Suppressed insulin signaling and increased apoptosis in Cd38-null islets

James D. Johnson, Eric L. Ford, Ernesto Bernal-Mizrachi, Kim L. Kusser, Dan S. Luciani, Zhiqiang Han, Hung Tran, Troy D. Randall, Frances E. Lund, Kenneth S. Polonsky

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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 β-cells. In the present study, we report altered Ca2+ homeostasis and reduced responsiveness to insulin, but not glucose, in Cd38-/- β-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 β-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 β-cells.

Original languageEnglish (US)
Pages (from-to)2737-2746
Number of pages10
JournalDiabetes
Volume55
Issue number10
DOIs
StatePublished - Oct 2006
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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