title: Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel.
abstract: Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATPchannels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATPchannel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATPchannels and a contributory role for these subunits in the control of insulin secretion.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 mremedi@wustl.edu.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110.|Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Maria S
authors.identifier: http://orcid.org/0000-0003-2048-472X
authors.initials: MS
authors.lastname: Remedi
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Friedman
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110.|Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D054086:KATP Channels / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation
chemical_list: D007328:Insulin; D054086:KATP Channels; C092520:uK-ATP-1 potassium channel