom RW, et al. 1995 Earlier appearance of impaired insulin secretion than of visceral
adiposity in the pathogenesis of NIDDM: 5-year follow-up of initially
nondiabetic Japanese-American men. Diabetes Care 18:747753[Abstract]
-
Haffner SM, Miettinen H, Gaskill SP, Stern MP 1995 Decreased insulin secretion and increased insulin resistance are
independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes 44:13861391[Abstract]
-
Pimenta W, Korytkowski M, Mitrakou A, et al. 1995 Pancreatic beta-cell dysfunction as the primary genetic lesion in
NIDDM. Evidence from studies in normal glucose-tolerant individuals
with a first-degree NIDDM relative. JAMA 273:18551861[Abstract]
-
Larsson H, Ahren B 1996 Failure to adequately
adapt reduced insulin sensitivity with increased insulin secretion in
women with impaired glucose tolerance. Diabetologia 39:10991107[CrossRef][Medline]
-
Mykkanen L, Haffner SM, Hales CN, Ronnemaa T, Laakso
M 1997 The relation of proinsulin, insulin, and
proinsulin-to-insulin ratio to insulin sensitivity and acute insulin
response in normoglycemic subjects. Diabetes 46:19901995[Abstract]
-
Kahn SE, Leonetti DL, Prigeon RL, Bergstrom RW,
Fujimoto WY 1995 Proinsulin as a marker for the development of
NIDDM in Japanese-American men. Diabetes 44:173179[Abstract]
-
Larsson H, Ahren B 1995 Effects of arginine on
the secretion of insulin and islet amyloid polypeptide in humans. Pancreas 11:201205[Medline]
-
Dechenes CJ, Verchere CB, Andrikopoulos S, Kahn
SE 1998 Human aging is associated with parallel reductions in
insulin and amylin release. Am J Physiol 275:E785E791
-
Landchild MJ, Knowles NG, Yao Q, et al. 2000 Increased ß-cell secretory demand is not the simple explanation for
inefficient proinsulin processing and islet amyloid formation in type 2
diabetes. J Invest Med 48:21A[Medline]
-
Knowles NG, Landchild MJ, Kahn SE 2000 Non-diabetic first degree relatives of individuals with type 2 diabetes
have diminished insulin and amylin release as markers of islet B-cell
function. Proc American Geriatrics Society Annual Meeting, Nashville,
TN; p 69
-
DeFronzo RA, Bonadonna RC, Ferrannini E 1992 Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15:318368[Abstract]
-
Yki-Järvinen H 1992 Glucose toxicity. Endocr
Rev 13:415431[Medline]
-
Robertson RP, Olson LK, Zhang HJ 1994 Differentiating glucose toxicity from glucose desensitization: a new
message from the insulin gene. Diabetes 43:10851089[Abstract]
-
Unger RH 1995 Lipotoxicity in the pathogenesis of
obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863870[Abstract]
-
Johnson KH, OBrien TD, Betsholtz C, Westermark P 1989 Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 321:513518[Abstract]
-
Kahn SE, Andrikopoulos S, Verchere CB 1999 Islet
amyloid: a long-recognized but underappreciated pathological feature of
type 2 diabetes. Diabetes 48:241253[Abstract/Free Full Text]
-
Kolterman OG, Insel J, Saekow M, Olefsky JM 1980 Mechanisms of insulin resistance in human obesity: evidence for
receptor and postreceptor defects. J Clin Invest 65:12721284[Medline]
-
Rewers M, Hamman RF 1995 Risk factors for
non-insulin-dependent diabetes. In: Harris ML, Cowie CC, Stern MF,
Boyko EJ, Reiber GE, Bennett PH, eds. Diabetes in America, ed 2. NIH
publication no. 95-1468. Bethesda, MD: NIH;179220
-
Kahn SE, Beard JC, Schwartz MW, et al. 1989 Increased ß-cell secretory capacity as mechanism for islet adaptation
to nicotinic acid-induced insulin resistance. Diabetes 38:562568[Abstract]
-
Kahn SE, McCulloch DK, Schwartz MW, Palmer JP, Porte Jr
D 1992 Effect of insulin resistance and hyperglycemia on
proinsulin release in a primate model of diabetes mellitus. J Clin
Endocrinol Metab 74:192197[Abstract]
-
Bonner-Weir S, Trent DF, Weir GC 1983 Partial
pancreatectomy in the rat and subsequent defect in glucose-induced
insulin release. J Clin Invest 71:15441553[Medline]
-
Leahy JL, Bonner-Weir S, Weir GC 1992 ß-Cell
dysfunction induced by chronic hyperglycemia. Current ideas on
mechanism of impaired glucose-induced insulin secretion. Diabetes Care 15:442455[Abstract]
-
Sharma A, Olson LK, Robertson RP, Stein R 1995 The
reduction of insulin gene transcription in HIT-T15 ß cells
chronically exposed to high glucose concentration is associated with
the loss of RIPE3b1 and STF-1 transcription factor expression. Mol
Endocrinol 9:11271134[Abstract]
-
Sharma A, Zangen DH, Reitz P, et al. 1999 The
homeodomain protein IDX-1 increases after an early burst of
proliferation during pancreatic regeneration. Diabetes 48:507513[Abstract]
-
Kahn SE, Bergman RN, Schwartz MW, Taborsky Jr GJ, Porte
Jr D 1992 Short-term hyperglycemia and hyperinsulinemia improve
insulin action but do not alter glucose action in normal humans.
Am J Physiol 262:E518E523
-
Byrne MM, Sturis J, Polonsky KS 1995 Insulin
secretion and clearance during low-dose graded glucose infusion.
Am J Physiol 268:E21E27
-
Ward WK, Halter JB, Beard JC, Porte Jr D 1984 Adaptation of B and A cell function during prolonged glucose infusion
in human subjects. Am J Physiol 246:E405E411
-
Herman WH, Morrow LA, Halter JB 1988 Maladaptation
of beta cell function to hyperglycemia in noninsulin-dependent diabetes
mellitus. Diabetes 37(Suppl 1):5A
-
Hartling SG, Røder ME, Dinesen B, Binder C 1996 Proinsulin, C-peptide, and insulin in normal subjects during an 8-h
hyperglycemic clamp. Eur J Endocrinol 134:197200[Medline]
-
Martin SK, Carroll R, Benig M, Steiner DF 1994 Regulation by glucose of the biosynthesis of PC2, PC3 and proinsulin in
(ob/ob) mouse islets of Langerhans. FEBS Lett 356:279282[CrossRef][Medline]
-
Skelly RH, Schuppin GT, Ishihara H, Oka Y, Rhodes
CJ 1996 Glucose-regulated translational control of proinsulin
biosynthesis with that of the proinsulin endopeptidases PC2 and PC3 in
the insulin- producing MIN6 cell line. Diabetes 45:3743[Abstract]
-
Shimabukuro M, Koyama K, Chen G, et al. 1997 Direct antidiabetic effect of leptin through triglyceride depletion of
tissues. Proc Natl Acad Sci USA 94:46374641[Abstract/Free Full Text]
-
Cnop M, Grupping A, Hoorens A, Bouwens L,
Pipeleers-Marichal M, Pipeleers D 2000 Endocytosis of
low-density lipoprotein by human pancreatic beta cells and uptake in
lipid-storing vesicles, which increase with age. Am J Pathol 156:237244[Abstract/Free Full Text]
-
Tsunehara CH, Leonetti DL, Fujimoto WY 1990 Diet
of second-generation Japanese-American men with and without
non-insulin-dependent diabetes. Am J Clin Nutr 52:731738[Abstract]
-
Chen M, Halter JB, Porte Jr D 1987 The role of
dietary carbohydrate in the decreased glucose tolerance of the elderly. J Am Geriatr Soc 35:417424[Medline]
-
Chen M, Bergman RN, Porte Jr D 1988 Insulin
resistance and ß-cell dysfunction in aging: the importance of dietary
carbohydrate. J Clin Endocrinol Metab 67:951957[Abstract]
-
Brunzell JD, Lerner RL, Hazzard WR, Porte Jr D, Bierman
EL 1971 Improved glucose tolerance with high carbohydrate feeding
in mild diabetes. N Engl J Med 284:521524[Medline]
-
Lee SK, Opara EC, Surwit RS, Feinglos MN, Akwari
OE 1995 Defective glucose-stimulated insulin release from
perifused islets of C57BL/6J mice. Pancreas 11:206211[Medline]
-
Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, Porte Jr D,
Schwartz MW 1999 Reduced ß-cell function contributes to
impaired glucose tolerance in dogs made obese by high-fat feeding.
Am J Physiol 277:E659E667
-
Mittelman SD, Van Citters GW, Kim SP, et al. 2000 Longitudinal compensation for fat-induced insulin resistance includes
reduced insulin clearance and enhanced ß-cell response. Diabetes 49:21162125[Abstract]
-
Bjorntorp P 1996 The regulation of adipose tissue
distribution in humans. Int J Obes Relat Metab Disord 20:291302[Medline]
-
Sako Y, Grill VE 1990 A 48-hour lipid infusion in
the rat time-dependently inhibits glucose-induced insulin secretion and
B cell oxidation through a process likely coupled to fatty acid
oxidation. Endocrinology 127:15801589[Abstract]
-
Zhou YP, Grill VE 1994 Long-term exposure of rat
pancreatic islets to fatty acids inhibits glucose-induced insulin
secretion and biosynthesis through a glucose fatty acid cycle. J
Clin Invest 93:870876[Medline]
-
Zhou YP, Grill V 1995 Long term exposure to fatty
acids and ketones inhibits B-cell functions in human pancreatic islets
of Langerhans. J Clin Endocrinol Metab 80:15841590[Abstract]
-
Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V 2001 Lipotoxicity of the pancreatic ß-cell is associated with
glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315321[Abstract/Free Full Text]
-
Boden G, Chen X, Rosner J, Barton M 1995 Effects
of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes 44:12391242[Abstract]
-
Kulkarni RN, Wang ZL, Wang RM, et al. 1997 Leptin
rapidly suppresses insulin release from insulinoma cells, rat and human
islets and, in vivo, in mice. J Clin Invest 100:27292736[Abstract/Free Full Text]
-
Poitout V, Rouault C, Guerre-Millo M, Briaud I, Reach
G 1998 Inhibition of insulin secretion by leptin in normal rodent
islets of Langerhans. Endocrinology 139:822826[Abstract/Free Full Text]
-
Seufert J, Kieffer TJ, Leech CA, et al. 1999 Leptin suppression of insulin secretion and gene expression in human
pancreatic islets: implications for the development of adipogenic
diabetes mellitus. J Clin Endocrinol Metab 84:670676[Abstract/Free Full Text]
-
Zhang S, Kim KH 1995 TNF-alpha inhibits
glucose-induced insulin secretion in a pancreatic ß-cell line
(INS-1). FEBS Lett 377:237239[CrossRef][Medline]
-
Dunger A, Cunningham JM, Delaney CA, et al. 1996 Tumor necrosis factor-
and interferon-
inhibit insulin secretion
and cause DNA damage in unweaned-rat islets. Extent of nitric oxide
involvement. Diabetes 45:183189[Abstract]
-
Saito K, Yaginuma N, Takahashi T 1979 Differential
volumetry of A, B, and D cells in the pancreatic islets of diabetic and
nondiabetic subjects. Tohoku J Exp Med 129:273283[Medline]
-
Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz
PU 1985 Islet pathology and the pathogenesis of type 1 and type 2
diabetes mellitus revisited. Surv Synth Pathol Res 4:110125[Medline]
-
Westermark P, Wilander E 1978 The influence of
amyloid deposits on the islet volume in maturity onset diabetes
mellitus. Diabetologia 15:417421[Medline]
-
Efanova IB, Zaitsev SV, Zhivotovsky B, et al. 1998 Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A
process dependent on intracellular Ca2+ concentration. J Biol Chem 273:3350133507[Abstract/Free Full Text]
-
Shimabukuro M, Zhou YT, Levi M, Unger RH 1998 Fatty acid-induced beta cell apoptosis: a link between obesity and
diabetes. Proc Natl Acad Sci USA 95:24982502[Abstract/Free Full Text]
-
Opie E 1901 The relation of diabetes mellitus to
lesions of the pancreas. Hyaline degeneration of the islets of
Langerhans. J Exp Med 5:527540
-
Howard Jr CF 1986 Longitudinal studies on the
development of diabetes in individual Macaca nigra. Diabetologia 29:301306[Medline]
-
Verchere CB, DAlessio DA, Palmiter RD, et al. 1996 Islet amyloid formation associated with hyperglycemia in
transgenic mice with pancreatic beta cell expression of human islet
amyloid polypeptide. Proc Natl Acad Sci USA 93:34923496[Abstract/Free Full Text]
-
Soeller WC, Janson J, Hart SE, et al. 1998 Islet
amyloid-associated diabetes in obese Avy/a mice
expressing human islet amyloid polypeptide. Diabetes 47:743750[Abstract]
-
Höppener JW, Oosterwijk C, Nieuwenhuis MG, et
al. 1999 Extensive islet amyloid formation is induced by
development of Type II diabetes mellitus and contributes to its
progression: pathogenesis of diabetes in a mouse model. Diabetologia 42:427434[CrossRef][Medline]
-
Kahn SE, Andrikopoulos S, Verchere CB, Wang F, Hull RL,
Vidal J 2000 Oophorectomy promotes islet amyloid formation in a
transgenic mouse model of type 2 diabetes. Diabetologia 43:13091312[CrossRef][Medline]
-
Andrikopoulos S, Verchere CB, Terauchi K, Kadowaki T,
Kahn SE 2000 ß-cell glucokinase deficiency and hyperglycemia are
associated with reduced islet amyloid deposition in a mouse model of
type 2 diabetes. Diabetes 49:20562062[Abstract]
-
Marshall JA, Hamman RF, Baxter J 1991 High-fat,
low-carbohydrate diet and the etiology of non-insulin- dependent
diabetes mellitus: the San Luis Valley Diabetes Study. Am J
Epidemiol 134:590603[Abstract]
-
Manson JE, Rimm EB, Colditz GA, et al. 1992 A
prospective study of postmenopausal estrogen therapy and subsequent
incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol 2:665673[Medline]
-
Westermark P, Engstrom U, Johnson KH, Westermark GT,
Betsholtz C 1990 Islet amyloid polypeptide: pinpointing amino
acid residues linked to amyloid fibril formation. Proc Natl Acad Sci
USA 87:50365040[Abstract]
-
Lorenzo A, Razzaboni B, Weir GC, Yankner BA 1994 Pancreatic islet cell toxicity of amylin associated with type-2
diabetes mellitus. Nature 368: 756760
-
Janson J, Ashley RH, Harrison D, McIntyre S, Butler
PC 1999 The mechanism of islet amyloid polypeptide toxicity is
membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48:491498[Abstract]
-
Steppan CM, Bailey ST, Bhat S, et al. 2001 The
hormone resistin links obesity to diabetes. Nature 409:307312[CrossRef][Medline]
-
de Souza CJ, Yu JH, Robinson DD, Ulrich RG, Meglasson
MD 1995 Insulin secretory defect in Zucker fa/fa rats is
improved by ameliorating insulin resistance. Diabetes 44:984991[Abstract]
-
Brown KK, Henke BR, Blanchard SG, et al. 1999 A
novel N-aryl tyrosine activator of peroxisome proliferator-activated
receptor-gamma reverses the diabetic phenotype of the Zucker diabetic
fatty rat. Diabetes 48:14151424[Abstract]
-
Welch S, Gebhart SSP, Bergman RN, Phillips LS 1990 Minimal model analysis of intravenous glucose tolerance test-derived
insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab 71:15081518[Abstract]
-
Vidal J, Kahn SE 2001 Regulation of insulin
secretion in vivo. In: Lowe Jr WL, eds. Genetics of diabetes
mellitus. Stamford, CT: Kluwer; 109131