Metabotropic Glutamate Receptor Type 4 Is Involved in Autoinhibitory Cascade for Glucagon Secretion by α-Cells of Islet of Langerhans

Uehara, Satoshi; Muroyama, Akiko; Echigo, Noriko; Morimoto, Riyo; Otsuka, Masato; Yatsushiro, Shouki; Moriyama, Yoshinori

doi:10.2337/diabetes.53.4.998

Cited by 74 publications

(77 citation statements)

References 40 publications

(40 reference statements)

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“…Although data are somewhat controversial, a recognized effect of glutamate is to modulate the release of insulin, glucagon, and GABA induced by changes in glucose concentration (15)(16)(17)(18)(19). In our experiments, glutamate decreased the physiological release of glucagon in response to an acute fall in glucose concentrations (Fig.…”

Section: Glt1 Expressed By ␤-Cells Regulates Clearance Of Glutamate Imentioning

confidence: 59%

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Cairano

Davalli

Perego

et al. 2011

Journal of Biological Chemistry

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Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained at physiological concentrations by high affinity glutamate transporters of the solute carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans where it is secreted by the ␣-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal ␤-cell lines and human islet ␤-cells but not in ␣-cells. In human islets, glutamate-induced ␤-cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of ␤-cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced ␤-cell death, whereas GLT1 up-regulation promoted ␤-cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that ␤-cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.

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Section: Glt1 Expressed By ␤-Cells Regulates Clearance Of Glutamate Imentioning

confidence: 59%

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Cairano

Davalli

Perego

et al. 2011

Journal of Biological Chemistry

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“…(see NOTE ADDED IN PROOF) The fact that zinc, independent of insulin, can have insulin-like effects is well appreciated (21). Furthermore, other endogenous substances, such as intra-␣-cell L-glutamate directly or via stimulation of ␥-aminobutyric acid secretion from ␤-cells, may also negatively regulate glucagon secretion (22).…”

Section: Discussionmentioning

confidence: 99%

Zinc, Not Insulin, Regulates the Rat α-Cell Response to Hypoglycemia In Vivo

et al. 2007

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The intraislet insulin hypothesis proposes that the decrement in ␤-cell insulin secretion during hypoglycemia provides an activation signal for ␣-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open ␣-cell ATPsensitive K ؉ channels. Since insulin binds zinc, and zinc is cosecreted with insulin, we tested whether decreased zinc delivery to the ␣-cell activates glucagon secretion. In streptozotocin-induced diabetic Wistar rats, we observed that switching off intrapancreatic artery insulin infusions in vivo during hypoglycemia greatly improved glucagon secretion (area under the curve [AUC]: control group 240 ؎ 261 and experimental group 4,346 ؎ 1,259 pg ⅐ ml ؊1 ⅐ 90 min ؊1 ; n ‫؍‬ 5, P < 0.02). Switching off pancreatic artery infusions of zinc chloride during hypoglycemia also improved the glucagon response (AUC: control group 817 ؎ 107 and experimental group 3,445 ؎ 573 pg ⅐ ml ؊1 ⅐ 90 min ؊1 ; n ‫؍‬ 6, P < 0.01). However, switching off zinc-free insulin infusions had no effect. Studies of glucose uptake in muscle and liver cell lines verified that the zinc-free insulin was biologically active. We conclude that zinc atoms, not the insulin molecule itself, provide the switch-off signal from the ␤-cell to the ␣-cell to initiate glucagon secretion during hypoglycemia. Diabetes 56:1107-1112, 2007 G lucagon secretion into the hepatic portal circulation is critical for counterregulation of hypoglycemia by virtue of its stimulatory effect on hepatic glycogenolysis, which releases glucose into the systemic circulation to return blood glucose to normal levels. The decrement in insulin release from ␤-cells has been proposed to signal the ␣-cell to release glucagon (1-3). Recently, we demonstrated this phenomenon directly in vivo in streptozotocin-induced diabetic rats and in vitro using isolated islets from these animals. In the in vivo studies, an insulin infusion into the pancreatic artery was switched off when the animals were made hypoglycemic by a jugular-vein infusion of insulin (4).Glucagon secretion, absent in control diabetic animals, was fully restored by this maneuver. Glucagon release was not initiated by this maneuver if saline rather than insulin was used, or if insulin was infused but not switched off. The glucagon response was not observed during normoglycemic or hyperglycemic conditions; the switch-off signal was effective only in the setting of hypoglycemia. We corroborated these findings with in vitro islet perifusion studies (5).Recent work from several laboratories has demonstrated that zinc atoms are capable of suppressing ␣-cell function via activation of rat ␣-cell ATP-sensitive K ϩ (K ATP ) channels (6 -9). Since zinc atoms are bound by and cosecreted with insulin, we hypothesized that zinc might provide the switch-off signal during hypoglycemia. To evaluate this hypothesis, we performed in vivo studies using intrapancreatic artery infusions of zinc-containing insulin, zinc chloride alone, or zinc-free insulin in streptozo...

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“…Our findings in this study suggest that the GABA system may function as a negative feedback regulating mechanism in the islets. Under low glucose conditions, GABA release from beta cells increases [33,34], which in turn may enhance insulin secretion. It has been demonstrated that insulin is a physiological inhibitor of glucagon release within islets [35] under in vitro [36,37] and in vivo [38] conditions.…”

Section: Discussionmentioning

confidence: 99%

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

et al. 2006

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Aims/hypothesis: The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABA A Rs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA A Rs in the pancreatic islets. However, the reported effects of GABA A R activation on insulin secretion from islet beta cells have been controversial. Methods: This study examined the hypothesis that the effect of GABA on beta cell insulin secretion is dependent on glucose concentration. Results: Perforated patchclamp recordings in INS-1 cells demonstrated that GABA, at concentrations ranging from 1 to 1,000 μmol/l, induced a transmembrane current (I GABA ) which was sensitive to the GABA A R antagonist bicuculline. The current-voltage relationship revealed that I GABA reversed at −42±2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (V M ), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous V M of INS-1 cells was below the I GABA reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous V M of INS-1 cells was above the I GABA reversal potential. Therefore, GABA dose-dependently induced membrane depolarisation at a low glucose concentration, but hyperpolarisation at a high glucose concentration. Consistent with electrophysiological findings, insulin secretion assays demonstrated that at 2.8 mmol/l glucose, GABA increased insulin secretion in a dose-dependent fashion (p<0.05, n=7). This enhancement was blocked by bicuculline (p<0.05, n=4). In contrast, in the presence of 28 mmol/l glucose, GABA suppressed the secretion of insulin (p<0.05, n=5). Conclusions/interpretation: These findings indicate that activation of GABA A Rs in beta cells regulates insulin secretion in concert with changes in glucose levels.

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Metabotropic Glutamate Receptor Type 4 Is Involved in Autoinhibitory Cascade for Glucagon Secretion by α-Cells of Islet of Langerhans

Cited by 74 publications

References 40 publications

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Zinc, Not Insulin, Regulates the Rat α-Cell Response to Hypoglycemia In Vivo

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

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