Type 2 diabetes susceptibility genes on mouse chromosome 11 under high sucrose environment

Abstract

Background: Both genetic and environmental factors contribute to type 2 diabetes development. We used consomic mice established from an animal type 2 diabetes model to identify susceptibility genes that contribute to type 2 diabetes development under specific environments. We previously established consomic strains (C3H-Chr 11 NSY and C3H-Chr 14 NSY) that possess diabetogenic Chr 11 or 14 of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes, in the genetic background of C3H mice. To search genes contribute to type 2 diabetes under specific environment, we first investigated whether sucrose administration deteriorates type 2 diabetesrelated traits in the consomic strains. We dissected loci on Chr 11 by establishing congenic strains possessing different segments of NSY-derived Chr 11 under sucrose administration. Results: In C3H-Chr 11 NSY mice, sucrose administration for 10 weeks deteriorated hyperglycemia, insulin resistance, and impaired insulin secretion, which is comparable to NSY mice with sucrose. In C3H-Chr 14 NSY mice, sucrose administration induced glucose intolerance, but not insulin resistance and impaired insulin secretion. To dissect the gene(s) existing on Chr 11 for sucrose-induced type 2 diabetes, we constructed four novel congenic strains (R1, R2, R3, and R4) with different segments of NSY-derived Chr 11 in C3H mice. R2 mice showed marked glucose intolerance and impaired insulin secretion comparable to C3H-Chr 11 NSY mice. R3 and R4 mice also showed impaired insulin secretion. R4 mice showed significant decreases in white adipose tissue, which is in the opposite direction from parental C3H-Chr 11 NSY and NSY mice. None of the four congenic strains showed insulin resistance. Conclusions: Genes on mouse Chr 11 could explain glucose intolerance, impaired insulin secretion, insulin resistance in NSY mice under sucrose administration. Congenic mapping with high sucrose environment localized susceptibility genes for type 2 diabetes associated with impaired insulin secretion in the middle segment (26.0-63.4 Mb) of Chr 11. Gene(s) that decrease white adipose tissue were mapped to the distal segment of Chr 11. The identification of diabetogenic gene on Chr 11 in the future study will facilitate precision medicine in type 2 diabetes by controlling specific environments in targeted subjects with susceptible genotypes.

β‐Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes

“…The impaired insulin secretion was accelerated under a high-sucrose environment 75,78 , suggesting the contribution of b-cell vulnerability in the development of diabetes in this model. Susceptibility to high-sucrose induced diabetes is also mapped to chromosome 11 (Figure 6a) and genes for impaired b-cell function under a high-sucrose environment was localized to the central and distal segments of chromosome 11 (Figure 6b) 75 . In this region, a susceptibility locus for type 1 diabetes, Idd4, was mapped by genome scanning and congenic mapping in the NOD mice 71,[79][80][81] , suggesting the presence of a common susceptibility gene for both type 1 and type 2 diabetes in this region.…”

“…Among these, chromosome 11 in mice is of particular interest (Figure 6). In our previous studies on genome scanning and congenic mapping for type 2 diabetes genes in the NSY mouse, susceptibility loci for type 2 diabetes were mapped on chromosome 11 [72][73][74][75] . To directly investigate the contribution of chromosome 11 to genetic susceptibility in type 2 diabetes, chromosome 11 of the control C3H/He mice was substituted with chromosome 11 from the NSY mice (C3H-Chr11 NSY in Figure 6a) 73 .…”

“…Substitution of a single chromosome 11 of C3H mice with chromosome 11 from NSY mice (C3H-Chr11 NSY ) converted the STZ-resistant C3H mice to STZ-susceptible mice, indicating that chromosome 11 harbored susceptibility genes responsible for STZ-induced diabetes 82 . A susceptibility locus mapped to chromosome 11 in spontaneous type 2 diabetes 73 , high-sucrose accelerated diabetes 75 and STZinduced diabetes [82][83][84] is likely to determine the intrinsic vulnerability of the b-cells under external stress, which consequently leads to b-cell failure and diabetes. Altogether, these data Once the b-cell mass is reduced, each b-cell faces increased stress, such as increased insulin demand (overload) and hyperglycemia, leading to the acceleration of b-cell failure because of oxidative stress and endoplasmic reticulum stress.…”

“…Modified from Ikegami et al The support interval of quantitative trait loci for glucose intolerance 72 . #2 Regions of impaired insulin secretion by congenic mapping under a highsucrose environment 75 . #3 The support interval of STZ sensitivity locus in NOD mice was not clearly defined because of a limited number of markers 83 .…”

A novel model mouse for type 2 diabetes mellitus with early onset and persistent hyperglycemia

“…Dietary factors are regarded as an important environmental factor in T2DM in both humans and model mice [3,4,22]. NSY mice fed a high sucrose diet showed increased body weight, liver steatosis, and higher glucose intolerance compared to mice fed a high-fat diet [23,24]. The effect of environmental factors, such as high-sucrose diets, on the severity and outcome of diabetes in yellow NSY mice will provide useful information on gene-environment interactions in diabetes.…”