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

Am J Physiol Endocrinol Metab. 2000 Feb;278(2):E340-51. doi: 10.1152/ajpendo.2000.278.2.E340.

Abstract

To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines 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 thapsigargin (10 microM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-x(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(L) mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-x(L) islets had impaired insulin secretory and intracellular free Ca(2+) ([Ca(2+)](i)) responses to glucose and KCl. Furthermore, insulin and [Ca(2+)](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 oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(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(L) islets. Thus, although Bcl-x(L) promotes beta-cell survival, high levels of expression of Bcl-x(L) result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Blood Glucose / metabolism
  • Calcium / metabolism
  • DNA Fragmentation / drug effects
  • Gene Expression*
  • Glucose / pharmacology
  • Glucose Tolerance Test
  • Immunohistochemistry
  • Insulin / analysis
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / ultrastructure
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Transgenic
  • Mitochondria / physiology*
  • Potassium Chloride / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Rats
  • Thapsigargin / pharmacology
  • bcl-X Protein

Substances

  • Bcl2l1 protein, mouse
  • Bcl2l1 protein, rat
  • Blood Glucose
  • Insulin
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Potassium Chloride
  • Thapsigargin
  • Glucose
  • Calcium