Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes

Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K(+) (K(ATP)) channel. To better understand this...

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Hauptverfasser: Girard, Christophe A., Wunderlich, F. Thomas, Shimomura, Kenju, Collins, Stephan, Kaizik, Stephan, Proks, Peter, Abdulkader, Fernando, Clark, Anne, Ball, Vicky, Zubcevic, Lejla, Bentley, Liz, Clark, Rebecca, Church, Chris, Hugill, Alison, Galvanovskis, Juris, Cox, Roger, Rorsman, Patrik, Brüning, Jens C., Ashcroft, Frances M.
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Veröffentlicht: American Society for Clinical Investigation 2008
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Research Article
Online Zugang:https://ncbi.nlm.nih.gov/pmc/articles/PMC2613450/
https://ncbi.nlm.nih.gov/pubmed/19065048
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1172/JCI35772
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spelling pubmed-26134502009-01-05 Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes Girard, Christophe A. Wunderlich, F. Thomas Shimomura, Kenju Collins, Stephan Kaizik, Stephan Proks, Peter Abdulkader, Fernando Clark, Anne Ball, Vicky Zubcevic, Lejla Bentley, Liz Clark, Rebecca Church, Chris Hugill, Alison Galvanovskis, Juris Cox, Roger Rorsman, Patrik Brüning, Jens C. Ashcroft, Frances M. J Clin Invest Research Article Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K(+) (K(ATP)) channel. To better understand this disease, we generated a mouse expressing a Kir6.2 mutation (V59M) that causes neonatal diabetes in humans and we used Cre-lox technology to express the mutation specifically in pancreatic β cells. These β-V59M mice developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Islets isolated from β-V59M mice secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose. This was due to a reduced sensitivity of K(ATP) channels in pancreatic β cells to inhibition by ATP or glucose. In contrast, the sulfonylurea tolbutamide, a specific blocker of K(ATP) channels, closed K(ATP) channels, elevated intracellular calcium levels, and stimulated insulin release in β-V59M β cells, indicating that events downstream of K(ATP) channel closure remained intact. Expression of the V59M Kir6.2 mutation in pancreatic β cells alone is thus sufficient to recapitulate the neonatal diabetes observed in humans. β-V59M islets also displayed a reduced percentage of β cells, abnormal morphology, lower insulin content, and decreased expression of Kir6.2, SUR1, and insulin mRNA. All these changes are expected to contribute to the diabetes of β-V59M mice. Their cause requires further investigation. American Society for Clinical Investigation 2008-12-08 2009-01-05 /pmc/articles/PMC2613450/ /pubmed/19065048 http://dx.doi.org/10.1172/JCI35772 Text en Copyright © 2009, American Society for Clinical Investigation
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Research Article
spellingShingle Research Article
Girard, Christophe A.
Wunderlich, F. Thomas
Shimomura, Kenju
Collins, Stephan
Kaizik, Stephan
Proks, Peter
Abdulkader, Fernando
Clark, Anne
Ball, Vicky
Zubcevic, Lejla
Bentley, Liz
Clark, Rebecca
Church, Chris
Hugill, Alison
Galvanovskis, Juris
Cox, Roger
Rorsman, Patrik
Brüning, Jens C.
Ashcroft, Frances M.
Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
description Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K(+) (K(ATP)) channel. To better understand this disease, we generated a mouse expressing a Kir6.2 mutation (V59M) that causes neonatal diabetes in humans and we used Cre-lox technology to express the mutation specifically in pancreatic β cells. These β-V59M mice developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Islets isolated from β-V59M mice secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose. This was due to a reduced sensitivity of K(ATP) channels in pancreatic β cells to inhibition by ATP or glucose. In contrast, the sulfonylurea tolbutamide, a specific blocker of K(ATP) channels, closed K(ATP) channels, elevated intracellular calcium levels, and stimulated insulin release in β-V59M β cells, indicating that events downstream of K(ATP) channel closure remained intact. Expression of the V59M Kir6.2 mutation in pancreatic β cells alone is thus sufficient to recapitulate the neonatal diabetes observed in humans. β-V59M islets also displayed a reduced percentage of β cells, abnormal morphology, lower insulin content, and decreased expression of Kir6.2, SUR1, and insulin mRNA. All these changes are expected to contribute to the diabetes of β-V59M mice. Their cause requires further investigation.
author Girard, Christophe A.
Wunderlich, F. Thomas
Shimomura, Kenju
Collins, Stephan
Kaizik, Stephan
Proks, Peter
Abdulkader, Fernando
Clark, Anne
Ball, Vicky
Zubcevic, Lejla
Bentley, Liz
Clark, Rebecca
Church, Chris
Hugill, Alison
Galvanovskis, Juris
Cox, Roger
Rorsman, Patrik
Brüning, Jens C.
Ashcroft, Frances M.
author_facet Girard, Christophe A.
Wunderlich, F. Thomas
Shimomura, Kenju
Collins, Stephan
Kaizik, Stephan
Proks, Peter
Abdulkader, Fernando
Clark, Anne
Ball, Vicky
Zubcevic, Lejla
Bentley, Liz
Clark, Rebecca
Church, Chris
Hugill, Alison
Galvanovskis, Juris
Cox, Roger
Rorsman, Patrik
Brüning, Jens C.
Ashcroft, Frances M.
author_sort Girard, Christophe A.
title Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
title_short Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
title_full Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
title_fullStr Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
title_full_unstemmed Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
title_sort expression of an activating mutation in the gene encoding the k(atp) channel subunit kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes
publisher American Society for Clinical Investigation
publisher_facet American Society for Clinical Investigation
publishDate 2008
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2613450/
https://ncbi.nlm.nih.gov/pubmed/19065048
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1172/JCI35772
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