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

Abstract

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.

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

“…SUR1 is mainly expressed in the pancreas, and its mutations may lead to neonatal diabetes by disrupting inhibitory binding/gating or enhancing nucleotide stimulation. Some SUR1 mutant models in mice did not recapitulate the human phenotype ( Sachse et al, 2020 ; Usher et al, 2020 ). SUR1-mutant (a homozygous c.560T > A (V187D) mutation in exon four of the ABCC8 gene encoding the SUR1 protein) stem cell-derived islet-like clusters (SC islets) leads to increased beta-cell proliferation and mass, higher insulin secretion in hypoglycemia and makes K ATP channels-acting pharmaceuticals ineffective ( Lithovius et al, 2021 ).…”