Activation of Somatostatin Receptor Subtype 2 Inhibits Insulin Secretion in the Isolated Perfused Human Pancreas

Fc, Brunicardi; Atiya, A; Moldovan, Stefan; Tc, Lee; Sp, Fagan; Rm, Kleinman; Adrian, TE; Dh, Coy; Jh, Walsh; We, Fisher

doi:10.1097/00006676-200311000-00019

Cited by 23 publications

(18 citation statements)

References 14 publications

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“…Although our findings do not entirely match the expression pattern of SSTR they are in agreement with two previous studies on perfused human pancreas, describing SSTR2 as an inhibitor of insulin secretion (15,28). However, in these studies less SSTR2-selective agonists have been tested.…”

Section: Discussionsupporting

confidence: 65%

Characterization of Somatostatin Receptor Subtype-Specific Regulation of Insulin and Glucagon Secretion: An in Vitro Study on Isolated Human Pancreatic Islets

Singh

Brendel

Zacharias

et al. 2006

The Journal of Clinical Endocrinology &Amp; Metabolism

110

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Section: Discussionsupporting

confidence: 65%

Characterization of Somatostatin Receptor Subtype-Specific Regulation of Insulin and Glucagon Secretion: An in Vitro Study on Isolated Human Pancreatic Islets

Singh

Brendel

Zacharias

et al. 2006

The Journal of Clinical Endocrinology &Amp; Metabolism

110

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“…Although the effects of the SSTR3 agonist did not reach overall statistical significance, a clear and reversible inhibition of exocytosis was obtained in some ␣-cells, which is compatible with heterogeneous receptor expression. A similar order of potency for SSTR1, -2, and -5 agonists (i.e., SSTR2 Ͼ SSTR5 Ͼ SSTR1 for insulin, SSTR2 Ͼ SSTR1 Ͼ SSTR5 for glucagon) was observed in hormone secretion measurements from isolated human islets (9,37), but an SSTR3 agonist was found to be ineffective in these studies. It is likely that the same SSTR3 agonist employed in the present study was also used in the studies of Brunicardi et al (9) and Singh et al (37) (based on its K i values for SSTR isoforms), but it is unclear which concentrations were tested in those studies.…”

Section: Discussionsupporting

confidence: 64%

“…A similar order of potency for SSTR1, -2, and -5 agonists (i.e., SSTR2 Ͼ SSTR5 Ͼ SSTR1 for insulin, SSTR2 Ͼ SSTR1 Ͼ SSTR5 for glucagon) was observed in hormone secretion measurements from isolated human islets (9,37), but an SSTR3 agonist was found to be ineffective in these studies. It is likely that the same SSTR3 agonist employed in the present study was also used in the studies of Brunicardi et al (9) and Singh et al (37) (based on its K i values for SSTR isoforms), but it is unclear which concentrations were tested in those studies. The low affinity of the compound for SSTR2 makes it unlikely that the effects observed here were mediated by a different receptor isoform.…”

Section: Discussionsupporting

confidence: 64%

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SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells

Kailey

Bunt

Cheley

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

133

129

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Somatostatin-14 (SST) inhibits insulin and glucagon secretion by activating G protein-coupled somatostatin receptors (SSTRs), of which five isoforms exist (SSTR1-5). In mice, the effects on pancreatic β-cells are mediated by SSTR5, whereas α-cells express SSTR2. In both cell types, SSTR activation results in membrane hyperpolarization and suppression of exocytosis. Here, we examined the mechanisms by which SST inhibits secretion from human β- and α-cells and the SSTR isoforms mediating these effects. Quantitative PCR revealed high expression of SSTR2, with lower levels of SSTR1, SSTR3, and SSTR5, in human islets. Immunohistochemistry showed expression of SSTR2 in both β- and α-cells. SST application hyperpolarized human β-cells and inhibited action potential firing. The membrane hyperpolarization was unaffected by tolbutamide but antagonized by tertiapin-Q, a blocker of G protein-gated inwardly rectifying K⁺ channels (GIRK). The effect of SST was mimicked by an SSTR2-selective agonist, whereas a SSTR5 agonist was marginally effective. SST strongly (>70%) reduced depolarization-evoked exocytosis in both β- and α-cells. A slightly weaker inhibition was observed in both cell types after SSTR2 activation. SSTR3- and SSTR1-selective agonists moderately reduced the exocytotic responses in β- and α-cells, respectively, whereas SSTR4- and SSTR5-specific agonists were ineffective. SST also reduced voltage-gated P/Q-type Ca²⁺ currents in β-cells, but normalization of Ca²⁺ influx to control levels by prolonged depolarizations only partially restored exocytosis. We conclude that SST inhibits secretion from both human β- and α-cells by activating GIRK and suppressing electrical activity, reducing P/Q-type Ca²⁺ currents, and directly inhibiting exocytosis. These effects are mediated predominantly by SSTR2 in both cell types.

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“…We used a modified in-house sliding scale equation for bolus insulin administration, which takes into account initial blood glucose levels and a target glucose concentration of~5.0 mmol/l, in an attempt to modestly elevate relative insulin levels during exercise. However, insulin concentrations were not measured during this protocol and it is unclear if the SSTR2a promoted increased insulin secretion, which has been reported for cultured human islets [44]. Nonetheless, Yue et al [26] found no change in systemic insulin levels in rats with STZ-induced diabetes given SSTR2a, likely because SSTR5 is the main receptor isoform in beta cells in rats [25].…”

Section: Discussionmentioning

confidence: 83%

Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes

et al. 2016

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Aims/hypothesis Regular exercise is at the cornerstone of care in type 1 diabetes. However, relative hyperinsulinaemia and a blunted glucagon response to exercise promote hypoglycaemia. Recently, a selective antagonist of somatostatin receptor 2, PRL-2903, was shown to improve glucagon counterregulation to hypoglycaemia in resting streptozotocin-induced diabetic rats. The aim of this study was to test the efficacy of PRL-2903 in enhancing glucagon counterregulation during repeated hyperinsulinaemic exercise. Methods Diabetic rats performed daily exercise for 1 week and were then exposed to saline (154 mmol/l NaCl) or PRL-2903, 10 mg/kg, before hyperinsulinaemic exercise on two separate occasions spaced 1 day apart. In the following week, animals crossed over to the alternate treatment for a third hyperinsulinaemic exercise protocol. Results Liver glycogen content was lower in diabetic rats compared with control rats, despite daily insulin therapy (p < 0.05). Glucagon levels failed to increase during exercise with saline but increased three-to-six fold with PRL-2903 (all p < 0.05). Glucose concentrations tended to be higher during exercise and early recovery with PRL-2903 on both days of treatment; this difference did not achieve statistical significance (p > 0.05). Conclusions/interpretation PRL-2903 improves glucagon counterregulation during exercise. However, liver glycogen stores or other factors limit the prevention of exercise-induced hypoglycaemia in rats with streptozotocin-induced diabetes.

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Activation of Somatostatin Receptor Subtype 2 Inhibits Insulin Secretion in the Isolated Perfused Human Pancreas

Cited by 23 publications

References 14 publications

Characterization of Somatostatin Receptor Subtype-Specific Regulation of Insulin and Glucagon Secretion: An in Vitro Study on Isolated Human Pancreatic Islets

Characterization of Somatostatin Receptor Subtype-Specific Regulation of Insulin and Glucagon Secretion: An in Vitro Study on Isolated Human Pancreatic Islets

SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells

Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes

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