OBJECTIVE-Somatostatin (SST) is secreted by islet ␦-cells and by extraislet neuroendocrine cells. SST receptors have been identified on ␣-and ␤-cells, and exogenous SST inhibits insulin and glucagon secretion, consistent with a role for SST in regulating ␣-and ␤-cell function. However, the specific intraislet function of ␦-cell SST remains uncertain. We have used Sst Ϫ/Ϫ mice to investigate the role of ␦-cell SST in the regulation of insulin and glucagon secretion in vitro and in vivo. RESEARCH DESIGN AND METHODS-Islet morphology wasassessed by histological analysis. Hormone levels were measured by radioimmunoassay in control and Sst Ϫ/Ϫ mice in vivo and from isolated islets in vitro. RESULTS-Islet size and organization did not differ between SstϪ/Ϫ and control islets, nor did islet glucagon or insulin content. Sst Ϫ/Ϫ mice showed enhanced insulin and glucagon secretory responses in vivo. In vitro stimulus-induced insulin and glucagon secretion was enhanced from perifused Sst Ϫ/Ϫ islets compared with control islets and was inhibited by exogenous SST in Sst Ϫ/Ϫ but not control islets. No difference in the switch-off rate of glucose-stimulated insulin secretion was observed between genotypes, but the cholinergic agonist carbamylcholine enhanced glucose-induced insulin secretion to a lesser extent in Sst Ϫ/Ϫ islets compared with controls. Glucose suppressed glucagon secretion from control but not Sst Ϫ/Ϫ islets.CONCLUSIONS-We suggest that ␦-cell SST exerts a tonic inhibitory influence on insulin and glucagon secretion, which may facilitate the islet response to cholinergic activation. In addition, ␦-cell SST is implicated in the nutrient-induced suppression of glucagon secretion. Diabetes 58:403-411, 2009

Aims/hypothesis We investigated the production of kisspeptin (KISS1) and the KISS1 receptor, GPR54, in pancreatic islets and determined the effects of exogenous kisspeptin on insulin secretion. Methods RT-PCR and immunohistochemistry were used to detect expression of KISS1 and GPR54 mRNAs and the production of KISS1 and GPR54 in human and mouse islets and in beta (MIN6) and alpha-(alphaTC1) cell lines. The effects of KISS1 on basal and glucose-induced insulin secretion from mouse and human islets were measured in a perifusion system. Results KISS1 and GPR54 mRNAs were both detected in human and mouse islets, and GPR54 mRNA expression was also found in the MIN6 and alphaTC1 endocrine cell lines. In sections of mouse pancreas, KISS1 and GPR54 immunoreactivities were co-localised in both beta and alpha cells within islets, but were not detected in the exocrine pancreas. Exposure of mouse and human islets to KISS1 caused a stimulation of glucose-induced (20 mmol/l) insulin secretion, but had no effect on the basal rate of secretion at a sub-stimulatory concentration of glucose (2 mmol/l). In contrast, KISS1 inhibited insulin secretion from MIN6 cells at both 2 and 20 mmol/l glucose. KISS1 had no significant effect on glucagon secretion from mouse islets. Conclusions/interpretation This is the first report to show that the GPR54/KISS1 system is expressed in the endocrine pancreas, where it influences beta cell secretory function. These observations suggest an important role for this system in the normal regulation of islet function.

The presence of autoantibodies to multiple islet autoantigens confers high risk for development of Type 1 diabetes. Four major autoantigens are established (insulin, glutamate decarboxylase, IA-2, and zinc transporter-8), but the molecular identity of a fifth, a 38kDa membrane glycoprotein (Glima), is unknown. Glima antibodies have been detectable only by immunoprecipitation from extracts of radiolabeled islet or neuronal cells. We sought to identify Glima to enable efficient assay of these autoantibodies. Mouse brain and lung were shown to express Glima. Membrane glycoproteins from extracts of these organs were enriched by detergent phase separation, lectin affinity chromatography and SDS-PAGE. Proteins were also immunoaffinity purified from brain extracts using autoantibodies from diabetic patients' sera before SDS-PAGE. Eluates from gel regions equivalent to 38kDa were analyzed by LC-MS/MS for protein identification. Three proteins were detected in samples from the brain and lung extracts, and in the immunoaffinity purified sample, but not the negative control. Only tetraspanin-7, a multipass transmembrane glycoprotein with neuroendocrine expression, had physical characteristics expected of Glima. Tetraspanin-7 was confirmed as an autoantigen by demonstrating binding to autoantibodies in Type 1 diabetes. We identify tetraspanin-7 as a target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy.

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