TY - JOUR
T1 - Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel
AU - Remedi, Maria S.
AU - Friedman, Jonathan B.
AU - Nichols, Colin G.
N1 - Funding Information:
We are extremely grateful to Dr. Pedro Herrera (Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland) for providing us with Rip-Cre mice and Dr. Susumu Seino for providing us with Kir6.1KO mice. We are also grateful to Dr. Michael McDaniel and Mrs. Connie Marshall (Department of Pathology and Immunology, Washington University School of Medicine) for kindly providing human islets for this study. This work was supported by National Institutes of Health grants DK098584 to M.S. Remedi and DK109407 to C.G. Nichols. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no competing financial interests. Angus C. Nairn served as editor.
Publisher Copyright:
© 2017 Remedi et al.
PY - 2016
Y1 - 2016
N2 - Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels 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 KATP channel 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 KATP channels and a contributory role for these subunits in the control of insulin secretion.
AB - Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels 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 KATP channel 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 KATP channels and a contributory role for these subunits in the control of insulin secretion.
UR - http://www.scopus.com/inward/record.url?scp=85010211627&partnerID=8YFLogxK
U2 - 10.1085/jgp.201611653
DO - 10.1085/jgp.201611653
M3 - Article
C2 - 27956473
AN - SCOPUS:85010211627
VL - 149
SP - 75
EP - 84
JO - Journal of General Physiology
JF - Journal of General Physiology
SN - 0022-1295
IS - 1
ER -