title: Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion.
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.
authors.affiliation: Department of Medicine, Section of Endocrinology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Y P
authors.initials: YP
authors.lastname: Zhou
authors.forename: J C
authors.initials: JC
authors.lastname: Pena
authors.forename: M W
authors.initials: MW
authors.lastname: Roe
authors.forename: A
authors.initials: A
authors.lastname: Mittal
authors.forename: M
authors.initials: M
authors.lastname: Levisetti
authors.forename: A C
authors.initials: AC
authors.lastname: Baldwin
authors.forename: W
authors.initials: W
authors.lastname: Pugh
authors.forename: D
authors.initials: D
authors.lastname: Ostrega
authors.forename: N
authors.initials: N
authors.lastname: Ahmed
authors.forename: V P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: L H
authors.initials: LH
authors.lastname: Philipson
authors.forename: D
authors.initials: D
authors.lastname: Hanahan
authors.forename: C B
authors.initials: CB
authors.lastname: Thompson
authors.forename: K S
authors.initials: KS
authors.lastname: Polonsky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics*; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D001786:Blood Glucose; D007328:Insulin; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011189:Potassium Chloride; D019284:Thapsigargin; D005947:Glucose; D002118:Calcium