Dinâmica da secreção de insulina, dm2,obesidade

Review series

Dynamics of insulin secretion and the clinical
implications for obesity and diabetes
Susumu Seino,1,2,3 Tadao Shibasaki,2 and Kohtaro Minami2
1Divisionof Diabetes and Endocrinology, Department of Internal Medicine, and 2Division of Cellular and Molecular Medicine,
Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
3Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Japan.

Insulin secretion is a highly dynamic process regulated by various factors including nutrients, hormones, and
neuronal inputs. The dynamics of insulin secretion can be studied at different levels: the single β cell, pancreatic
islet, whole pancreas, and the intact organism. Studies have begun to analyze cellular and molecular mechanisms
underlying dynamics of insulin secretion. This review focuses on our current understanding of the dynamics of
insulin secretion in vitro and in vivo and discusses their clinical relevance.

Introduction pancreatic islets from dogs (15–17). Thus, oscillation of insulin secre-
Insulin, which is secreted from pancreatic β cells, is the key hor- tion is likely caused by intrinsic β cell mechanisms and modified by
mone in regulating glucose metabolism. Insulin secretion is a highly exogenous signals such as hormonal and neuronal inputs. Oscilla-
dynamic process regulated by complex mechanisms. It is regulated by tions in [Ca2+]i rather than metabolism in the β cell are thought to be
nutrient status, hormonal factors such as gastrointestinal hormone the direct cause of these oscillations in insulin secretion (17).
incretins (i.e., glucagon-like peptide 1 [GLP-1] and glucose-depen- Hyperglycemic clamps and experiments in isolated pancreatic
dent insulinotropic polypeptide [GIP; originally termed “gastric islets have demonstrated that glucose induces insulin secretion in a
inhibitory polypeptide”]), and neural factors (1–5). In addition, the biphasic pattern: an initial component (first phase), which develops
regulation of insulin secretion is a multi-tiered process, occurring at rapidly but lasts only a few minutes, followed by a sustained com-
the level of the single β cell, the pancreatic islet, the whole pancreas, ponent (second phase) (18–20). Loss of first-phase secretion and
and the intact organism. Thus, in vivo, the dynamics of insulin secre- reduced second-phase secretion are characteristic features of type
tion is the consequence of an integration of all of these systems. 2 diabetes mellitus (T2DM); it is well known that a decrease in the
first phase of GSIS is found in the early stage of T2DM and also in
Fundamental mechanism of insulin secretion impaired glucose tolerance (IGT) (18, 21). Thus, in order to under-
Stimulus-secretion coupling is an essential biologic event in pan- stand the pathogenesis and pathophysiology of these diseases, it is
creatic β cells. Ca2+, ATP, cAMP, and phospholipid-derived signals important to clarify the cellular and molecular mechanisms respon-
such as diacylglycerol and inositol 1,4,5-triphosphate are the major sible for the alterations in the dynamics of insulin secretion. Bio-
intracellular signals in insulin secretion (6, 7). Glucose-stimulated chemical experiments and capacitance measurement have suggested
insulin secretion (GSIS) is the principal mechanism of insulin secre- that secretory vesicles generally exist in functionally distinct pools
tion. Glucose is transported into the β cell by glucose transporters, and that sequential release of these pools underlies the dynamically
and then metabolized, leading to increases in the ATP concentra- separable components of exocytosis (22). Pancreatic β cells contain
tion (or ATP/ADP ratio), closure of ATP-sensitive K+ (KATP) chan- at least two pools of insulin secretory granules that differ in release
nels, depolarization of the β cell membrane, and opening of the volt- competence: a reserve pool (RP), which accounts for the vast major-
age-dependent Ca2+ channels (VDCCs), thereby allowing Ca2+ influx ity of granules, and a readily releasable pool (RRP), which accounts
(8). The resultant rise in intracellular Ca2+ concentration ([Ca2+]i) in for the remaining granules (less than 5%). The prevailing hypothesis
the β cell triggers insulin secretion. In addition to this KATP chan- is that the release of RRP granules accounts for the first phase of
nel–dependent pathway, which triggers GSIS, there is also a KATP GSIS, and that mobilization of a subsequent supply of new granules
channel–independent pathway that amplifies the effects of Ca2+ on for release by mobilization accounts for the second phase (22).
exocytosis (9) and does not require an additional increase in [Ca2+]i. Recently, investigation of insulin granule dynamics has been
refined by use of the total internal reflection fluorescence micros-
Dynamics of insulin secretion copy (TIRFM) system. TIRFM is a technology that provides a
It is well known that the insulin concentration in the blood oscillates means to selectively excite fluorophores in an aqueous or cellular
even during postabsorptive periods (10, 11). There are two major environment very near a solid surface (within 100 nm) without
oscillatory secretion patterns, ultradian oscillations (pulsatile secre- exciting fluorescence from regions farther from the surface. The
tion), which have a period of 1–2 hours and may be due to a feed- unique features of TIRFM analysis have enabled numerous appli-
back loop between glucose production and insulin secretion (12), cations in biochemistry and cell biology (23–26).
and more rapid oscillations, which have a period of 10–15 minutes Revising previous models, our group used TIRFM to analyze
(13). Insulin is more effective at reducing blood glucose levels if it is insulin granule dynamics induced by various stimuli in detail,
delivered in pulses rather than continuously (14). Oscillatory insulin using primary cultured mouse pancreatic β cells (25). In contrast to
secretion has also been detected in vitro in isolated dog pancreas and the findings of Ohara-Imaizumi et al. (27), we found three different
modes of insulin exocytosis based on the dynamics of insulin gran-
Conflict of interest: The authors have declared that no conflict of interest exists. ules: mode 1, in which predocked granules are immediately fused to
Citation for this article: J Clin Invest. 2011;121(6):2118–2125. doi:10.1172/JCI45680. the plasma membrane by stimulation (old face); mode 2, in which

2118 The Journal of Clinical Investigation http://www.jci.org Volume 121 Number 6 June 2011

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Figure 1
Three modes of insulin granule dynamics. (A) Old face. Predocked granules are fused to the membrane by stimulation. (B) Restless newcomer.
Granules are newly recruited and immediately fused to the plasma membrane by stimulation. (C) Resting newcomer. Granules are newly
recruited, docked, and fused to the plasma membrane by stimulation. Sequential images (1 μm × 1 μm) acquired every 300 ms indicate insulin
granule dynamics. Flash indicates fusion events of insulin granules. Reproduced from Proceedings of the National Academy of Sciences of
the United States of America (25).

granules are newly recruited by stimulation and immediately fused Based on these data, we propose a new model of GSIS, in which
to the plasma membrane (restless newcomer); and mode 3, in which both the first and second phases are caused by newly recruited
granules are newly recruited by stimulation but are first docked and granules without docking (restless newcomer) (Figure 2). These
then fused to the plasma membrane (resting newcomer) (Figure 1 granules are more than 50 nm away from the plasma membrane
and ref. 25). Our group further demonstrated a biphasic pattern of but are readily releasable. Although both phases of insulin secre-
glucose-induced insulin granule exocytosis, and found that both tion are caused by these granules, the mechanisms of the first and
phases of glucose-induced insulin granule exocytosis are caused second phases of insulin secretion are distinct, and the two phases
primarily by restless newcomer (25). In contrast, most potassium- are caused by granules of separate pools. It is known that the actin
induced insulin granule exocytosis that occurs immediately and cytoskeleton is a highly dynamic and complex structure that is
transiently after stimulation results from release by old face. This remodeled in response to various stimuli (31), and the dynamics
was confirmed by sequential stimulation by glucose and potassium of insulin granules by glucose stimulation could also be affected
using two protocols: first, glucose stimulation followed by potas- by actin remodeling. Indeed, glucose stimulation triggers tran-
sium stimulation, and then the reverse (28). sient F-actin remodeling to allow access to the plasma membrane
The difference in the granules involved in the first phase of (32, 33). Since most insulin granules reside in a region deeper
glucose-induced fusion events and those involved in potassium- than the F-actin barrier, and F-actin remodeling could mobilize
induced fusion events is noteworthy. Our group recently demon- granules to t-SNARE proteins at the plasma membrane (34), it
strated that interaction of Rim2α with the vesicle protein Rab3 is is likely that actin remodeling is involved in the second phase of
required for docking of insulin granules but not for either potas- GSIS. Moreover, a recent study found that inhibition of RhoGDI
sium-induced or glucose-induced insulin granule exocytosis (29). enhanced the second phase of GSIS through activation of Cdc42
Docking is considered to be a braking state that prevents the (35). The finding that Cdc42 promotes actin polymerization
fusion of granules to the plasma membrane (26, 29). Stimulation (36) further supports the hypothesis that dynamics of the actin
of pancreatic β cells with high concentrations of potassium induc- network regulate the second phase of GSIS. However, the role of
es supraphysiologic levels of [Ca2+]i that can force insulin granule F-actin in the first phase of insulin secretion is still unknown, and
exocytosis by overwhelming the braking state. We hypothesize that it is possible that the roles of the actin cytoskeleton differ in the
glucose stimulation may not elicit fusion events by old face because first and second phases of insulin secretion.
the rise in [Ca2+]i induced by glucose is insufficient to overwhelm Some insulin granules are known to partially fuse to the plasma
the braking state, in contrast to that induced by potassium. While membrane, release small molecules, and then undergo endocytosis
potassium-induced insulin secretion requires only the Ca2+ signal, (termed “kiss-and-run exocytosis”) (37, 38). However, since crystal-
glucose-induced insulin secretion requires Ca2+ and other signals lized insulin cannot pass the small pore formed by kiss-and-run
including metabolites (30), permitting different modes of insulin exocytosis, the full fusion of granules is required for the release of
granule exocytosis induced by the two stimuli. insulin (39). The interaction of insulin granules with VDCC, which

The Journal of Clinical Investigation http://www.jci.org Volume 121 Number 6 June 2011 2119

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Figure 2
Existing and new models of GSIS in the normal state. (A) In the existing model of GSIS, the first phase of insulin secretion results from a RRP composed
of docked insulin granules (old face); the second phase of secretion results from a RP composed of granules located farther away (resting newcomer)
that are newly recruited upon stimulation, docked, and fused to the plasma membrane. (B) In the new model, both phases consist of insulin granules
that are recruited upon stimulation and immediately fused to the plasma membrane (restless newcomer). A RRP responsible for the first phase is
located more than 50 nm from the plasma membrane, yet is immediately releasable. The second phase of insulin secretion involves exocytosis of
insulin granules from a RP associated with the cortical actin network regulated by glucose-evoked signals in a mechanism yet to be elucidated.

promotes the local increase of [Ca2+]i at the fusion site, is proposed ential effects of GLP-1 and GIP on insulin secretion are also found
to be involved in the full fusion (38). in a clinical setting. For example, treatment with GLP-1 improves
insulin secretion in T2DM, whereas GIP does not (52). These and
Regulation of dynamics of insulin secretion other data suggest that cAMP signaling in distinct intracellular
by cAMP signaling compartments mediates the distinct cellular responses in pan-
It is well known that the insulin secretory response is much greater creatic β cells (53). Interestingly, a recent study showed that the
after oral than after i.v. glucose administration, even when plasma mouse β cell line MIN6-K20, which does not exhibit either GLP-1
glucose levels are matched. This phenomenon, called the “incretin or GIP responsiveness in monolayer culture, clearly exhibits respon-
effect,” is mediated by two gastrointestinal hormones, GLP-1 and siveness almost comparable with that of normal mouse islets when
GIP (40). GLP-1 and GIP are released in response to the ingestion pseudoislets (exhibiting three-dimensional structure) are formed by
of nutrients from gastrointestinal endocrine L cells and K cells, the cell line. These data suggest that β cell–β cell interaction is criti-
respectively (41). Both of these hormones potentiate GSIS (42, 43) cal for induction of cAMP responsiveness (54).
by activation of cAMP signaling in pancreatic β cells (44–46). cAMP
acts in the insulin secretory process at various steps (1, 47, 48). In Role of cAMP signaling in insulin granule dynamics
normal mouse pancreatic islets, in vitro concentration dependency Although cAMP potentiates GSIS, how cAMP acts in the exocy-
of GSIS displays a sigmoid curve (49), in which glucose concentra- totic processes of recruitment, docking, and fusion of secretory
tion exceeding 6 mM is required for triggering insulin secretion. granules is not clear. Our group has examined regulation of insu-
GLP-1 and GIP are known to potentiate both the first and second lin granule dynamics by cAMP signaling using the TIRFM system
phases of GSIS from perfused pancreas (50). In addition, it has been (25). 8-Br-cAMP alone did not increase the number of docking
reported that although single β cells dispersed from rat pancreatic granules or elicit fusion events but clearly potentiated both the
islets are often found to be glucose-insensitive, as assessed by elec- first and second phases of glucose-induced insulin granule exocy-
trical activity, GLP-1 endows these cells with glucose competency, tosis. 8-Br-cAMP enhanced the exocytosis by increasing the num-
probably by modulating KATP channel activity (51). These findings ber of restless newcomers, suggesting that activation of cAMP sig-
suggest a mechanism by which cAMP induces glucose responsive- naling increases the size of the pools (both RRP and RP) of insulin
ness of pancreatic β cells. We recently reported that small and step- granules and/or facilitates recruitment of insulin granules from
wise increases in the glucose concentration from 2.8 to 12.5 mM the pools to the plasma membrane.
do not trigger insulin secretion from perfused mouse pancreas It has been shown that cAMP oscillations occur in pancreatic
(48). However, in the presence of the cAMP analog 8-Br-cAMP or β cells (55–57). A close temporal and causal interrelationship
GLP-1, insulin secretion is readily evoked in response to such small between the increase in cytoplasmic Ca2+ and cAMP levels follow-
increases in glucose concentration. Thus, cAMP signaling is critical ing membrane depolarization has been reported (55, 56). A recent
not only for potentiation of GSIS, but also for induction of glucose study demonstrated that glucose metabolism directly controls
responsiveness. Treatment with GLP-1 induces a delayed but mea- cAMP signaling (57), suggesting that cAMP oscillations regulate
surable GSIS response, even in KATP channel–deficient (Kcnj11–/–) dynamics of insulin granule exocytosis.
mice (47), indicating that some of the effect of GLP-1 in induction
of glucose responsiveness is independent of the KATP channels. In Role of Epac2A/Rap1 signaling in the regulation
contrast, induction of glucose responsiveness by GIP in Kcnj11–/– of dynamics of insulin secretion
mice is much less than that by GLP-1, which indicates that the cAMP regulates the potentiation of insulin secretion by a PKA-
action of GIP is critically dependent on KATP channels (47). Differ- dependent mechanism and by a PKA-independent mechanism


review series

It has been proposed that SUs also bind to a putative receptor
expressed on insulin granules (gSURs) and that gSURs couple
with the granular chloride channel ClC-3 (70–72). Acidification of
insulin granules enhanced by ClC-3 might facilitate GSIS in pan-
creatic β cells (73–75).

Clinical implications of dynamics of insulin secretion
Obesity and insulin resistance. Clinically, obesity is characterized
by insulin resistance and hyperinsulinemia. Hyperinsulinemia
results from increased insulin secretion, decreased insulin clear-
ance (particularly hepatic insulin extraction), or a combination of
these two factors (76–79). One study indicates that insulin secre-
tion is increased in moderate obesity under basal conditions over
a 24-hour period on a mixed diet and in response to i.v. glucose
and is highly correlated with BMI, while hepatic insulin clear-
ance does not differ in normal and obese subjects, suggesting that
increased insulin secretion is the major determinant of hyperinsu-
linemia (78). However, in patients with more marked basal hyper-
Figure 3 insulinemia and during intense stimulation of insulin secretion,
Effect of cAMP signaling on the dynamics of insulin secretion. Activa- a reduction in insulin clearance also contributes to the greater
tion of cAMP signaling enhances both the first and the second phases
increase in peripheral insulin concentrations (78, 79).
of GSIS. Epac2A/Rap1 signaling increases the size of a RRP near the
plasma membrane. Whether Epac2A/Rap1 quantitatively or function- Because insulin secretion is related to insulin sensitivity (SI) as a
ally increases the size is not known. The mechanism of potentiation hyperbolic function (80, 81), compensation of insulin secretion for
of the second phase of GSIS by cAMP is still unclear, but PKA may SI is usually estimated from the disposition index (DI), which is cal-
be involved in regulating the size of the RP. The black line indicates culated as the product of SI and the first-phase acute insulin secre-
dynamics of insulin secretion by glucose stimulation, whereas the red tory response to i.v. glucose (AIRg), using the frequently sampled i.v.
line indicates potentiation of GSIS by cAMP signaling. glucose tolerance test (ref. 82 and Figure 4). It has been shown that SI
progressively and significantly decreases with obesity, whereas AIRg
rises, and thus DI declines significantly among obese family mem-
that involves the cAMP-binding protein Epac2 (now called Epa- bers (83). A study of obese youth with normal glucose tolerance, IGT,
c2A) (6, 58–63). Although there is no defect in the dynamics of and T2DM indicated that the first-phase insulin response to glucose
glucose-induced insulin granule exocytosis in Epac2a–/– mice, and DI progressively decrease with the degree of impairment of glu-
potentiation by cAMP of the first phase of glucose-induced exo- cose tolerance, with a more profound defect in obese subjects with
cytosis was significantly impaired (25). In addition, Rap1, which T2DM involving both the first- and second-phase insulin responses
is activated by cAMP specifically through Epac2A in pancreatic (84). In addition, because the early-phase insulin secretory defect is
β cells, was found to be required for PKA-independent, cAMP- not found in subjects with simple obesity (obesity in the absence of
potentiated insulin secretion. Thus, Epac2A/Rap1 signaling is metabolic syndrome) and progressive decline of glucose tolerance is
important for the potentiation by cAMP of the first phase of only seen in subjects with decreased insulin secretion (85), the glu-
GSIS. A simulation model of insulin granule exocytosis (25) cose intolerance would seem to be evoked not by obesity itself but by
suggests that Epac2A/Rap1 signaling promotes insulin gran- the insulin secretory defect, especially in the first phase.
ule exocytosis by increasing the size of an RRP near the plasma The temporal pattern of insulin secretion and the secretory pulses
membrane (Figure 3). that occur every 1.5–2 hours in normal subjects are maintained in
obese subjects, although the amplitude of these pulses postprandi-
Epac2A is an intracellular target of sulfonylureas ally is greater in obese subjects (78). Rapid oscillations also occur
Sulfonylureas (SUs), widely used drugs in diabetes treatment, in obese subjects with a periodicity similar to that of normal sub-
stimulate insulin secretion by closing the KATP channels in the jects (10–12 minutes). Thus, the intrinsic regulatory mechanism of
pancreatic β cell membrane through binding to the SU receptor the dynamics of insulin secretion appears to be normal in an obese
SUR1, a regulatory subunit of the channels (64–66). state, and the increase in insulin secretion in obese subjects is not
Epac2A is a direct intracellular target of SUs, as demonstrated likely due to hyperresponsiveness to various stimuli in individual
in a fluorescence resonance energy transfer–based assay (67, 68). β cells but rather to the larger functional β cell mass (Figure 5A).
Moreover, SU-stimulated insulin secretion is significantly reduced In a mouse model with β cell–specific disruption of the insulin
both in vitro and in vivo in mice lacking Epac2a (67). These data receptor, loss of acute-phase insulin secretion in response to glucose
indicate that in addition to closure of the KATP channels, which but not to arginine (86) suggests that insulin signaling in pancreatic
is a prerequisite for SU action, activation of Epac2A/Rap1 signal- β cells itself is critical to GSIS. In humans, extreme insulin resistance
ing is required for SUs to exert their effects on insulin secretion. syndrome associated with a primary defect in insulin signaling due to
Considering the role of Epac2A/Rap1 signaling in insulin granule mutations of the insulin receptor gene has been reported (87). Lack
exocytosis described above, SUs may well increase the size of a RRP of insulin signal transduction in the peripheral tissues is responsible
of insulin granules near the plasma membrane that is primarily for the continuous elevation of plasma glucose levels after glucose
responsible for the early phase of insulin secretion. In fact, SUs are challenge. However, these patients show hyperinsulinemia follow-
known to stimulate the first phase of GSIS (69). ing glucose stimulation despite the defect in insulin signaling in the


review series

Figure 4
Changes in AIRg relative to changes in SI index in Pima Indian sub-
jects in whom glucose tolerance deteriorated from normal glucose tol-
erance (NGT) to impaired glucose tolerance (IGT) to diabetes (DIA)
(progressors) and in subjects who retained NGT (nonprogressors).
Lines represent the prediction line and the lower and upper limits of
the 95% confidence interval of the regression between AIRg and SI
index, as derived from a reference population of Pima Indians with
NGT. Adapted from Journal of Clinical Investigation (82).

In addition, Welch et al. reported that all patients with T2DM in a
European population exhibited decreased SI (90), whereas Taniguchi
et al. found that SI in Japanese T2DM is distributed from low to high
values (91). In contrast, AIRg was decreased in Japanese patients with
T2DM, while AIRg in those of European descent varied.
Impaired insulin secretion may be due to β cell dysfunction,
reduced β cell mass, or both. Whether β cell dysfunction or
reduced β cell mass precedes clinical onset of diabetes remains an
open question. However, in mice, surgical and chemical reductions
of β cell volume demonstrate that the functional adaptation of the
β cells (88). Thus, the significance of insulin signaling in human normal β cell prevents a rise in fasting glucose or reduction in the
β cells in the dynamics of acute insulin secretion remains unclear. first phase of insulin secretion (92, 93), suggesting that β cell dys-
T2DM. T2DM is characterized by impaired insulin secretion and/or function, rather than a decrease in β cell mass, is likely to be more
insulin resistance. However, insulin secretory capacity is the major closely associated with the pathophysiology of T2DM.
factor contributing to the development of T2DM because neither The insulin secretory response to glucose has been studied using
hyperglycemia nor glucose intolerance develops in insulin-resistant i.v. bolus glucose administration and hyperglycemic clamp, the
patients, so long as sufficient insulin is secreted from β cells in a timely former suitable for evaluation of the early phase (first phase) of
fashion in response to various stimuli. Genetic variation between pop- insulin secretion, the latter suitable for evaluation of the second
ulations likely contributes to differences in insulin secretory capacity, phase (94, 95). The first phase of AIRg (81) is often used to evalu-
and thus to the proclivity to develop T2DM. For example, although ate β cell function. As mentioned above (and shown in Figure 4),
obesity (defined by a BMI of greater than 30) is less prevalent in Japan AIRg is related to the degree of SI as a hyperbolic function (81, 82).
than the US, the prevalence of T2DM is similar in both countries (89). It is accepted that abnormal dynamics of insulin secretion selec-

Figure 5
Dynamics of insulin secretion in obesity, IGT, and T2DM. (A) In obesity, the function of individual β cells appears to be normal and both phases
of GSIS are enhanced primarily due to an increase in β cell mass. (B) In IGT, the first phase is slightly impaired because of a decrease in the size
of the RRP and/or partial defect in the exocytotic process of the granules in this pool, and the second phase is only moderately reduced. (C) In
T2DM, the first phase is absent because of a complete loss of the RRP and/or a complete defect in the exocytotic process. The second phase
is also reduced, probably due to the decreased RP and/or disturbance of cortical actin network in T2DM. Black lines indicate dynamics of insulin
secretion in normal state, whereas red lines indicate insulin secretion in disease.


review series

tive for glucose stimulation, especially the first phase of the insu- response (109, 114–116). Acute i.v. infusion of GLP-1 (110), liraglu-
lin response to i.v. glucose, is already reduced in the early stages of tide (117), and exenatide (118) improves insulin secretory response
T2DM (96, 97), first-degree relatives of patients with T2DM (98, to i.v. glucose in patients with relatively mild T2DM by enhancing
99), and those with IGT and their first-degree relatives (91, 100, both the first and second phases of insulin secretion. The first phase
101). In addition, even across the range of normal fasting glucose of the insulin response is also improved in patients with T2DM after
levels, the first-phase response decreases as the glucose level increas- treatment with liraglutide for 14 weeks, as assessed by i.v. glucose
es (97, 102). Furthermore, as glucose tolerance decreases, for any tolerance test. Interestingly, in patients with T2DM, the defect in
degree of SI, the first-phase response is lower in those with lower amplification of the second-phase insulin response to glucose by
glucose tolerance (97). As mentioned above, since the early phase GIP is more pronounced than that in amplification of the first phase
of insulin secretion is determined by the RRP, a reduction in its size (119). Thus, although both GLP-1 and GIP act on insulin secretion
and/or impaired exocytosis of RRP granules might develop in IGT through cAMP signaling in pancreatic β cells as described above,
and in the early stages of T2DM (Figure 5B). The RRP is completely these hormones have distinct effects on the dynamics of GSIS.
depleted, and the RP is markedly reduced in the developed stage of In vitro, the dynamics of GSIS are usually assessed by a large
T2DM (Figure 5C). Signaling mechanisms underlying exocytosis of and rapid increase in glucose concentration, e.g., an immedi-
insulin granules from the RRP and the RP may also be defective in ate increase from 3–4 mM to 16–20 mM glucose. However, such
T2DM. Clarification of the mechanisms regulating insulin granule a drastic change in glucose concentration is unlikely to occur in
exocytosis from the RRP as well as the size of RRP should be helpful the physiological state in vivo. As described above, although small
for understanding a defect in the first phase of GSIS in T2DM. and stepwise increases in the glucose concentration do not trigger
The pulsatile nature of insulin secretion is maintained in patients insulin secretion in perfused pancreas, activation of cAMP signal-
with T2DM, with the number of pulses similar to that in healthy ing evokes insulin secretion even in this setting (45). Thus, in addi-
control subjects (103). Pulses are detected even in patients with very tion to potentiation of GSIS, incretins and incretin-related drugs
low rates of insulin secretion, suggesting that this rhythmic secre- might contribute to triggering the first phase of GSIS in the physi-
tion is a fundamental characteristic of β cell function that is retained ological state in vivo, since circulating levels of GLP-1 and GIP rise
even when there is a severe loss of secretory reserve (103). However, concomitantly with blood glucose after meal ingestion.
in patients with T2DM, the pulses after meals are less frequent, are
irregular, and have a significantly lower amplitude, resulting in a Conclusion
marked disruption in the dynamics of post-meal insulin secretion. Since the first report of biphasic insulin secretion in response to glu-
Interestingly, pulsatility and/or rapid oscillation of insulin secretion cose by Curry et al. (19), the dynamics of insulin secretion have been
is lost or disordered in first-degree relatives of T2DM patients who studied extensively in both normal and disease states such as diabetes
show minimal glucose intolerance or normal glucose tolerance, and and obesity using in vitro and in vivo systems. It is generally accepted
subjects with IGT (104–107). A loss of coordinated insulin secretory that the abnormalities in the dynamics of insulin secretion, especially
responses to oscillatory glucose infusion is found in subjects with a defect in the first phase of GSIS, represent an early event in the
IGT, indicating a defect in the ability of the β cell to properly sense development of T2DM. While studies so far have focused primarily
and respond to parallel changes in the plasma glucose level (107). on phenomenology of the dynamics of insulin secretion, the underly-
Moreover, a recent mouse study revealed that the molecular clock ing cellular and molecular mechanisms can now be investigated by
in β cells has a role in rhythmic control of insulin secretion and various approaches. Clarification of these mechanisms should yield
that ablation of the pancreatic clock can trigger the onset of T2DM novel therapeutic strategies as well as further understating of the
(108). These findings suggest that abnormalities in the dynamics pathogenesis and pathophysiology of obesity and T2DM.
of insulin secretion are an early manifestation of β cell dysfunction
that precedes the development of T2DM. Acknowledgments
We are grateful to Kenneth Polonsky of the University of Chicago
Effects of incretins and incretin-related drugs for careful reading of, and helpful suggestions for, the manuscript,
on the dynamics of insulin secretion and Mitsuo Fukushima of Okayama Prefectural University for
The incretin effect is estimated to underlie approximately 60%–70% helpful discussion. We also thank Grace Honkawa for assistance
of insulin secretion in response to glucose in normal healthy sub- in the manuscript. This work was supported by a CREST grant
jects (109). Studies using hyperglycemic clamps and i.v. bolus glu- from the Japan Science and Technology Agency and Grant-in-Aid
cose administration indicate that incretin-related agents including for Scientific Research and by a grant for the Global Centers of
GLP-1, GIP, the GLP-1 receptor agonist exenatide, and the GLP-1 Excellence Program ‘‘Global Center of Excellence for Education
analog liraglutide augment both the first and second phases of the and Research on Signal Transduction Medicine in the Coming
insulin secretory response to glucose, with the most predominant Generation’’ from the Ministry of Education, Culture, Sports, Sci-
effect on the first phase (110). The timing of administration results ence and Technology. The Obesity Review Series is supported in
in differential effects of incretins or incretin-related drugs on the part by unrestricted educational grants from Merck & Co. and the
dynamics of insulin secretion (110, 111). Although the effects of i.v. Life Sciences Institute of the University of Michigan.
infusion of GLP-1 and GIP on potentiation of insulin secretion in
response to glucose are similar (112) and additive in normal healthy Address correspondence to: Susumu Seino, Division of Diabetes
subjects (113), they have distinct insulinotropic effects in T2DM. and Endocrinology, Department of Internal Medicine, Division of
GLP-1 infusion can readily normalize hyperglycemia in patients Cellular and Molecular Medicine, Department of Physiology and
with T2DM (114). On the other hand, the insulinotropic effect of Cell Biology, Kobe University Graduate School of Medicine, Kobe
GIP is markedly impaired in patients with T2DM, and GIP infusion 650-0017, Japan. Phone: 81.78.382.5860; Fax: 81.78.382.6762;
in diabetic patients elicits just 40% of the normal insulin secretory E-mail: seino@med.kobe-u.ac.jp.


review series

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