Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus
- R. K. P. BenningerAffiliated withMolecular Physiology and Biophysics, Vanderbilt University
- , M. S. RemediAffiliated withCell Biology and Physiology, Washington University
- , W. S. HeadAffiliated withMolecular Physiology and Biophysics, Vanderbilt University
- , A. UstioneAffiliated withMolecular Physiology and Biophysics, Vanderbilt University
- , D. W. PistonAffiliated withMolecular Physiology and Biophysics, Vanderbilt University Email author
- , C. G. NicholsAffiliated withCell Biology and Physiology, Washington University Email author
Mutations that render ATP-sensitive potassium (KATP) channels insensitive to ATP inhibition cause neonatal diabetes mellitus. In mice, these mutations cause insulin secretion to be lost initially and, as the disease progresses, beta cell mass and insulin content also disappear. We investigated whether defects in calcium signalling alone are sufficient to explain short-term and long-term islet dysfunction.
We examined the metabolic, electrical and insulin secretion response in islets from mice that become diabetic after induction of ATP-insensitive Kir6.2 expression. To separate direct effects of KATP overactivity on beta cell function from indirect effects of prolonged hyperglycaemia, normal glycaemia was maintained by protective exogenous islet transplantation.
In endogenous islets from protected animals, glucose-dependent elevations of intracellular free-calcium activity ([Ca2+]i) were severely blunted. Insulin content of these islets was normal, and sulfonylureas and KCl stimulated increased [Ca2+]i. In the absence of transplant protection, [Ca2+]i responses were similar, but glucose metabolism and redox state were dramatically altered; sulfonylurea- and KCl-stimulated insulin secretion was also lost, because of systemic effects induced by long-term hyperglycaemia and/or hypoinsulinaemia. In both cases, [Ca2+]i dynamics were synchronous across the islet. After reduction of gap-junction coupling, glucose-dependent [Ca2+]i and insulin secretion was partially restored, indicating that excitability of weakly expressing cells is suppressed by cells expressing mutants, via gap-junctions.
The primary defect in KATP-induced neonatal diabetes mellitus is failure of glucose metabolism to elevate [Ca2+]i, which suppresses insulin secretion and mildly alters islet glucose metabolism. Loss of insulin content and mitochondrial dysfunction are secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of glucose-dependent insulin secretion.
KeywordsBeta cell Calcium Gap-junctions KATP channel Neonatal diabetes mellitus Transgenic mice
- Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus
Volume 54, Issue 5 , pp 1087-1097
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- Beta cell
- KATP channel
- Neonatal diabetes mellitus
- Transgenic mice
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- Author Affiliations
- 1. Molecular Physiology and Biophysics, Vanderbilt University, 2215 Garland Avenue, Nashville, TN, 37232, USA
- 2. Cell Biology and Physiology, Washington University, 660 S Euclid Avenue, St Louis, MO, 63110, USA