Targeted Disruption of Pancreatic-Derived Factor (PANDER, FAM3B) Impairs Pancreatic β-Cell Function

Abstract

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.

Quantitative proteomic profiling reveals hepatic lipogenesis and liver X receptor activation in the PANDER transgenic model

“…Pancreatic islets obtained from the PANDER knockout mouse (PANDER KO) displayed an impaired glucose stimulated insulin secretion (GSIS) (Robert-Cooperman et al, 2010). The mechanism for this decreased biological function has yet to be determined precisely, although the observed inhibited intracellular Ca 2+ response is believed to have a role in the impaired GSIS of the PANKO model.…”

“…Over the past decade PANcreatic-DERived factor (PANDER or FAM3B) has been investigated with regard to secretion from the endocrine pancreas and biological impact on glycemic regulation both in-vitro and in-vivo (Zhu, Xu, Patel et al, 2002, Burkhardt, Cook, Young et al, 2008, Burkhardt, Greene, White et al, 2006, Cao, Yang, Burkhardt et al, 2005, Hou, Wang, Li et al, 2011, Mou, Li, Yao et al, 2013, Robert, 2005, Robert-Cooperman, Carnegie, Wilson et al, 2010, Wang, Cai, Pang et al, 2008, Xiang, Chen and Yang, 2012, Xu, Gao, Wu et al, 2005, Yang, Gao, Robert et al, 2005, Yang, Robert, Burkhardt et al, 2005, Zhuang, Guan, Gao et al, 2011). Our recently generated pancreas specific overexpressing transgenic mouse model (PANTG) exhibits both fasting and fed glucose intolerance primarily attributed to impaired hepatic insulin signaling concordantly coupled with both increased gluconeogenesis and lipogenesis (Robert-Cooperman, Dougan, Moak et al, 2014).…”

Family with sequence similarity 3 gene family and nonalcoholic fatty liver disease

“…Immunohistochemical staining and confocal microscopy assays further revealed that FAM3B protein is specifically localized in the islets within the pancreas . Therefore, FAM3B is also called PANDER in subsequent studies . Human and mouse PANDER proteins are composed of 235 amino acid residues with a 29‐amino acid N‐terminal signal peptide and share high‐sequence homology among species.…”

“…These studies strongly indicate that the expression and secretion of PANDER and insulin are tightly coupled in β cells, which is critical in the maintenance of β cell function. In support, PANDER gene deficient ( PANDER −/−) mice show glucose intolerance because of impaired insulin secretion from pancreatic islets, and isolated PANDER −/− islets exhibit blunted insulin secretion in response to glucose or potassium chloride challenge when compared with PANDER +/+ islets . Furthermore, mutation of Tyr26 and Leu27 in the signal peptide of PANDER, which enhances PANDER secretion, is associated with increased insulin secretion in β cells in the absence or presence of low glucose stimulation .…”

“…Because FAM3B is highly expressed in pancreatic islets, it was also called pancreatic‐derived factor (PANDER) . So far, it has been revealed that PANDER is involved in the development and progression of insulin resistance, NAFLD, and type 2 diabetes . There is also evidence that FAM3D may play a role in the regulation of lipid and energy metabolism in mice and humans .…”