MINI REVIEW

Glucose-stimulated insulin secretion: A newer

perspective
Mitsuhisa Komatsu*, Masahiro Takei, Hiroaki Ishii, Yoshihiko Sato

ABSTRACT
Existing concepts and models for glucose-stimulated insulin secretion (GSIS) are overviewed and a newer perspective has been for-
mulated toward the physiological understanding of GSIS. A conventional model has been created on the basis of in vitro data on
application of a square wave high glucose in the absence of any other stimulatory inputs. Glucose elicits rapid insulin release
through an adenosine triphosphate-sensitive K+ channel (KATP channel)-dependent mechanism, which is gradually augmented in a
KATP channel-independent manner. Biphasic GSIS thus occurs. In the body, the b-cells are constantly exposed to stimulatory signals,
such as glucagon-like peptide 1 (GLP-1), parasympathetic inputs, free fatty acid (FFA), amino acids and slightly suprathreshold levels
of glucose, even at fasting. GLP-1 increases cellular cyclic adenosine monophosphate, parasympathetic stimulation activates protein
kinase C, and FFA, amino acids and glucose generate metabolic amplification factors. Plasma glucose concentration gradually rises
postprandially under such tonic stimulation. We hypothesize that these stimulatory inputs together make the b-cells responsive to
glucose independently from its action on KATP channels. Robust GSIS in patients with a loss of function mutation of the sulfonylurea
receptor, a subunit of KATP channels, is compatible with this hypothesis. Furthermore, pre-exposure of the islets to an activator of
protein kinase A and/or C makes b-cells responsive to glucose in a KATP channel- and Ca2+-independent manner. We hypothesize
that GSIS occurs in islet b-cells without glucose regulation of KATP channels in vivo, for which priming with cyclic adenosine mono-
phosphate, protein kinase C and non-glucose nutrients are required. To understand the physiology of GSIS, comprehensive integra-
tion of accumulated knowledge is required. (J Diabetes Invest, doi: 10.1111/jdi.12094, 2013)

KEY WORDS: Adenosine triphosphate-sensitive K+ channel, Modulatory signals, Physiological insulin secretion

INTRODUCTION the present review. We present an overview of existing concepts

Insulin is the exclusive hormone that lowers plasma glucose and models for GSIS, and provide a newer perspective based
concentration, and glucose homeostasis is maintained primarily on recent developments in this field toward its physiological
as a result of regulated insulin secretion. Pancreatic b-cells rec- understanding. Although evidence for a ‘glucose receptor’ has
ognize extracellular glucose concentration and secrete insulin as recently been reported4, this topic will not be discussed in the
required at a given time. Glucose-stimulated insulin secretion present review, because its physiological relevance remains to
(GSIS) is modulated by a number of factors, such as non- be determined.
glucose nutrients, hormones and neural inputs (Figure 1). Thus,
the intracellular network for regulation of insulin secretion is ADENOSINE TRIPHOSPHATE-SENSITIVE POTASSIUM
complex and multifactorial. Although GSIS has been viewed as CHANNEL: THE CENTRAL DOGMA
analogous to excitation-contraction coupling of muscle1 and On elevation of plasma glucose concentration, glucose enters
stimulus-secretion coupling of neuron/chromaffin cells2, the the pancreatic b-cells through the glucose transporter on the
regulatory system for GSIS is far more complex than these plasma membrane. Glucose is then phosphorylated by glucoki-
other two systems. In addition, the time frames of insulin secre- nase and subjected to glycolysis, by which pyruvate is generated
tion and neurotransmitter release are different: insulin secretion in the cytoplasm. Pyruvate is metabolized equally by pyruvate
is tuned over minutes to hours, whereas neurotransmitter dehydrogenase and pyruvate carboxylase (PC) in the b-cells,
release occurs instantaneously; that is, within the subsecond and passes into the mitochondria. The former reaction leads to
range. As a counterpart for excitation-contraction coupling and generation of adenosine triphosphate (ATP) in the respiratory
stimulus-secretion coupling, Wollheim3 coined the term ‘metab- chain and the latter is accompanied by efflux of tricarboxylic
olism-secretion coupling’ for GSIS, which will form the basis of acid (TCA) cycle intermediates as anaplerosis. ATP is a signal-
ing molecule for insulin secretion in b-cells, because the cell is
Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, equipped with ATP-sensitive K+ channels (KATP channels),
Shinshu University School of Medicine, Matsumoto, Nagano, Japan which close on elevation of cytoplasmic ATP or ATP/adenosine
*Corresponding author. Mitsuhisa Komatsu Tel.: +81-263-37-2686 Fax: +81-263-37-2710
E-mail address: [email protected] diphosphate ratio. As the KATP channel is the primary determi-
Received 8 March 2013; accepted 12 March 2013 nant of the membrane potential of the b-cells, closure of these

ª 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd Journal of Diabetes Investigation Volume 4 Issue 6 November 2013 511
Komatsu et al.

Free fatty acids

Glucose
GLP-1
GIP
GPR40 Glucagon
Glut PACAP
Gs AC Adrenaline

Metabolism ATP
PDH PC
Acetyl-CoA cAMP
SUR1 Anaplerosis
KATP channel Acetylcholine
Kir6.2 ATP PKC Gq
PLC

Depolarization KATP channel-independent

Ca2+ Cytosolic Ca2+

LVDCC KATP channel-dependent
Insulin exocytosis
Go/Gi

Somatostatin
Adrenaline/noradrenaline

Figure 1 | A proposed signaling network of insulin exocytosis in pancreatic b-cells. AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP,
cyclic adenosine monophosphate; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like polypeptide-1; Glut, glucose transporter; KATP
channel, adenosine triphosphate-sensitive K+ channel; Kir6.2, K+ channel 6.2 subunits; LVDCC, L-type voltage-dependent calcium channel PACAP,
pituitary adenylate cyclase activating peptide; PDH, pyruvate dehydrogenase; PC, pyruvate carboxylase; PKC, protein kinase C; PLC, phospholipase C;
SUR1, sulfonylurea receptor 1.

channels causes membrane depolarization. The membrane the latter10. In addition, glucose-induced electrophysiological
depolarization opens L-type voltage-dependent Ca2+ channels events; that is, KATP channel closure and elevation of [Ca2+]i,
(VDCC), followed by Ca2+ influx and elevation of cytosolic free do not faithfully reflect the time-course and concentration
Ca2+ concentration ([Ca2+]i). The elevation of [Ca2+]i rapidly dependency of GSIS. These phenomena had been overlooked
increases the rate of insulin exocytosis. or left unanswered.
This model has its origin in the pioneering work of Dean
and Matthews5, and was formulated based on the nature of BIPHASIC INSULIN RELEASE AND KATP CHANNEL-
b-cell electrophysiology6,7. Inagaki et al.8,9 successfully identified INDEPENDENT GLUCOSE ACTION
the KATP channel in b-cells as a tetra-octamer composed of In the early 1970s, Grodsky11 established that GSIS is biphasic
four sulfonylurea receptor 1 (SUR1) and inwardly rectifying K+ when extracellular glucose concentration is abruptly raised from
channel 6.2 subunits (Kir6.2). SUR1 is the target of insulin sub- (3 mmol/L) to suprastimulatory concentrations (16.7–
secretagogues, such as sulfonylurea (SU) and glinide used in 22.2 mmol/L). He suggested that glucose triggers insulin secre-
the treatment of type 2 diabetes, such that the channel is closed tion from a threshold-sensitive packet of insulin in the labile
on binding of SU or glinide to the SUR1. GSIS was completely pool, and glucose potentiates insulin release by replenishing
abolished in vitro by treatment with diazoxide, a KATP channel this labile pool by distinct mechanism(s). The first phase culmi-
opener, or nifedipine, a dihydropyridine Ca2+ channel blocker nates 5–6 min after stimulation, and a gradual increase in
that inhibits opening of the VDCC. On the basis of these insulin release over 60 min ensues, which is called the second
observations, signaling through KATP channels, VDCC and phase11.
[Ca2+]i elevation had been considered the exclusive mechanism The temporal profile of the ionic events after glucose stimula-
underlying GSIS until 1992. tion is significantly different from that of GSIS: glucose-induced
An acute elevation of [Ca2+]i facilitates fusion of insulin membrane depolarization and [Ca2+]i rise are continuously oscil-
granules and the plasma membrane leading to an increased lating, and by no means biphasic. The biphasic nature of GSIS
rate of exocytosis. This reaction is mediated by the assembly of is robust in rat and human islets, weak in mouse islets, and
soluble N-ethylmaleimide-sensitive factor attachment protein absent in most tumor b-cell lines. A square wave application of a
receptor protein. However, the kinetics of exocytosis are con- depolarizing concentration of K+ sharply increases the rate of
siderably different between exocytosis of synaptic vesicles in insulin exocytosis for several minutes, which temporarily resem-
neuronal cells and large dense-core vesicles in b-cells, with the bles the first phase12. However, in contrast to the insulin response
former being more than five orders of magnitude faster than to high glucose, high K+-induced insulin release is monophasic

512 Journal of Diabetes Investigation Volume 4 Issue 6 November 2013 ª 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd
 Physiological insulin secretion

and followed by gradual lowering; that is, there is no second and high K+, do not prime the b-cells in this manner. In con-
phase. Nevertheless, the time-courses of membrane depolariza- trast, metabolic inhibition abolishes TDP by glucose and the
tion and [Ca2+]i elevation seen after K+ depolarization are similar, amino acids. Therefore, metabolic stimulus, the mitochondrial
if not identical, to those induced by high glucose. These observa- intermediates in the case of amino acids, is required for TDP.
tions indicated that high glucose produces signal(s) for insulin Interestingly, pharmacological activation of protein kinase C
secretion in addition to elevation of [Ca2+]i. by phorbol ester also time-dependently potentiates insulin
In 1992, the present authors and another group showed that secretion26.
glucose augments insulin exocytosis evoked by K+ depolarization The b-cell priming by glucose occurs in a KATP channel-
even when the KATP channels are fully open or closed by the independent manner, because the potentiation was totally resis-
presence of diazoxide or SU, respectively13,14. In the presence of tant to a high concentration of diazoxide, an opener of KATP
a high concentration of SU with the KATP channels fully closed, channels12. Furthermore, TDP occurs under stringent Ca2+-free
glucose induces an increase, not a decrease, in 86Rb+ outflow conditions and therefore [Ca2+]i elevation is not required27.
from the islet cells, which is a surrogate index of K+ outflow15. Taken together, these observations suggest that the second
Importantly, GSIS in the presence of a depolarizing concentra- phase observed under a square wave high-glucose application is
tion of K+ and diazoxide occurs without any further increase in the triggered insulin release followed by enhancement by TDP.
[Ca2+]i16. Thus, KATP-independent GSIS was established.
It has long been considered that there are distinct pools of Permissive Role of Hormones, Non-Glucose Fuels and Neural
insulin granules in the b-cells, known as readily releasable pools Inputs
(RRP) and reserve pools (RP)17. RRP is not necessarily physi- Incretins
cally docked to the plasma membrane. The biphasic GSIS has Glucagon-like peptide-1 (GLP-1) and glucose-dependent insu-
been understood as a product of a combination of triggering linotropic polypeptide are gastrointestinal hormones called
and amplification/augmentation along with this concept. That incretins, which robustly enhance nutrient-induced insulin
is, triggering denotes the initial rapid insulin exocytosis from secretion, and they are very important in the physiology of
the RRP by the KATP-dependent mechanism, and amplifica- insulin secretion. Incretins bind to G protein-coupled recep-
tion/augmentation indicates gradual enhancement by the KATP- tors on the b-cell membrane and increase cellular 3′,5′-cyclic
independent signal. The latter can occur with replenishment of adenosine monophosphate (cAMP). When the b-cells are
the RRP from the RP, so we proposed viewing the biphasic exposed to a stimulatory concentration of glucose, cAMP fur-
insulin release as ‘fusion and replenishment’18. ther elevates GSIS. Incretin action is resistant to diazoxide,
The aforementioned series of secretory and ionic events are and therefore it is independent of KATP channel closure28.
observed on sudden increase in glucose from sub- to supra- cAMP enhances GSIS through protein kinase A (PKA)-
stimulatory concentration in the absence of any other stimuli, dependent and -independent mechanisms29. As one of the
and so the conditions are markedly different from those seen latter mechanisms, activation of the Epac2/Rap1 signaling cas-
physiologically. cade was proposed30. With regard to the insulin granule
dynamics, cAMP increases the size of RRP in a glucose con-
METABOLIC AMPLIFICATION FACTOR centration-dependent manner. This finding strongly indicates
Although the molecule(s) responsible for the KATP-independent that incretin primes the b-cells in the presence of stimulatory
GSIS have yet to be identified, anaplerotic metabolism of pyru- ambient glucose concentration. Incretin priming occurs in a
vate by PC and subsequent efflux of the TCA cycle intermediates Ca2+-independent manner, even under stringent Ca2+-free
are considered key events (Figure 1)19,20. The candidate mole- conditions31.
cules suggested to date as possible mediators of the KATP chan-
nel-independent glucose action include ATP, guanosine Free Fatty Acid
5′-triphosphate, the reduced form of nicotinamide-adenine dinu- Free fatty acid (FFA) participates in the regulation of GSIS.
cleotide, glutamate, malonyl-CoA and Rab27a21,22. It is possible Insulin secretion is suppressed with long-term exposure of
that thermosensitive transient receptor potential channel and Kv b-cells to excessively high concentration of FFA, which is called
channels are involved in KATP-independent glucose signaling23,24. lipotoxicity32. However, short-term (hours) exposure to the
physiological concentration of FFA causes TDP33,34. The action
PRIMING OF b-CELLS of FFA appears to be mediated by FFA oxidation per se or
Time-Dependent Potentiation accumulation of long chain acyl-CoA in the cytoplasm. The in-
Glucose causes time-dependent potentiation (TDP) of insulin sulinotropic action of FFA might be partially mediated by
secretion; that is, exposure of islet b-cells to high glucose membrane receptor(s) for FFA, which is called GPR40
enhances insulin release in response to the stimulus applied (Figure 1)35. An agonist of GPR40 that is currently in clinical
later25. Metabolizable amino acids and the glycolytic intermedi- trials36 elevates [Ca2+]i through activation of phospholipase C
ate, glyceraldehyde, show similar enhancement of insulin secre- and protein kinase D137. At any rate, FFA augmentation of
tion. In contrast, non-metabolizable secretagogues, such as SU GSIS is also independent of KATP channel33,34.

ª 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd Journal of Diabetes Investigation Volume 4 Issue 6 November 2013 513
Komatsu et al.

Parasympathetic Nerves and Neuropeptides hours by continuous glucose infusion43. This in vivo observa-
Activation of the parasympathetic nervous system causes release tion was supported by experimental data showing rapid insulin
of acetylcholine in the islets, and binding of acetylcholine to the secretion in response to a square wave application of glucose
membrane receptor leads to hydrolysis of phospholipids, accu- by the islets from such patients or KATP channel knockout
mulation of cellular inositol 1, 4, 5-triphosphate and activation mice44,45. It is also important to recognize that the b-cells from
of PKC38. As a result, GSIS is strongly enhanced. This pathway patients with persistent hyperinsulinemic hypoglycemia of
might play a role in the cephalic phase of insulin release39 and infancy (PHHI) or KATP channel knockout mice do not secrete
TDP (as aforementioned). Pituitary adenylate cyclase-activating excess insulin in vitro with substimulatory concentration of glu-
polypeptide (PACAP), which is located in the nerve endings cose despite persistent elevation of [Ca2+]i46,47. Under these
around pancreatic islets, binds to its receptor on b-cells and conditions, b-cell [Ca2+]i is elevated, but there are no other
enhances insulin secretion at the picomolar range by increasing stimuli/priming, such as incretin/cAMP elevation, FFA and
cellular cAMP40. Although the physiological significance of parasympathetic input/PKC activation. We hypothesize that
PACAP in controlling insulin secretion is still controversial, it is GSIS occurs in the islet b-cells, even in the absence of glucose
interesting that PACAP is one of the substrates for dipeptidyl- regulation of KATP channels in vivo under priming with cAMP,
peptidase 4. non-glucose nutrients and PKC. GSIS in PHHI patients after
partial pancreatectomy provides further support for this
Inhibitory Signals for Insulin Secretion hypothesis. The patients maintain non-diabetic glycemia for
An important aspect of the physiological control of insulin years, and oral GSIS and meal-stimulated insulin secretion do
secretion is the presence of inhibitory signals41. Heightened occur in them48. Post-challenge incretin secretion would signifi-
sympathetic tone suppresses insulin secretion through an cantly assist GSIS on oral glucose or meal intake.
increase in noradrenaline42. Noradrenaline binds to the Additional experimental evidence for the hypothesis is as fol-
a2-adrenergic receptor and activates the heterotrimeric G lows. Glucose increases insulin secretion by the islets, even
protein. Somatostatin, which is secreted from pancreatic d-cells, under stringently Ca2+-free conditions, given pre-exposure of
suppresses insulin secretion by binding to the specific heterotri- the islets to forskolin and phorbol ester, activators of PKA and
meric G protein-coupled receptor as well. These inhibitory hor- PKC, respectively49. Recently, we showed rapid insulin secretion
mones activate Gi and/or Go, and inhibit insulin exocytosis at
multiple sites. It is likely that changes in the inhibitory signals Glucose
(a)
are intimately involved in the physiology of insulin secretion
Insulin secretion

in vivo.

TOWARD A PHYSIOLOGICAL UNDERSTANDING

In the body, the b-cells are primed by glucose, incretins, FFA
and parasympathetic neural input, even under fasting condi-
tions, because fasting plasma concentrations of glucose, active
GLP-1, and FFA are 5 mmol/L, 10 pmol/L and 500 lEq/L, (b) Plasma glucose
respectively, which are within the stimulatory ranges for b-cells.
Insulin secretion

On intake of a meal, gradual elevation of glucose and amino

acids occurs, and incretins and the parasympathetic input fur-
ther increase. Concomitant suppression of sympathetic nerve
input might influence to increase in insulin secretion.

Role of KATP Channels Figure 2 | Distinction of glucose-stimulated insulin release in (a) in vitro
SU and diazoxide, a closer and opener of KATP channels, and (b) in vivo. (a) Square-wave application of high glucose produces
biphasic insulin release in vitro. Adenosine triphosphate-sensitive K+
enhance and reduce meal-induced insulin secretion, respec-
channel (KATP channel) closure is mandatory for this response.
tively. The absence of KATP channels; that is, persistent closure,
Nevertheless, glucose gradually enhances the Ca2+-stimulated secretion
causes persistent hyperinsulinemic hypoglycemia, and activating in a KATP channel-independent manner. (b) Under the physiological
mutation of the channel causes impaired insulin secretion and condition, the b-cells are being continuously primed. Namely, the
diabetes. Taken together, these observations imply that GSIS is plasma level of glucose and other nutrients is at the weakly stimulatory
affected by KATP channel closing and opening in vivo. range, and hormonal and neural stimuli are also present, even at
fasting. A gradual elevation of plasma glucose after a meal robustly
KATP-Independent GSIS raises the rate of insulin exocytosis adenosine triphosphate-sensitive
Robust insulin secretion in response to the intravenous bolus K+ channel-independently under this condition. , Constitutive
injection of glucose occurs in patients with loss of function secretion; , K+ channel-dependent secretion; , K+ channel-
SUR1 mutation, provided euglycemia has been maintained for independent secretion.

514 Journal of Diabetes Investigation Volume 4 Issue 6 November 2013 ª 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd
 Physiological insulin secretion

in islets pre-exposed to forskolin on exposure to square wave 11. Grodsky GM. A threshold distribution hypothesis for packet
high glucose in the presence of diazoxide and nifedipine50. storage of insulin and its mathematical modeling. J Clin
cAMP enhancement of GSIS has attracted renewed interest Invest 1972; 51: 2047–2059.
with the development of incretin mimetics for clinical use. 12. Komatsu M, Yokokawa N, Takeda T, et al. Pharmacological
Although detailed discussion of this topic is beyond the scope characterization of the voltage-dependent calcium channel
of the present review, it occurs only when ambient glucose con- of pancreatic B-cell. Endocrinology 1989; 125: 2008–2014.
centration exceeds a threshold and is resistant to diazoxide, and 13. Sato Y, Aizawa T, Komatsu M, et al. Dual functional role of
so is a manifestation of KATP-independent GSIS28. membrane depolarization/Ca2+ influx in rat pancreatic
B-cell. Diabetes 1992; 41: 438–443.
SUMMARY 14. Gembal M, Gilon P, Henquin JC. Evidence that glucose can
Insulin secretion in vivo is finely tuned by a variety of stimula- control insulin release independently from its action on
tory and inhibitory signals. It is important to appreciate that ATP-sensitive K+ channels in mouse B cells. J Clin Invest
the b-cells are being tonically primed with nutrients, and hor- 1992; 89: 1288–1295.
monal and neural inputs, even in the fasting state (Figure 2). 15. Best L, Yates AP, Tomlinson S. Stimulation of insulin secretion
Meal intake produces gradual rather than instantaneous eleva- by glucose in the absence of diminished potassium (86Rb+)
tion of glucose. Thus, to gain a comprehensive understanding permeability. Biochem Pharmacol 1992; 43: 2483–2485.
of the physiology of GSIS, careful experimentation and integra- 16. Gembal M, Detimary P, Gilon P, et al. Mechanisms by
tion of accumulated knowledge are required. Further studies which glucose can control insulin release independently
are needed to fully understand the complex and multifactorial from its action on adenosine triphosphate-sensitive K+
mechanisms involved in GSIS. channels in mouse B cells. J Clin Invest 1993; 91: 871–880.
17. Bratanova-Tochkova TK, Cheng H, Daniel S, et al. Triggering
ACKNOWLEDGEMENTS and augmentation mechanisms, granule pools, and biphasic
The authors declare no conflict of interest. We express our insulin secretion. Diabetes 2002; 51(Suppl 1): S83–S90.
gratitude to Professor Toru Aizawa for constructive discussion. 18. Aizawa T, Komatsu M. Rab27a: a new face in beta cell
metabolism-secretion coupling. J Clin Invest 2005; 115:
REFERENCES 227–230.
1. Sandow A. Excitation-contraction coupling in muscular 19. Brun T, Roche E, Assimacopoulos-Jeannet F, et al. Evidence
response. Yale J Biol Med 1952; 25: 176–201. for an anaplerotic/malonyl-CoA pathway in pancreatic b-cell
2. Douglas WW. Stimulus-secretion coupling: the concept and nutrient signaling. Diabetes 1996; 45: 190–198.
clues from chromaffin and other cells. Br J Pharmacol 1968; 20. Sugden MC, Holness MJ. The pyruvate carboxylase-pyruvate
34: 451–474. dehydrogenase axis in islet pyruvate metabolism: going
3. Maechler P, Kennedy ED, Pozzan T, et al. Mitochondrial round in circles? Islets 2011; 3: 302–319.
activation directly triggers the exocytosis of insulin in 21. Kasai K, Ohara-Imaizumi M, Takahashi N, et al. Rab27a
permeabilized pancreatic b-cells. EMBO J 1997; 16: 3833–3841. mediates the tight docking of insulin granules onto the
4. Nakagawa Y, Nagasawa M, Yamada S, et al. Sweet taste plasma membrane during glucose stimulation. J Clin Invest
receptor expressed in pancreatic beta-cells activates the 2005; 115: 388–396.
calcium and cyclic AMP signaling systems and stimulates 22. Komatsu M, Sato Y, Aizawa T, et al. KATP channel-
insulin secretion. PLoS ONE 2009; 4: e5106. independent glucose action: an elusive pathway in
5. Dean PM, Matthews EK. Electrical activity in pancreatic islet stimulus-secretion coupling of pancreatic b-cell. Endocr J
cells. Nature 1968; 219: 389–390. 2001; 48: 275–288.
6. Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose induces 23. Uchida K, Tominaga M. The role of thermosensitive TRP
closure of single potassium channels in isolated rat (transient receptor potential) channels in insulin secretion.
pancreatic b-cells. Nature 1984; 312: 446–448. Endocr J 2011; 58: 1021–1028.
7. Cook DL, Hales CN. Intracellular ATP directly blocks K+ 24. Yoshida M, Nakata M, Yamato S, et al. Voltage-dependent
channels in pancreatic B-cells. Nature 1984; 311: 271–273. metabolic regulation of Kv2.1 channels in pancreatic b-cells.
8. Inagaki N, Gonoi T, Clement JP, et al. Reconstitution of Biochem Biophys Res Commun 2010; 396: 304–309.
IKATP: an inward rectifier subunit plus the sulfonylurea 25. Grill V, Adamson U, Cerasi E. Immediate and time-
receptor. Science 1995; 270: 1166–1170. dependent effects of glucose on insulin release from rat
9. Inagaki N, Gonoi T, Seino S. Subunit stoichiometry of the pancreatic tissue. Evidence for different mechanisms of
pancreatic beta-cell ATP-sensitive K+ channel. FEBS Lett 1997; action. J Clin Invest 1978; 61: 1034–1043.
409: 232–236. 26. Niki I, Tamagawa T, Niki H, et al. Possible involvement of
10. Kasai H, Takahashi N, Tokumaru H. Distinct initial SNARE diacylglycerol-activated, Ca2+-dependent protein kinase in
configurations underlying the diversity of exocytosis. Physiol glucose memory of the rat pancreatic B-cell. Acta Endocrinol
Rev 2012; 92: 1915–1964. (Copenh) 1988; 118: 204–208.

ª 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd Journal of Diabetes Investigation Volume 4 Issue 6 November 2013 515
Komatsu et al.

27. Yamada S, Komatsu M, Aizawa T, et al. Time-dependent 39. Ahren B. Autonomic regulation of islet hormone secretion–
potentiation of the b-cell is a Ca2+-independent implications for health and disease. Diabetologia 2000; 43:
phenomenon. J Endocrinol 2002; 172: 345–354. 393–410.
28. Yajima H, Komatsu M, Schermerhorn T, et al. cAMP enhances 40. Yada T, Sakurada M, Ishihara H, et al. Pituitary adenylate
insulin secretion by an action on the ATP-sensitive K+ cyclase-activating polypeptide (PACAP) is an islet substance
channel-independent pathway of glucose signaling in rat serving as an intra-islet amplifier of glucose-induced insulin
pancreatic islets. Diabetes 1999; 48: 1006–1012. secretion in rats. J Physiol 1997; 505: 319–328.
29. Seino S, Shibasaki T. PKA-dependent and PKA-independent 41. Sharp GW. Mechanisms of inhibition of insulin release. Am J
pathways for cAMP-regulated exocytosis. Physiol Rev 2005; Physiol 1996; 271: C1781–C1799.
85: 1303–1342. 42. Zhao Y, Fang Q, Straub SG, et al. Noradrenaline inhibits
30. Shibasaki T. Elucidation of the function and role of cAMP exocytosis via the G protein betagamma subunit and
sensor Epac2A in insulin secretion. Diabetol Int 2012; 3: refilling of the readily releasable granule pool via the
187–196. alphai1/2 subunit. J Physiol 2010; 588: 3485–3498.
31. Yamada S, Komatsu M, Sato Y, et al. Time-dependent 43. Grimberg A, Ferry RJ Jr, Kelly A, et al. Dysregulation of
stimulation of insulin exocytosis by 3′,5′-cyclic adenosine insulin secretion in children with congenital hyperinsulinism
monophosphate in the rat islet beta-cell. Endocrinology due to sulfonylurea receptor mutations. Diabetes 2001; 50:
2002; 143: 4203–4209. 322–328.
32. Liu YQ, Tornheim K, Leahy JL. Shared biochemical 44. Straub SG, Cosgrove KE, Ammala C, et al. Hyperinsulinism
properties of glucotoxicity and lipotoxicity in islets decrease of infancy: the regulated release of insulin by KATP
citrate synthase activity and increase phosphofructokinase channel-independent pathways. Diabetes 2001; 50:
activity. Diabetes 1998; 47: 1889–1893. 329–339.
33. Komatsu M, Sharp GW. Palmitate and myristate selectively 45. Seghers V, Nakazaki M, DeMayo F, et al. Sur1 knockout
mimic the effect of glucose in augmenting insulin release mice. A model for K(ATP) channel-independent regulation
in the absence of extracellular Ca2+. Diabetes 1998; 47: of insulin secretion. J Biol Chem 2000; 275: 9270–9277.
352–357. 46. Aguilar-Bryan L, Bryan J. Molecular biology of adenosine
34. Komatsu M, Yajima H, Yamada S, et al. Augmentation of triphosphate-sensitive potassium channels. Endocr Rev 1999;
Ca2+-stimulated insulin release by glucose and long-chain 20: 101–135.
fatty acids in rat pancreatic islets: free fatty acids mimic 47. Aguilar-Bryan L, Bryan J, Nakazaki M. Of mice and men:
ATP-sensitive K+ channel-independent insulinotropic action K(ATP) channels and insulin secretion. Recent Prog Horm
of glucose. Diabetes 1999; 48: 1543–1549. Res 2001; 56: 47–68.
35. Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids 48. Beltrand J, Caquard M, Arnoux JB, et al. Glucose
regulate insulin secretion from pancreatic beta cells metabolism in 105 children and adolescents after
through GPR40. Nature 2003; 422: 173–176. pancreatectomy for congenital hyperinsulinism. Diabetes
36. Ferdaoussi M, Bergeron V, Zarrouki B, et al. G protein- Care 2012; 35: 198–203.
coupled receptor (GPR)40-dependent potentiation of insulin 49. Komatsu M, Schermerhorn T, Aizawa T, et al. Glucose
secretion in mouse islets is mediated by protein kinase D1. stimulation of insulin release in the absence of extracellular
Diabetologia 2012; 55: 2682–2692. Ca2+ and in the absence of any increase in intracellular
37. Kaku K, Araki T, Yoshinaka R. Randomized, double-blind, Ca2+ in rat pancreatic islets. Proc Natl Acad Sci USA 1995;
dose-ranging study of TAK-875, a novel GPR40 agonist, in 92: 10728–10732.
Japanese patients with inadequately controlled Type 2 50. Takei M, Dezaki K, Ishii H, et al. A new experimental model
diabetes. Diabetes Care 2013; 36: 245–250. of ATP-sensitive K+ channel-independent insulinotropic
38. Gilon P, Henquin JC. Mechanisms and physiological action of glucose: a permissive role of cAMP for triggering
significance of the cholinergic control of pancreatic beta- of insulin release from rat pancreatic b-cells. Endocr J 2013;
cell function. Endocr Rev 2001; 22: 565–604. 60: 599–607.

516 Journal of Diabetes Investigation Volume 4 Issue 6 November 2013 ª 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd