Although it has long been assumed that insulin resistance is the leading factor in
the pathogenesis of type 2 diabetes (1), evidence for the importance of the pancreatic
β-cells has accumulated over the past decades. In fact, the vast majority of genes
associated with type 2 diabetes have been linked to the β-cell, and impairments in
β-cell mass and in insulin secretion have been reported in numerous studies in patients
with type 2 diabetes. One misconception that has prevented the appreciation of the
β-cell defects for a long time is the idea of a “hyperinsulinemia” in patients with
type 2 diabetes. This concept has arisen from the observation that patients with type
2 diabetes often present with higher fasting insulin concentrations than nondiabetic
individuals. However, if insulin concentrations are interpreted in the context of
the concurrently elevated glucose levels in patients with type 2 diabetes, a relative
insulin deficit rather than hyperinsulinemia becomes apparent. Furthermore, when insulin
secretion is evaluated under stimulated conditions (e.g., after intravenous glucose
administration), the typical defects, especially in early-phase insulin release, can
be unmasked (2,3).
It has also been suggested that obesity causes type 2 diabetes through impaired insulin
action. Undoubtedly, the risk of developing type 2 diabetes increases markedly with
BMI. However, if obesity were really the cause of type 2 diabetes, one would expect
the vast majority of obese individuals to develop hyperglycemia, whereas in reality
∼80% of obese individuals remain free of diabetes (4). These findings suggest that
obesity and insulin resistance are indeed important cofactors that increase the individual
risk of diabetes but that the actual cause of the disease seems to be clearly linked
to the β-cells.
If one accepts this notion, the next question is whether β-cell defects are primarily
functional in nature or whether a reduction in the number of insulin-secreting cells
(i.e., β-cell mass) is the leading problem in type 2 diabetes. This article will summarize
the arguments in favor of both sides, aiming to reach a consensus as to the importance
of reduced β-cell mass and impaired β-cell function in the pathogenesis of type 2
diabetes.
Is type 2 diabetes primarily caused by a deficit in β-cell mass?
That type 2 diabetes develops largely because of a deficit in β-cell mass is supported
by several lines of evidence. Autopsy studies in various populations (European, Asian,
and North American) have reported significant reductions in the amount of pancreatic
β-cells in patients with type 2 diabetes compared with nondiabetic individuals (5–7).
The extent of this deficit ranges from ∼20% in some studies to ∼65% in others (5–7).
There is also evidence for a β-cell deficit in prediabetic individuals with impaired
fasting glucose (6). The reasons underlying the heterogeneous results from different
studies are probably multifactorial in nature. Presumably, the individual contribution
of the β-cell deficit versus that of β-cell dysfunction and insulin resistance to
the overall pathogenesis of type 2 diabetes varies between different populations.
While based on these studies there is no doubt that β-cell mass is reduced to a variable
extent in patients with type 2 diabetes, the reasons underlying this β-cell deficit
are less well established. A common view is that increased β-cell apoptosis leads
to the continuous loss of β-cells (8). In support of this theory, apoptosis was found
to be increased in islets from patients with type 2 diabetes compared with nondiabetic
subjects based on two different studies using either immunohistochemistry or Western
blot analysis (6,9). Controversy exists regarding the presumed causes of β-cell apoptosis
in type 2 diabetes. Under in vitro conditions, β-cell death has been induced by various
factors linked to the type 2 diabetes phenotype, such as high concentrations of glucose,
free fatty acids, or human islet amyloid polypeptide (10). Also commonly assumed is
that a high secretory demand in overtly hyperglycemic or obese individuals causes
generation of reactive oxygen species (oxidative stress) as well as protein misfolding
in the endoplasmatic reticulum (ER stress), both of which can result in the induction
of apoptosis (11). Finally, inflammatory signals, such as local production of interleukin-1β
within islet β-cells, have been linked to β-cell death in type 2 diabetes (12). Estimating
which of these mechanisms is most important for induction of β-cell death in patients
with type 2 diabetes seems difficult.
Although accelerated β-cell death would reasonably explain the overt β-cell deficit
in type 2 diabetes and would also be consistent with the clinical observation of a
progressive deterioration of insulin secretion in patients with type 2 diabetes over
time (13), an alternative hypothesis would be insufficient islet development during
the pre- and postnatal growth period (14). In support of such reasoning, we have previously
noted a remarkable variation in fractional β-cell area (>30-fold) in individuals of
similar age-groups throughout the pre- and postnatal growth period (15). It has also
been suggested that intrauterine malnutrition as well as certain polymorphisms may
predispose children to an insufficient formation of islets, which might lead to an
increased risk of diabetes later in life (16).
What are the consequences of a β-cell deficit for the maintenance of glucose homoeostasis?
Not surprisingly, postchallenge insulin levels are reduced after a β-cell loss (17,18).
There is also evidence that hyperglycemia causes additional functional impairments
in insulin release that go beyond the actual β-cell deficit (19). This is most likely
the result of β-cell exhaustion (i.e., depletion of insulin granules) and subsequent
loss of early-phase insulin release (20). In fact, if β-cell mass is reduced by 50%,
the secretory burden for the remaining β-cells increases by 100%, thereby leading
to chronic β-cell stress. This is probably the reason why the functional impairment
of insulin secretion (especially glucose-stimulated first-phase insulin release) in
patients with type 2 diabetes often markedly exceeds the estimated deficit in β-cell
mass (2,3). In turn, induction of β-cell rest by means of insulin therapy or even
an overnight infusion of somatostatin has been found to largely restore the functional
defect in glucose-induced insulin secretion in hyperglycemic patients with type 2
diabetes (21,22). That glucose-induced insulin secretion can be almost fully normalized
even within <1 day sheds doubts on the idea of a primary functional β-cell abnormality
in type 2 diabetes (23,24). Along the same line, progressive deterioration of glycemic
control over time occurred despite significant improvements in β-cell function in
a large randomized prospective trial (A Diabetes Outcome Progression Trial [ADOPT])
(13).
One way to address the impact of a β-cell loss is to study individuals with a β-cell
deficit due to causes other than type 2 diabetes, such as chronic pancreatitis. When
we examined a large group of patients who underwent partial pancreatectomy for various
pancreatic diseases, we found that on average diabetes occurred when β-cell area (as
quantified in the resected pancreatic tissue) was reduced by ∼65% (25). This number
is consistent with the mean reduction in β-cell area reported in a recent autopsy
study in patients with type 2 diabetes (6). The impact of an acute 50% reduction in
β-cell mass has also been examined prospectively in individuals who donated 50% of
their pancreas for transplantation (17). In this study, hemipancreatectomy led to
abnormal glucose tolerance in 7 of 28 donors after 1 year, along with a significant
impairment in insulin secretion (17). Four of eight patients who had been followed
up for 9–18 years after the hemipancreatectomy had developed overt diabetes in the
meantime (26). Notably, the risk of diabetes was greatest in obese patients (26),
probably owing to the higher insulin demand in such patients. Also, disproportionate
hyperproinsulinemia, which was initially believed to be a primary functional abnormality
in type 2 diabetes (27), was found after hemipancreatectomy, suggesting that exaggerated
secretion of proinsulin results from an increased insulin demand subsequent to the
β-cell loss (28). These data from organ donors are in good agreement with studies
in patients undergoing partial pancreatectomy for chronic pancreatitis or tumors showing
significant impairments in insulin secretion as well as a high risk of diabetes after
surgery (18).
The impact of an ∼50% reduction of β-cell mass has also been examined in various large
animal models. Indeed, most of the characteristic features of type 2 diabetes, such
as reduced maximum insulin secretion, reduced amplitude of pulsatile insulin secretion,
reduced insulin clearance, impaired postprandial glucagon suppression, and insulin
resistance, have been found after an experimental β-cell loss resembling the β-cell
deficit in patients with type 2 diabetes (29,30). Studies in mice or rats suggesting
preserved glucose homoeostasis after 60–90% partial pancreatectomy are difficult to
interpret because of the unusually high capacity for β-cell regeneration in rodents
of young age (31). Notably, studies in older animals or in adult humans have not confirmed
such high potential for β-cell regeneration after partial pancreatectomy (32,33).
An important functional parameter that has been tightly linked to β-cell mass in various
studies is the amplitude of pulsatile insulin secretion (34). A recent series of studies
examining the interaction between pulsatile insulin secretion and hepatic insulin
signaling has convincingly demonstrated that reduced pulsatile insulin secretion (which
typically results from a β-cell deficit) causes impaired activation of the hepatic
insulin receptor substrate (IRS)-1 and IRS-2, as well as downstream insulin-signaling
molecules (35). Also, a failure to suppress glucagon levels in response to glucose
administration as well as peripheral insulin resistance has been linked to abnormalities
in pulsatile insulin secretion (29,36,37). Collectively, these studies lend strong
support to the hypothesis that reductions in β-cell mass secondarily cause various
abnormalities in β-cell function (especially pulsatile insulin secretion), α-cell
function, and insulin action in patients with type 2 diabetes (38,39). The importance
of β-cell mass for the maintenance of glucose homoeostasis is further emphasized by
studies showing restoration of glucose control after pancreas transplantation even
in insulin-resistant patients and in spite of steroid-based immunosuppressive treatment
regimens (40). A working hypothesis on the consequences of reduced β-cell mass on
the pathogenesis of type 2 diabetes is presented in Fig. 1.
Figure 1
Working model for the impact of reduced β-cell mass on the pathogenesis of type 2
diabetes. In patients with type 2 diabetes, β-cell mass is reduced by ∼20–65%, leading
to impaired and delayed insulin secretion and a specific reduction in the amplitude
of pulsatile insulin secretion. The reduction of insulin secretion and insulin pulsatility
leads to disruption of the intraislet insulin-glucagon cross-talk, causing insufficient
suppression of glucagon release. Reduced pulsatile insulin secretion impairs hepatic
insulin signaling and perturbs peripheral insulin action. Increased hepatic glucose
release is further augmented by the exaggerated glucagon concentrations. Together,
these defects cause hyperglycemia in patients with type 2 diabetes.
Is β-cell loss of function the main determinant of β-cell defects in type 2 diabetes?
The case for a prevalent role of β-cell loss of function versus β-cell loss of mass
in the etiology and pathogenesis of human type 2 diabetes is a thorny issue, essentially
because we have an incomplete knowledge of the exact role played by the β-cell in
the natural history of this disease (41,42). In humans, only in the last decade has
a reasonable consensus been reached regarding how one should measure β-cell functional
mass in vivo (43). β-Cell functional mass can hardly be summarized in one single number
for the simple reason that the β-cell copes with awfully complex and diverse tasks.
The minimum level of description of β-cell functional mass should include measurement
of both derivative, or dynamic, control (i.e., the β-cell response to the rate of
glucose increase) and proportional, or static, control (i.e., the stimulus response
curve relating insulin secretion rate to glucose concentration) of β-cell functional
mass during both intravenous and oral glucose challenges (43) so as to also be able
to quantify the incretin effect on insulin secretion (44,45).
During appropriate intravenous glucose challenges, the derivative (dynamic) control
is the time-honored first-phase insulin release, whereas the stimulus response curve
of the proportional (static) control embodies the traditional basal insulin secretion
rate plus the second-phase insulin response (46) (Fig. 2). The incretin effect can
be quantified as the amplification of insulin secretion rate (or either control of
β-cell functional mass) induced by the oral versus the venous route of glucose administration
(44,45). Extensive evidence supports the notion that different insulin granule pools
(47) and distinct voltage-gated calcium channels (48) sustain the derivative and the
proportional control of insulin secretion, whereas it is obvious that the incretin
effect is served by specific β-cell receptors and signaling molecules (49). Attempts
to build more sophisticated modeling of in vivo β-cell function that embodies these
additional features of the insulin secretory machinery are under way (50,51).
Figure 2
Stimulus response curve for first-phase (derivative control of β-cell function) (continuous
lines) and second-phase (proportional control of β-cell function) (dotted lines) insulin
release in control subjects (C) and in patients with type 2 diabetes (T2DM). All subjects
underwent a number of hyperglycemic clamps at graded glucose levels to construct a
stimulus response curve in each. Although both first- and second-phase insulin releases
are severely impaired in the patients (P < 0.01 for both, type 2 diabetic vs. control),
second phase shows a graded response to the glucose challenge, whereas first phase
is virtually absent in the patients, thereby showing asymmetric functional defects.
Data are redrawn from ref. 52.
Patients with type 2 diabetes display reductions in the derivative (dynamic) and proportional
(static) controls of β-cell functional mass (52,53) and in the incretin effect (44).
All of these impairments concur to cause β-cell failure in these patients. At this
qualitative level of description, these findings may be equally compatible with a
prevalent role of either a β-cell loss of function or a β-cell loss of mass in β-cell
failure (41). If the latter were the only β-cell alteration, the β-cell functional
profiling in human type 2 diabetes would show 1) parallel defects in both controls
of β-cell functional mass, 2) no possibility of rapid reversibility of either defect,
3) no defect in the incretin effect when expressed as percent, and 4) no involvement
of genes regulating β-cell function.
However, under close inspection the available data fulfill none of the above predictions,
thereby lending support to the existence of β-cell loss of function independently
of β-cell loss of mass in type 2 diabetes. We herein briefly review the experimental
evidence falsifying the four statements above.
1. Lack of parallelism between defects of derivative (dynamic) and proportional (static)
control of β-cell functional mass in patients with type 2 diabetes.
In his Banting Lecture of 1990, Daniel Porte, beautifully summarizing several decades
of research on the β-cell, reported that first-phase insulin secretion (derivative
or dynamic control) is disproportionately more impaired than second-phase insulin
secretion (proportional or static control) in patients with overt type 2 diabetes
(54). Until then, most studies were conducted with intravenous glucose challenges,
in which the β-cell metrics were based on insulin concentration. Potential critiques
were the (lack of) generalizability of these observations to the oral route of administration
and the potential pitfalls introduced by the use of insulin concentration, which is
heavily determined not only by insulin secretion rate but also by insulin catabolism,
with the latter process being variably altered in states of insulin resistance such
as diabetes. These potential drawbacks have been overcome by in vivo β-cell metrics
resting on mathematical modeling of C-peptide (43,55,56), from which one can compute
the β-cell insulin secretion rate (units: picomoles per minute) and quantify the derivative
control and proportional control of β-cell functional mass. These tools have confirmed
that in type 2 diabetes, there are severe impairments of both derivative (dynamic)
and proportional (static) control of β-cells (53), and that these defects are evident
also during an oral mixed-meal test (57).
However, during intravenous glucose challenges, the defect in the derivative (dynamic)
control exceeds the impairment in the proportional (static) control of β-cell secretion
(Fig. 2). Importantly, this lack of parallelism between the two defects is evident
also in the prediabetes stage. While the derivative (dynamic) control displays an
approximately linear decline (58), which starts already at glucose levels well within
the limits of normalcy (59), the proportional (static) control is characterized by
a somewhat abrupt fall in the passage from impaired glucose regulation to overt diabetes
(58,60).
2. Fast reversibility of β-cell defects in type 2 diabetes.
Looking at fast reversibility of defects in β-cell functional mass as evidence of
function-related—not mass-related—impairments is predicated on the tenet that β-cells
in human adults turn over very slowly. Although life span and regeneration rates of
β-cells are quite arduous to measure in humans, the few current data show that the
β-cell pool turns over at a very slow rate of years (61,62). Bariatric surgery performed
in patients with type 2 diabetes has been reported to cause significant improvements
in β-cell function in the time span of a few weeks (63) or even days (64), i.e., orders
of magnitude faster than it can be accounted for by changes in mass. However, the
perturbations brought about by complex and different surgical intervention always
leave room for the possibility that, inadvertently, not all factors may have been
controlled for appropriately in these comparisons. From this viewpoint, a recent paper
by Lim et al. (65) may be of help. These authors treated patients with type 2 diabetes
with a very-low-calorie diet (VLCD) and monitored changes in insulin secretion and
insulin action by performing isoglycemic insulin clamps and hyperglycemic clamps,
respectively. In the time frame of weeks, they detected a robust improvement in the
β-cell functional mass of these patients before any change in insulin sensitivity
could be documented. Similar results were reported by us in a small group of morbidly
obese patients with type 2 diabetes after only 1 week of VLCD (66). Finally, in a
clinical trial conducted by Weng et al. (22) patients with newly diagnosed type 2
diabetes were intensively treated for 4 weeks with insulin pump therapy, basal-bolus
insulin therapy, or a number of oral hypoglycemic agents, with the goal of normalizing
blood glucose levels over the entire day. At the end of the 4-week treatment period,
there was a dramatic improvement in first-phase insulin release during the intravenous
glucose tolerance test, which was also partially maintained after 1 year off of therapy.
Therefore, different interventions, such as bariatric surgery, VLCD, or intensive
diabetes treatment, can result in marked improvements in β-cell functional mass in
the time frame of a few weeks.
3. Presence of an incretin defect in type 2 diabetes.
In the case of a pure β-cell loss of mass, the incretin effect would be decreased
in absolute terms but normal when expressed in percent figures. However, this requires
that the incretin effect be measured as insulin secretion rate—not insulin concentration.
Unfortunately, in most experiments the latter metric is used rather than the former.
A few years ago, a detailed study by Muscelli et al. (44) showed that the incretin
effect, computed as the ratio of total insulin secretion rate during the oral glucose
challenge to total insulin secretion rate during the intravenous challenge, was decreased
in type 2 diabetes. The same was also true for the incretin effect on proportional
(static) control, but not on derivative (dynamic) control, of β-cell functional mass.
Thus, this study provides two pieces of evidence in favor of β-cell loss of function
in type 2 diabetes: 1) there is a defect in the incretin effect on insulin secretion
rate when expressed as percent and 2) the defect in the incretin effect affects proportional
(static) but not derivative (dynamic) control of insulin secretion, thereby highlighting
one more asymmetry in β-cell functional mass defects associated with type 2 diabetes.
4. β-Cell loss-of-function gene variants are risk factors for type 2 diabetes and
are associated with decreased β-cell functional mass.
Several lines of evidence, including twin studies (67), support the notion that the
phenotype of β-cell functional mass is determined by genetic factors to quite a large
extent. Over the last 6 years, genetic variability at >60 genetic loci has been firmly
linked to type 2 diabetes risk (68). Many of these loci are believed to play a role
in diabetes etiology primarily through effects on β-cell function (69), and indeed,
they are associated with reduced β-cell functional mass in vivo in humans—even in
patients with type 2 diabetes (70–73). However, at this level of phenotypic resolution
and in the absence of an in vivo method to quantify β-cell mass, dissecting out the
role(s) of β-cell loss of mass versus loss of function is only presumptive.
Studies in human islets and isolated β-cells can be helpful. Indeed, glucose-induced
insulin secretion in islets taken from patients with type 2 diabetes is reduced by
50% after normalization for islet insulin content, which is a proxy for reduced β-cell
number in diabetic islets (74). Most importantly, the diabetogenic variants of four
loci (TCF7L2, ADRA2A, KCNJ11, and KCNQ1) were associated with reduced insulin exocytosis
or altered insulin granule distribution in isolated β-cells, which implies that part,
if not most, of the diabetogenic influence of these risk variants is mediated through
alterations in single β-cell function (74). Thus, there is converging evidence stemming
from distinct experimental settings that defects in β-cell function underlie and cause
β-cell failure in type 2 diabetes. However, this does not necessarily rule out a role,
even a prominent one, for β-cell loss of mass, for which extensive evidence also exists.
The relative roles played by each defect in β-cell failure remain unknown.
Concluding remarks
The conundrum of whether loss of mass or loss of function underlies the β-cell defects
in type 2 diabetes is not likely to be conclusively solved on the basis of the evidence
we have reviewed here. Decreased cell mass and acceleration of the biological processes
resulting in β-cell loss have been described in type 2 diabetes by a number of laboratories.
On the other hand, several lines of evidence suggest that β-cell functional defects
may exist in type 2 diabetes.
Both viewpoints tacitly assume that 1) type 2 diabetes is a rather homogeneous entity,
at least when it comes to β-cell biology, and 2) overall islet secretory capacity
is a linear function of the product between β-cell number and isolated β-cell function.
It is possible that neither assumption holds true.
The most likely scenario, indeed, is that a variable combination of the two processes,
loss of mass and loss of function, is at work in type 2 diabetes. Indeed, there appears
to be a tight relationship between mass of pancreatic β-cells and functional insulin
secretion (75) (Fig. 3). A working model for the potential interaction of β-cell mass
and β-cell function is presented in Fig. 4. If true, from the therapeutic viewpoint
this offers an opportunity and poses a challenge.
Figure 3
Relationship between pancreatic β-cell area, as determined from pancreatic tissue
removed at surgery, and the C-peptide–to–glucose ratio determined in the fasting state
(A) and 30 min after oral glucose ingestion in 8 individuals with normal glucose tolerance
(NGT), 14 with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT),
and 11 with diabetes. r and P values were calculated by linear regression analysis.
These analyses demonstrate the tight relationship between β-cell mass and β-cell function.
Modified from ref. 75.
Figure 4
Consensus model for the relationship between impaired β-cell function and mass in
type 2 diabetes. A reduction in β-cell mass increases the secretory demand to the
remaining β-cells, thereby disturbing β-cell function. This may lead to hyperglycemia
and hyperlipidemia, which may again induce β-cell apoptosis, thereby aggravating the
β-cell deficit. Along the same lines, the vicious circle may be initiated by a primary
defect in β-cell function. The detrimental effects of hyperglycemia and β-cell exhaustion
on β-cell mass and function may involve both oxidative stress and ER stress. FFA,
free fatty acid.
The opportunity is that the defect in β-cell function is susceptible to improvement,
even rapidly, with prompt beneficial effects on the patient, and it may even lead
to remission of the disease (22,63–65). The challenge is that the processes leading
to and the defect in β-cell mass itself need to be, at least partially, corrected
to prevent an otherwise inexorable progression and to find a cure of this disease.