OBJECTIVEPancreatic-derived factor (PANDER, FAM3B) is a pancreatic islet-specific cytokine-like protein that is secreted from β-cells upon glucose stimulation. The biological function of PANDER is unknown, and to address this we generated and characterized a PANDER knockout mouse.RESEARCH DESIGN AND METHODSTo generate the PANDER knockout mouse, the PANDER gene was disrupted and its expression was inhibited by homologous recombination via replacement of the first two exons, secretion signal peptide and transcriptional start site, with the neomycin gene. PANDER−/− mice were then phenotyped by a number of in vitro and in vivo tests to evaluate potential effects on glucose regulation, insulin sensitivity, and β-cell morphology and function.RESULTSGlucose tolerance tests demonstrated significantly higher blood glucose levels in PANDER−/− versus wild-type male mice. To identify the mechanism of the glucose intolerance, insulin sensitivity and pancreatic β-cell function were examined. Hyperinsulinemic-euglycemic clamps and insulin tolerance testing showed similar insulin sensitivity for both the PANDER−/− and wild-type mice. The in vivo insulin response following intraperitoneal glucose injection surprisingly produced significantly higher insulin levels in the PANDER−/− mice, whereas insulin release was blunted with arginine administration. Islet perifusion and calcium imaging studies showed abnormal responses of the PANDER−/− islets to glucose stimulation. In contrast, neither islet architecture nor insulin content was impacted by the loss of PANDER. Interestingly, the elevated insulin levels identified in vivo were attributed to decreased hepatic insulin clearance in the PANDER−/− islets. Taken together, these results demonstrated decreased pancreatic β-cell function in the PANDER−/− mouse.CONCLUSIONSThese results support a potential role of PANDER in the pancreatic β-cell for regulation or facilitation of insulin secretion.
The novel islet-specific protein PANcreatic DERived Factor (PANDER; FAM3B) has beenextensively characterized with respect to the β-cell, and these studies suggest a potential function for PANDER in the regulation of glucose homeostasis. Little is known regarding PANDER in pancreatic α-cells, which are critically involved in maintaining euglycemia. Here we present the first report elucidating the expression and regulation of PANDER within the α-cell. Pander mRNA and protein aredetected in α-cells, with primary localization to a glucagonnegative granular cytosolic compartment. PANDER secretion from α-cells is nutritionally and hormonally regulated by L-arginine and insulin, demonstrating similarities and differences with glucagon. Signaling via the insulin receptor (IR) through the PI3K and Akt/PKB node is required for insulin-stimulated PANDER release. The separate localization of PANDER and glucagon is consistent with their differential regulation, and the effect of insulin suggests a paracrine/ endocrine effect on PANDER release. This provides further insight into the potential glucoseregulatory role of PANDER.
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