Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells

Kaneko, Katsuya; Shirotani, Tetsuya; Araki, Eiichi; Matsumoto, Kazuya; Taguchi, Tetsuya; Motoshima, Hiroyuki; Yoshizato, Kazuaki; Kishikawa, Hiroki; Shichiri, Motoaki

doi:10.1016/s0168-8227(99)00021-2

Cited by 48 publications

(34 citation statements)

References 41 publications

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“…In non-diabetic gestate NOD mice, there are several reasons why hyperglucagonemia can result from an immune/endocrine imbalance in islets or the periphery. First, as insulin affects glucagon secretion [38,39], α-cell disturbance may be primary or secondary to β-cell anomalies or insulin signaling. Conversely, as glucagon stimulates insulin secretion [40][41][42], the relative hyperglucagonemia may be partially responsible for the basal hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Coulaud¹,

Durant²,

Homo‐Delarche³

2010

Rev Diabet Stud

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■ AbstractBACKGROUND: Unlike other strains, spontaneously type 1 non-obese diabetic (NOD) mice experience transient hyperinsulinemia after weaning. The same applies for NOD/SCID mice, which lack functional lymphocytes, and unlike NOD mice, do not develop insulitis and diabetes like NOD mice. AIMS: Given that β-cell stimulation is a natural feature of gestation, we hypothesized that glucose homeostasis is disturbed in gestate pre-diabetic NOD and non-diabetic NOD/SCID mice, which may accelerate the onset of diabetes and increase diabetes prevalence. METHODS: During gestation and postpartum, mice were analyzed under basal feed conditions, and following glucose injection (1 g/kg, i.p.) after overnight fast, using glucose tolerance test (GTT). Glycemia, corticosteronemia, blood and pancreatic insulin, glucagon levels, islet size, and islet morphology were evaluated. Glycemia and mortality were assessed after successive gestations in NOD mice mated for the first time at 2 different ages. RESULTS: 1. Basal glucagonemia rose markedly in first-gestation fed NOD mice. 2. β-cell hyperactivity was present earlier in first-gestation non-diabetic fasted NOD and NOD/SCID mice than in age-matched C57BL/6 mice, assessed by increased insulin/glucose ratio after GTT. 3. Overnight fasting increased corticosteronemia rapidly and sharply in pre-diabetic gestate NOD and NOD/SCID mice. 4. Islet size increased in non-diabetic gestate NOD mice compared with C57BL/6 mice. 5. Successive gestations accelerated diabetes onset, and contributed to increased mortality in NOD mice. CONCLUSIONS: First-gestation prediabetic NOD and non-diabetic NOD/SCID mice exhibited β-cell hyperactivity and deregulation of glucagon and/or corticosterone secretion. This amplified normally occurring insulin resistance, further exhausted maternal β-cells, and accelerated diabetes in NOD mice.

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Section: Discussionmentioning

confidence: 99%

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Coulaud¹,

Durant²,

Homo‐Delarche³

2010

Rev Diabet Stud

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“…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. Studies on islet microvasculature have shown that the alpha cells lie downstream from the beta cells, thus insulin released from beta cells can immediately act on alpha cells [39].…”

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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“…An appropriate expression of the insulin receptor in mouse a-cells seems to be essential for glucose-regulated glucagon secretion (Diao et al 2005). In INR1-G9 clonal a-cells, insulin has been found to inhibit glucagon release through the activation of phosphatidylinositol 3-kinase (PIK3; Kaneko et al 1999). The insulin receptor-PIK3 signalling pathway is also involved in the modification of the sensitivity of K ATP channels to ATP in mouse a-cells, which may affect the secretory response (Leung et al 2006).…”

Section: Regulation Of Glucagon Secretion By Fatty Acids and Amino Acidsmentioning

confidence: 99%

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Quesada¹,

Tudurí²,

Ripoll³

et al. 2008

Journal of Endocrinology

338

330

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The secretion of glucagon by pancreatic a-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of a-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on a-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to a-cell function are also discussed in this review. A better understanding of the a-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.

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Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells

Cited by 48 publications

References 41 publications

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

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

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

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