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 journalArticle

36 Citations (Scopus)

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

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Insulin
Apoptosis
Glucose
Homeostasis
Multifunctional Enzymes
High Fat Diet
Inbred C57BL Mouse
Knockout Mice
Diet
NAADP

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Johnson, J. D., Ford, E. L., Bernal Mizrachi, E., Kusser, K. L., Luciani, D. S., Han, Z., ... Polonsky, K. S. (2006). Suppressed insulin signaling and increased apoptosis in Cd38-null islets. Diabetes, 55(10), 2737-2746. https://doi.org/10.2337/db05-1455

Suppressed insulin signaling and increased apoptosis in Cd38-null islets. / Johnson, James D.; Ford, Eric L.; Bernal Mizrachi, Ernesto; Kusser, Kim L.; Luciani, Dan S.; Han, Zhiqiang; Tran, Hung; Randall, Troy D.; Lund, Frances E.; Polonsky, Kenneth S.

In: Diabetes, Vol. 55, No. 10, 10.2006, p. 2737-2746.

Research output: Contribution to journalArticle

Johnson, JD, Ford, EL, Bernal Mizrachi, E, Kusser, KL, Luciani, DS, Han, Z, Tran, H, Randall, TD, Lund, FE & Polonsky, KS 2006, 'Suppressed insulin signaling and increased apoptosis in Cd38-null islets', Diabetes, vol. 55, no. 10, pp. 2737-2746. https://doi.org/10.2337/db05-1455
Johnson JD, Ford EL, Bernal Mizrachi E, Kusser KL, Luciani DS, Han Z et al. Suppressed insulin signaling and increased apoptosis in Cd38-null islets. Diabetes. 2006 Oct;55(10):2737-2746. https://doi.org/10.2337/db05-1455
Johnson, James D. ; Ford, Eric L. ; Bernal Mizrachi, Ernesto ; Kusser, Kim L. ; Luciani, Dan S. ; Han, Zhiqiang ; Tran, Hung ; Randall, Troy D. ; Lund, Frances E. ; Polonsky, Kenneth S. / Suppressed insulin signaling and increased apoptosis in Cd38-null islets. In: Diabetes. 2006 ; Vol. 55, No. 10. pp. 2737-2746.
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