Suppressed insulin signaling and increased apoptosis in CD38-null islets.
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 beta-cells. In the present study, we report altered Ca2+ homeostasis and reduced responsiveness to insulin, but not glucose, in Cd38-/- beta-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 beta-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 beta-cells.
Johnson
James D
JD
Division of Metabolism, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. jimjohn@interchange.ubc.ca
Ford
Eric L
EL
Bernal-Mizrachi
Ernesto
E
Kusser
Kim L
KL
Luciani
Dan S
DS
Han
Zhiqiang
Z
Tran
Hung
H
Randall
Troy D
TD
Lund
Frances E
FE
Polonsky
Kenneth S
KS
D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D008562:Membrane Glycoproteins; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose; D002118:Calcium