1. Overexpression of Bcl-[x.sub.L] in [Beta]-cells prevents cell death but impairs mitochondrial signal for insulin secretion
- Author
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ZHOU, YUN-PING, PENA, JOHN C., ROE, MICHAEL W., MITTAL, ANSHU, LEVISETTI, MATTEO, BALDWIN, AARON C., PUGH, WILLIAM, OSTREGA, DIANE, AHMED, NOREEN, BINDOKAS, VYTAUTAS P., PHILIPSON, LOUIS H., HANAHAN, DOUGLAS, THOMPSON, CRAIG B., and POLONSKY, KENNETH S.
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Cell death -- Physiological aspects ,Mitochondria -- Physiological aspects ,Pancreas -- Secretions ,Biological sciences - Abstract
Zhou, Yun-Ping, John C. Pena, Michael W. Roe, Anshu Mittal, Matteo Levisetti, Aaron C. Baldwin, William Pugh, Diane Ostrega, Noreen Ahmed, Vytautas P. Bindokas, Louis H. Philipson, Douglas Hanahan, Craig B. Thompson, and Kenneth S. Polonsky. Overexpression of Bcl-[x.sub.L] in [Beta]-cells prevents cell death but impairs mitochondrial signal for insulin secretion. Am. J. Physiol. Endocrinol. Metab. 278: E340--E351, 2000.--To study effects of Bcl-[x.sub.L] in the pancreatic [Beta]-cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-[x.sub.L] 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 [micro]M for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-[x.sub.L] 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-[x.sub.L] mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-[x.sub.L] islets had impaired insulin secretory and intracellular free [Ca.sup.2+] ([[[Ca.sup.2+]].sub.i]) responses to glucose and KCL. Furthermore, insulin and [[[Ca.sup.2+]].sub.i] responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-[x.sub.L] islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-[x.sub.L] 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-[x.sub.L] islets. Thus, although Bcl-[x.sub.L] promotes [Beta]-cell survival, high levels of expression of Bcl-[x.sub.L] 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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- 2000