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

2006 ◽  
Vol 92 (2) ◽  
pp. 673-680 ◽  
Author(s):  
Vandana Singh ◽  
Mathias D. Brendel ◽  
Sylvia Zacharias ◽  
Stefan Mergler ◽  
Henning Jahr ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Somatostatin Receptor ◽  
In Vitro Study ◽  
Glucagon Secretion ◽  
Receptor Subtype ◽  
Human Pancreatic Islets ◽  
Insulin And Glucagon Secretion ◽  
Specific Regulation

scholarly journals Somatostatin Inhibits Insulin and Glucagon Secretion via Two Receptor Subtypes: An in Vitro Study of Pancreatic Islets from Somatostatin Receptor 2 Knockout Mice*

Endocrinology ◽  
2000 ◽  
Vol 141 (1) ◽  
pp. 111-117 ◽  
Author(s):  
M. Z. Strowski ◽  
R. M. Parmar ◽  
A. D. Blake ◽  
J. M. Schaeffer
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Endocrine Function ◽  
Receptor Subtype ◽  
Glucagon Release ◽  
Glucagon And Insulin

Abstract Somatostatin (SST) potently inhibits insulin and glucagon release from pancreatic islets. Five distinct membrane receptors (SSTR1–5) for SST are known, and at least two (SSTR2 and SSTR5) have been proposed to regulate pancreatic endocrine function. Our current understanding of SST physiology is limited by the receptor subtype selectivity of peptidyl SST analogs, making it difficult to assign a physiological function to an identified SST receptor subtype. To better understand the physiology of SSTRs we studied the in vitro effects of potent subtype-selective nonpeptidyl SST analogs on the regulation of pancreatic glucagon and insulin secretion in wild-type (WT) and in somatostatin receptor 2 knockout (SSTR2KO) mice. There was no difference in basal glucagon and insulin secretion between islets isolated from SSTR2KO and WT mice; however, potassium/arginine-stimulated glucagon secretion was approximately 2-fold higher in islets isolated from SSTR2KO mice. Neither SST nor any SSTR-selective agonist inhibited basal glucagon or insulin release. SST-14 potently inhibited stimulated glucagon secretion in islets from WT mice and much less effectively in islets from SSTR2KO mice. The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice. L-817,818, an SSTR5 selective analog, slightly reduced glucagon release in both animal groups, whereas SSTR1, -3, and -4 selective analogs were inactive. SST and L-817,818 inhibited glucose stimulated insulin release in islets from WT and SSTR2KO mice. L-779,976 much less potently reduced insulin secretion from WT islets. In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5.

Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues

2007 ◽  
Vol 138 (1) ◽  
pp. 1-9 ◽  
Author(s):  
E. Ludvigsen ◽  
M. Stridsberg ◽  
J.E. Taylor ◽  
M.D. Culler ◽  
K. Öberg ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Glucagon Secretion ◽  
Somatostatin Analogues ◽  
Rat Pancreatic Islets ◽  
Insulin And Glucagon Secretion

scholarly journals Somatostatin Receptor Subtype-2-Deficient Mice with Diet-Induced Obesity Have Hyperglycemia, Nonfasting Hyperglucagonemia, and Decreased Hepatic Glycogen Deposition

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3887-3899 ◽  
Author(s):  
Vandana Singh ◽  
Carsten Grötzinger ◽  
Krzysztof W. Nowak ◽  
Sylvia Zacharias ◽  
Eva Göncz ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Hepatic Glycogen ◽  
Receptor Subtype ◽  
Isolated Pancreatic Islets ◽  
Diet Induced Obesity ◽  
Hepatic Glucose ◽  
Somatostatin Receptor Subtype 2 ◽  
Deficient Mice

Hypersecretion of glucagon contributes to abnormally increased hepatic glucose output in type 2 diabetes. Somatostatin (SST) inhibits murine glucagon secretion from isolated pancreatic islets via somatostatin receptor subtype-2 (sst2). Here, we characterize the role of sst2 in controlling glucose homeostasis in mice with diet-induced obesity. Sst2-deficient (sst2−/−) and control mice were fed high-fat diet for 14 wk, and the parameters of glucose homeostasis were monitored. Hepatic glycogen and lipid contents were quantified enzymatically and visualized histomorphologically. Enzymes regulating glycogen and lipid synthesis and breakdown were measured by real-time PCR and/or Western blot. Gluconeogenesis and glycogenolysis were determined from isolated primary hepatocytes and glucagon or insulin secretion from isolated pancreatic islets. Nonfasting glucose, glucagon, and fasting nonesterified fatty acids of sst2−/− mice were increased. Inhibition of glucagon secretion from sst2-deficient pancreatic islets by glucose or somatostatin was impaired. Insulin less potently reduced blood glucose concentration in sst2-deficient mice as compared with wild-type mice. Sst2-deficient mice had decreased nonfasting hepatic glycogen and lipid content. The activity/expression of enzymes controlling hepatic glycogen synthesis of sst2−/− mice was decreased, whereas enzymes facilitating glycogenolysis and lipolysis were increased. Somatostatin and an sst2-selective agonist decreased glucagon-induced glycogenolysis, without influencing de novo glucose production using cultured primary hepatocytes. This study demonstrates that ablation of sst2 leads to hyperglucagonemia. Increased glucagon concentration is associated with impaired glucose control in sst2−/− mice, resulting from decreased hepatic glucose storage, increased glycogen breakdown, and reduced lipid accumulation. Sst2 may constitute a therapeutic target to lower hyperglucagonemia in type 2 diabetes.

scholarly journals Characterization of New Selective Somatostatin Receptor Subtype-2 (sst2) Antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH Release in Anesthetized Male Rats after Short-Term High-Dose Dexamethasone Treatment

Endocrinology ◽  
2002 ◽  
Vol 143 (4) ◽  
pp. 1218-1224 ◽  
Author(s):  
G. Tulipano ◽  
D. Soldi ◽  
M. Bagnasco ◽  
M. D. Culler ◽  
J. E. Taylor ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Male Rats ◽  
Receptor Subtype ◽  
High Dose ◽  
Dependent Manner ◽  
Short Term ◽  
Adult Rats ◽  
High Dose Dexamethasone

Abstract We here report a pharmacological characterization of two new somatostatin (SS) receptor subtype-2 (sst2) selective antagonists by evaluating their GH-releasing activity when administered, by different routes, in anesthetized adult rats and in freely moving 10-d-old rats. Moreover, we describe the effect of these SS antagonists on the GH response to GHRH after short-term high-dose dexamethasone (DEX) treatment in young male rats. BIM-23454 and BIM-23627, given iv, were able to counteract the SS-induced inhibition of GH secretion occurring after urethane anesthesia in a dose-dependent manner. In DEX-treated animals, the GH response to GHRH was partially blunted (5-min peak values, 270 ± 50 ng/ml in saline-treated vs. 160 ± 10 ng/ml in DEX-treated, P < 0.05); however, the simultaneous administration of BIM-23627 (0.2 mg/kg, iv) restored higher amplitude GH pulse, leading to a significantly higher overall mean GH response (area under the curve, 4200 ± 120 ng/ml/30 min vs. 2800 ± 100 ng/ml/30 min after GHRH alone; P < 0.05). The SS antagonists showed a reduced GH-releasing effect when administered sc or ip, likely attributable to decreased bioavailability, as compared with the iv route. SS antagonist administration also increased plasma glucagon, insulin, and glucose levels. Based on prior reports that sst2 tonically suppresses glucagon secretion, the antagonist most likely increased glucagon secretion from the pancreatic α-cells, with resultant increases in plasma glucose and then insulin.

scholarly journals Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE

2021 ◽  
Vol 14 (12) ◽  
pp. 1265
Author(s):  
Rosalba Mansi ◽  
Pascale Plas ◽  
Georges Vauquelin ◽  
Melpomeni Fani
Keyword(s):  
Binding Sites ◽  
Therapeutic Efficacy ◽  
Somatostatin Receptor ◽  
In Vitro Study ◽  
Receptor Subtype ◽  
High Concentration ◽  
Cellular Mechanisms ◽  
Competition Binding ◽  
Somatostatin Receptor Subtype 2

Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST2) peptide agonist [177Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST2 peptide antagonist [177Lu]Lu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences. In the present in vitro study, we compared kinetic binding, saturation binding, competition binding, cellular uptake and release of [177Lu]Lu-OPS201 versus [177Lu]Lu-DOTA-TATE using HEK cells stably transfected with the human SST2. While [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE exhibited comparable affinity (KD, 0.15 ± 0.003 and 0.08 ± 0.02 nM, respectively), [177Lu]Lu-OPS201 recognized four times more binding sites than [177Lu]Lu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of [177Lu]Lu-OPS201 bound to HEK-SST2 cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist. [177Lu]Lu-OPS201 showed faster association and slower dissociation than [177Lu]Lu-DOTA-TATE. Whereas most of [177Lu]Lu-OPS201 remained at the cell surface, [177Lu]Lu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE regarding the recognition of receptor binding sites (higher for [177Lu]Lu-OPS201) and their kinetics (faster association and slower dissociation of [177Lu]Lu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of [177Lu]Lu-OPS201 compared to [177Lu]Lu-DOTA-TATE.

339-LB: Modulation of Insulin and Glucagon Secretion by Optogenetic Control of Delta-Cell Electrical Activity in Pancreatic Islets

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 339-LB
Author(s):  
HAIQIANG DOU ◽  
CAROLINE A. MIRANDA ◽  
QUAN ZHANG ◽  
PATRIK RORSMAN ◽  
JOHAN TOLö
Keyword(s):  
Electrical Activity ◽  
Pancreatic Islets ◽  
Glucagon Secretion ◽  
Insulin And Glucagon Secretion ◽  
Delta Cell ◽  
Optogenetic Control

scholarly journals Ghrelin Receptor (GHS-R1a) and Its Constitutive Activity in Somatotroph Adenomas: A New Co-targeting Therapy Using GHS-R1a Inverse Agonists and Somatostatin Analogs

2014 ◽  
Vol 99 (12) ◽  
pp. E2463-E2471 ◽  
Author(s):  
Yves Mear ◽  
Marie-Pierre Blanchard ◽  
Céline Defilles ◽  
Thierry Brue ◽  
Dominique Figarella-Branger ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Inverse Agonist ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Constitutive Activity ◽  
Targeting Therapy ◽  
Ghrelin Receptor ◽  
Gh Secretion

Context: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. Objective: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target. Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. Results: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.

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