Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus.
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.
Remedi
Maria Sara
MS
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kurata
Harley T
HT
Scott
Alexis
A
Wunderlich
F Thomas
FT
Rother
Eva
E
Kleinridders
Andre
A
Tong
Ailing
A
Brüning
Jens C
JC
Koster
Joseph C
JC
Nichols
Colin G
CG
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
D001786:Blood Glucose; D007328:Insulin; D054086:KATP Channels; D013453:Sulfonylurea Compounds; D013629:Tamoxifen; D000255:Adenosine Triphosphate; D005905:Glyburide