title: Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus.
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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maria Sara
authors.initials: MS
authors.lastname: Remedi
authors.forename: Harley T
authors.initials: HT
authors.lastname: Kurata
authors.forename: Alexis
authors.initials: A
authors.lastname: Scott
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Eva
authors.initials: E
authors.lastname: Rother
authors.forename: Andre
authors.initials: A
authors.lastname: Kleinridders
authors.forename: Ailing
authors.initials: A
authors.lastname: Tong
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Koster
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D005905:Glyburide / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D054086:KATP Channels / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D054086:KATP Channels; D013453:Sulfonylurea Compounds; D013629:Tamoxifen; D000255:Adenosine Triphosphate; D005905:Glyburide