Phenotype of a transient neonatal diabetes point mutation (SUR1-R1183W) in mice

Wellcome Open Research

article

Gregor Sachse¹  Elizabeth Haythorne¹  Peter Proks¹  Michelle Stewart³  Heather Cater³  Sian Ellard⁴  Ben Davies⁵  Frances M. Ashcroft¹ 

[1] Department of Physiology, Anatomy and Genetics, University of Oxford;Department of Physics, University of Oxford;Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Campus;University of Exeter Medical School, Institute of Biomedical and Clinical Science;Wellcome Trust Centre for Human Genetics, University of Oxford

关键词: KATP channel;    diabetes;    transient neonatal diabetes;    high fat diet;    mouse model;   

DOI  :  10.12688/wellcomeopenres.15529.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: The KATP channel plays a key role in glucose homeostasis by coupling metabolically generated changes in ATP to insulin secretion from pancreatic beta-cells.  Gain-of-function mutations in either the pore-forming (Kir6.2) or regulatory (SUR1) subunit of this channel are a common cause of transient neonatal diabetes mellitus (TNDM), in which diabetes presents shortly after birth but remits within the first few years of life, only to return in later life. The reasons behind this time dependence are unclear.Methods: In an attempt to understand the mechanism behind diabetes remission and relapse, we generated mice expressing the common TNDM mutation SUR1-R1183W. We employed Cre/LoxP technology for both inducible and constitutive expression of SUR1-R1183W specifically in mouse beta-cells, followed by investigation of their phenotype using glucose tolerance tests and insulin secretion from isolated islets. Results: We found that the R1183W mutation impaired inhibition of KATP channels by ATP when heterologously expressed in human embryonic kidney cells. However, neither induced nor constitutive expression of SUR1-R1183W in mice resulted in changes in blood glucose homeostasis, compared to littermate controls. When challenged with a high fat diet, female mice expressing SUR1-R1183W showed increased weight gain, elevated blood glucose and impaired glycaemic control, but glucose-stimulated insulin secretion from pancreatic islets appeared unchanged.Conclusions: The mouse model of TNDM did not recapitulate the human phenotype. We discuss multiple potential reasons why this might be the case. Based on our findings, we recommend future TNDM mouse models employing a gain-of-function SUR1 mutation should be created using the minimally invasive CRISPR/Cas technology, which avoids many potential pitfalls associated with the Cre/LoxP system.

【 授权许可】

CC BY