Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion

To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic li nes were produced using different forms of the rat insulin promoter Bcl-x(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 t hapsigargin (10 mu M for 48 h), losses of cell viability in islets of Fd I 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 net Fd 1 Bcl-xL mice. Pancreatic insulin content and islet morpholog y were not different from control in either transgenic line. However Fd 2 B cl-x(L) 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-x(L) islets. Consistent with a mitochondrial defect, glucose o xidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(L) isle ts than in wild-type islets. Glucose-, PME-, and alpha-ketoisocaproate-indu ced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-xL islets. Thus, al though Bcl-x(L) promotes beta-cell survival, high levels of expression of B cl-xL result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for ins ulin secretion.