Study on Establishment of Congenic Strains and Screening of Characteristics in IRS-2 Deficient Mice to Support Translational Research on Type 2 Diabetes

Abstract

Abstract:In research into type 2 diabetes, diet-based approaches, i.e., nutritional intake, are important approaches for therapeutic research. We would like to make the following two proposals from the standpoint of laboratory animal science for reproducible animal studies using type 2 diabetes mouse models. These include congenic strains of diabetes mouse models and improvement of diets used in daily care and management. In this research, the Irs2homo-knockout mouse with both impaired glucose tolerance and insulin resistance, and thus type 2 diabetes, was established as a congenic strain. The effect of the genetic background on the onset of diabetes was examined. Next, we discussed which diets are appropriate for general care and management of mouse models in which the pathophysiology is controlled by nutritional conditions. Therefore, we prepared diets by converting the current Japanese and US diets to mice and adjusting the diet contents accordingly. We compared the insulin signals such as those of the liver, pancreas and white fat. We were thus able to establish an evaluation system closer to diabetes in the current population. Using this data as an example, we should consider the quality and ordinary diet of animals as important factors in animal experiments.

Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model

“…Male IRS2 -deficient mice ( IRS2 −/− ) are used as a type 2 diabetes model because they exhibit defects in hepatic insulin signalling, resulting in impaired suppression of glucose production ( Withers et al, 1998 ; Kubota et al, 2000 ; Previs et al, 2000 ), and β-cell failure due to disruption of the IGF-I receptor (IGF-IR) mitogenic signalling ( Withers et al, 1999 ) and increased β-cell apoptosis ( Lingohr et al, 2003 ). Furthermore, IRS2-deficient mice recapitulate the fulminate onset of human diabetes because a significant proportion of these mice develop diabetes abruptly at 12-16 weeks of age ( Hashimoto, 2011 ; Garcia-Barrado et al, 2011 ). Also, IRS2-deficient mice show central leptin resistance resulting in alterations in the control of neuropeptides in the arcuate nucleus ( Masaki et al, 2012 ).…”

“…Also, IRS2-deficient mice show central leptin resistance resulting in alterations in the control of neuropeptides in the arcuate nucleus ( Masaki et al, 2012 ). Interestingly, the magnitude of glucose deregulation in IRS2-deficient mice can be variable, with certain congenic strains only presenting prediabetic changes ( Hashimoto, 2011 ). This phenotypic divergence might allow an experimental tool to analyze pathogenic factors involved in central insulin signalling pathways leading to two different outcomes: prediabetes or overt diabetes ( Cai, 2012 ).…”

Vinyl Isolator Breeding Induces Insulin Resistance in C57BL/6JJcl Mice

“…Typical changes in lifestyle include increases in high fat diets, sedentary habits, and driving. The level of fat in modern Japanese diets in particular increased from 20.0 g/day in 1953 to -Original-59.9 g/day in 1995 according to a nationwide nutrition monitoring survey in Japan [13].…”

Expression of pancreatic and duodenal homeobox1 (PDX1) protein in the interior and exterior regions of the intestine, revealed by development and analysis ofPdx1knockout mice

“…The key characteristic of type 2 diabetes in the Japanese and Asians generally is insufficient insulin secretion from β-cells. We previously established insulin receptor substrate-2 ( Irs2 ) knockout mice with a C57BL/6JJcl genetic background with hyperinsulinemia [ 7 8 9 ] similar to the report by Terauchi et al [ 10 ]. However, the type 2 diabetes indicated by these Irs2 knockout mice was different from that of human, especially Japanese [ 11 ], because the atrophy of the Langearhans' islands and β-cells was not induced by insulin-oversecretions in mice [ 9 12 ].…”

“…By the way, Pdx1 gene expression is essential for the maintenance of β-cells and is related to the hyperplasia in Langerhans' islands [ 22 23 ]. We also established Irs2 -knockout mice with a C57BL/6J genetic background [ 7 8 ] and expected that Irs2 -knockout mice with an introduced Pdx1 deficient allele would show suppressed hyperplasia in Langerhans' islands, and so resemble the human diabetic process.…”