Pancreatic Somatostatin is a Mediator of Glucagon Inhibition by Hyperglycemia

Klaff, Leslie J.; Taborsky, Gerald J.

doi:10.2337/diab.36.5.592

Cited by 48 publications

(24 citation statements)

References 28 publications

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“…This observation is in complete agreement with earlier dose-response studies of Sorensen and Elde performed in the isolated rat pancreas (4). It may, however, appear to be in conflict with previous work from our laboratory (12,27 …”

Section: Discussioncontrasting

confidence: 45%

“…Previous experiments in man and experimental animals have suggested at least four possible mechanisms ofA cell suppression during hyperglycemia. Thus, A cell suppression could be caused by: (a) glucose per se (2)(3)(4)(5), (b) insulin (6-1 1), (c) pancreatic somatostatin (12), or (d) an action of glucose to directly suppress glucagon secretion which is dependent on adequate islet insulin levels (13). Such a permissive effect ofinsulin has recently been demonstrated in adipose tissue in which insulin exposure is required to maintain the biosynthesis of a glucose transporter ( 14).…”

Section: Introductionmentioning

confidence: 99%

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Intra-islet insulin permits glucose to directly suppress pancreatic A cell function.

Greenbaum

Havel²,

Taborsky³

et al. 1991

J. Clin. Invest.

100

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Inhibition of pancreatic glucagon secretion during hyperglycemia could be mediated by (a) glucose, (b) insulin, (c) somatostatin, or (d) glucose in conjunction with insulin. To determine the role of these factors in the mediation of glucagon suppression, we injected alloxan while clamping the arterial supply of the pancreatic splenic lobe of dogs, thus inducing insulin deficiency localized to the ventral lobe and avoiding hyperglycemia. Ventral lobe insulin, glucagon, and somatostatin outputs were then measured in response to a stepped IV glucose infusion. In control dogs glucagon suppression occurred at a glucose level of 150 mg/dl and somatostatin output increased at glucose > 250 mg/dl. In alloxan-treated dogs glucagon output was not suppressed nor did somatostatin output increase. We concluded that insulin was required in the mediation of glucagon suppression and somatostatin stimulation. Subsequently, we infused insulin at high rates directly into the artery that supplied the beta cell-deficient lobe in six alloxan-treated dogs. Insulin infusion alone did not cause suppression of glucagon or stimulation of somatostatin; however, insulin repletion during glucose infusions did restore the ability of hyperglycemia to suppress glucagon and stimulate somatostatin. We conclude that intra-islet insulin permits glucose to suppress glucagon secretion and stimulate somatostatin during hyperglycemia. (J. Clin. Invest.

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Section: Discussioncontrasting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Intra-islet insulin permits glucose to directly suppress pancreatic A cell function.

Greenbaum

Havel²,

Taborsky³

et al. 1991

J. Clin. Invest.

100

View full text Add to dashboard Cite

show abstract

“…The processing of pro-S is tissue-specific with D cells in the pancreas and stomach and some enteric neurons synthesizing S-14 and specialized intestinal epithelial cells producing S-28 (4)(5)(6). Although recent work has provided evidence that S-14 acts as a paracrine mediator of gastrin secretion in the stomach and glucagon secretion in the pancreatic islet (7)(8)(9), no physiologic role for S-28 has yet been proven.…”

Section: Introductionmentioning

confidence: 99%

A physiologic role for somatostatin 28 as a regulator of insulin secretion.

D’Alessio¹,

Sieber²,

Beglinger³

et al. 1989

J. Clin. Invest.

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Somatostatin 28 (S-28) is a peptide produced in the intestinal tract which rises in the circulation during nutrient absorption. We tested the hypothesis that S-28 regulates B-cell function by (a) studying the effects on insulin secretion of "physiologic" infusions of S-28 and (b) measuring insulin responses during elevated nutrient-stimulated endogenous S-28 levels. (a) Synthetic S-28 was infused on separate days into six healthy men at rates of 25 and 50 ng/kg per h which mimicked postprandial levels. Subjects were given a bolus of glucose (0.1 g/kg) after 120 min. Insulin responses during S-28 infusions were compared to a control study using a saline infusion in the same individuals. Glucose-stimulated insulin secretion was inhibited during the infusion of 50 ng/kg per h S-28 when compared to control (P < 0.05). (b) Insulin secretion during elevations of endogenous S-28 was studied in healthy men who received a bolus of 2.5 g arginine (n = 14) or 25 U of secretin (n = 8) 120 min after swallowing 50 g fat, or, on a separate day, an equivalent volume of water. S-28 levels rose significantly after fat ingestion but did not change after water. Arginine and secretin-stimulated insulin secretion was inhibited following ingestion of fat compared with intake of water (P < 0.05). Arginineenhanced glucagon secretion was not changed by fat ingestion. We conclude that elevations in plasma S-28 levels, occurring during the postprandial state, attenuate B-cell secretion and this peptide may be a physiologic modulator of nutrient-stimulated insulin release.

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“…Exogenous somatostatin inhibits glucagon (and insulin). [22][23][24][25][26][27][28][29][30][31][32][33] 2. The α and β cells express somatostatin receptors 25,31,32 that may mediate the inhibition of glucagon by endogenous δ-cell somatostatin.…”

Section: 13-21mentioning

confidence: 99%

Models of Glucagon Secretion, Their Application to the Analysis of the Defects in Glucagon Counterregulation and Potential Extension to Approximate Glucagon Action

Farhy

McCall

2010

J Diabetes Sci Technol

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Abbreviations: (BG) blood glucose, (GABA) γ-aminobutyric acid, (GCR) glucagon counterregulation, (GLP-1) glucagon-like peptide-1, (HGO) hepatic glucose output, (ID 50 AbstractThis review analyzes an interdisciplinary approach to the pancreatic endocrine network-like relationships that control glucagon secretion and glucagon counterregulation (GCR). Using in silico studies, we show that a pancreatic feedback network that brings together several explicit interactions between islet peptides and blood glucose reproduces the normal GCR axis and explains its impairment in diabetes. An α-cell auto-feedback loop drives glucagon pulsatility and mediates triggering of GCR by hypoglycemia by a rapid switch-off of β-cell signals. The auto-feedback explains the enhancement of defective GCR in β-cell deficiency by a switch-off of signals in the pancreas that suppress α cells. Our models also predict that reduced β-cell activity decreases and delays the GCR. A key application of our models is the in silico simulation and testing of possible scenarios to repair defective GCR in β-cell deficiency. In particular, we predict that partial suppression of hyperglucagonemia may repair the impaired GCR. We also outline how the models can be extended and tested using human data to become a part of a larger construct including the regulation of the hepatic glucose output by the pancreas, circulating glucose, and incretins. In conclusion, a model of the normal GCR control mechanisms and their dysregulation in insulin-deficient diabetes is proposed and partially validated. The model components are clinically measurable, which permits its application to the study of the abnormalities of the human endocrine pancreas and their role in the progression of many diseases, including diabetes, metabolic syndrome, polycystic ovary syndrome, and others. It may also be used to examine therapeutic responses.

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Pancreatic Somatostatin is a Mediator of Glucagon Inhibition by Hyperglycemia

Cited by 48 publications

References 28 publications

Intra-islet insulin permits glucose to directly suppress pancreatic A cell function.

Intra-islet insulin permits glucose to directly suppress pancreatic A cell function.

A physiologic role for somatostatin 28 as a regulator of insulin secretion.

Models of Glucagon Secretion, Their Application to the Analysis of the Defects in Glucagon Counterregulation and Potential Extension to Approximate Glucagon Action

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