Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus

Cell Metab. 2009 Feb;9(2):140-51. doi: 10.1016/j.cmet.2008.12.005.

Abstract

ATP-insensitive K(ATP) channel mutations cause neonatal diabetes mellitus (NDM). To explore the mechanistic etiology, we generated transgenic mice carrying an ATP-insensitive mutant K(ATP) channel subunit. Constitutive expression in pancreatic beta cells caused neonatal hyperglycemia and progression to severe diabetes and growth retardation, with loss of islet insulin content and beta cell architecture. Tamoxifen-induced expression in adult beta cells led to diabetes within 2 weeks, with similar secondary consequences. Diabetes was prevented by transplantation of normal islets under the kidney capsule. Moreover, the endogenous islets maintained normal insulin content and secretion in response to sulfonylureas, but not glucose, consistent with reduced ATP sensitivity of beta cell K(ATP) channels. In NDM, transfer to sulfonylurea therapy is less effective in older patients. This may stem from poor glycemic control or lack of insulin because glibenclamide treatment prior to tamoxifen induction prevented diabetes and secondary complications in mice but failed to halt disease progression after diabetes had developed.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Animals, Newborn
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / physiopathology
  • Glyburide / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • KATP Channels / genetics*
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Sulfonylurea Compounds / pharmacology
  • Tamoxifen / pharmacology

Substances

  • Blood Glucose
  • Insulin
  • KATP Channels
  • Sulfonylurea Compounds
  • Tamoxifen
  • Adenosine Triphosphate
  • Glyburide