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Am J Physiol Endocrinol Metab 278: E340-E351, 2000;
0193-1849/00 $5.00
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Vol. 278, Issue 2, E340-E351, February 2000

Overexpression of Bcl-xL in beta -cells prevents cell death but impairs mitochondrial signal for insulin secretion

Yun-Ping Zhou1, John C. Pena2, Michael W. Roe1, Anshu Mittal1, Matteo Levisetti1, Aaron C. Baldwin1, William Pugh1, Diane Ostrega1, Noreen Ahmed1, Vytautas P. Bindokas3, Louis H. Philipson1, Douglas Hanahan4, Craig B. Thompson2, and Kenneth S. Polonsky1

1 Department of Medicine, Section of Endocrinology; 2 Howard Hughes Medical Institute and Departments of Medicine, Molecular Genetics and Cell Biology, 3 Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637; and 4 Department of Biochemistry, University of California at San Francisco, San Francisco, California 94143

To study effects of Bcl-xL in the pancreatic beta -cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-xL expression in beta -cells was increased 2- to 3-fold in founder (Fd) 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 µM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-xL transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl-xL mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-xL islets had impaired insulin secretory and intracellular free Ca2+ ([Ca2+]i) responses to glucose and KCl. Furthermore, insulin and [Ca2+]i responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-xL islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-xL islets than in wild-type islets. Glucose-, PME-, and alpha -ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-xL islets. Thus, although Bcl-xL promotes beta -cell survival, high levels of expression of Bcl-xL result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.

apoptosis; calcium; islets of Langerhans; mitochondria


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