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Suppressed Insulin Signaling and Increased Apoptosis in Cd38-Null Islets

¹ Division of Metabolism, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
² Department of Cellular and Physiological Sciences and Department of Surgery, University of British Columbia, Vancouver, BC, Canada
³ Trudeau Institute, Saranac Lake, New York

Address correspondence and reprint requests to James D. Johnson, PhD, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3. E-mail: jimjohn{at}interchange.ubc.ca

Abbreviations: cADPR, cyclic ADP ribose; NAADP, nicotinic acid adenine dinucleotide phosphate; RyR2, ryanodine receptor

CD38 is a multifunctional enzyme capable of generating metabolites that release Ca²⁺ from intracellular stores, including nicotinic acid adenine dinucleotide phosphate (NAADP). A number of studies have led to the controversial proposal that CD38 mediates an alternate pathway for glucose-stimulated insulin release and contributes to the pathogenesis of diabetes. It has recently been shown that NAADP mediates Ca²⁺ mobilization by insulin in human pancreatic ß-cells. In the present study, we report altered Ca²⁺ homeostasis and reduced responsiveness to insulin, but not glucose, in Cd38^–/– ß-cells. In keeping with the antiapoptotic role of insulin signaling, Cd38^–/– islets were significantly more susceptible to apoptosis compared with islets isolated from littermate controls. This finding correlated with disrupted islet architecture and reduced ß-cell mass in Cd38^–/– mice, both in the context of a normal lab diet and a high-fat diet. Nevertheless, we did not find robust differences in glucose homeostasis in vivo or glucose signaling in vitro in Cd38^–/– mice on the C57BL/6 genetic background, in contrast to previous studies by others of Cd38 knockout mice on the ICR background. Thus, our results suggest that CD38 plays a role in novel antiapoptotic signaling pathways but does not directly control glucose signaling in pancreatic ß-cells.

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