Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice

Abstract

Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with b-cell dysfunction. A genomewide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a w211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucosemediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving b-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to b-cell dysfunction in T2D.

Two Novel Candidate Genes for Insulin Secretion Identified by Comparative Genomics of Multiple Backcross Mouse Populations

“…strains showed higher expression of Ffar2 and Ffar3, indicating that both genes are unlikely candidates for the phenotype contributed by the C3H allele. Moreover, a mutation of Abcc8 located close to the Nbg7p locus that results in strongly reduced expression of the gene has been reported previously to impair insulin secretion in the related NZO/ Wehi strain (Andrikopoulos et al 2016). Abcc8 was not differentially expressed between our strains, suggesting that this gene is rather an unlikely candidate for the Nbg7p QTL.…”

Discovering human diabetes-risk gene function with genetics and physiological assays

“…1b , Supplementary Fig. 1a ), reminiscent of increased insulin output after genetic or pharmacological inactivation of these factors in pancreatic islets 14 – 16 . Thus, in 9/9 cases, targeted gene inactivation in IPCs led to changes of insulin output similar to that observed after analogous loss-of-function studies in pancreatic islets, providing striking evidence that genetic approaches in Drosophila could be useful for predicting the function of genes in human beta cells.…”

Dapagliflozin improves insulin resistance and glucose intolerance in a novel transgenic rat model of chronic glucose overproduction and glucose toxicity

“…Real‐time PCR was conducted in a ViiA 7 real‐time PCR thermocycler system and analysed using ABI ViiA 7 version 1.2 software. The relative mRNA transcript levels of Acc1 (Rn00573474_m1), Acc2 (Rn00588290_m1), Cpt1a (Rn00580702_m1), G6pc (Rn00689876_m1), Pck1 (Rn01529014_m1), Glut2 (Rn00563565_m1), Gck (Rn00561265_m1), Sur1 (Rn01476317_m1) and Kir6.2 (Rn01764077_s1) were measured using pre‐developed rat TaqMan Gene Expression Assays (Applied Biosystems, Scoresby, Victoria, Australia) as previously described, normalized to the mRNA transcript level of 18S and reported as fold change. The comparative Ct (ΔΔCt) method was used for relative quantification.…”

“…Gck (Rn00561265_m1), Sur1 (Rn01476317_m1) and Kir6.2 (Rn01764077_s1) were measured using pre-developed rat TaqMan Gene Expression Assays (Applied Biosystems, Scoresby, Victoria, Australia) as previously described, 23 normalized to the mRNA transcript level of 18S and reported as fold change. The comparative Ct (ΔΔCt) method was used for relative quantification.…”