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Expression of metabolic hormone signalling genes in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes

ABSTRACT: There is a need for greater understanding of the molecular mechanism underlying the development of insulin resistance in type 2 diabetes, and new models in which to study this. The hormone amylin is postulated to be involved in the development of this disease, as human amylin (hA) forms amyloid in the pancreases of diabetic patients, and wild-type hA oligomers have been shown to be cytotoxic to β-cells. By contrast, rodent amylin is non-amyloidogenic, so mice expressing wild-type hA have been developed. However, amylin-evoked β-cell loss in these models limits the secretion of amylin and insulin. We have developed transgenic mice that overexpress [25, 28, 29triprolyl]human amylin, a non-amyloidogenic variant of amylin, designated the Line 44 (L44) model. These mice develop obesity and hyperglycaemia. We examined the expression of 43 genes involved in amylin, insulin and leptin signalling in the brain of this model, at different disease stages, using the NanoString nCounter (NanoString Technologies, Seattle, WA, USA). After onset of diabetes, mice remained hyperglycaemic for a period of time but blood glucose levels eventually returned to normoglycaemia. The incidence of diabetes (defined as having blood glucose measurements > 11 mM over 3 consecutive weeks) was gene-dose dependent; 81% of homozygous mice and 59% of hemizygous mice developed diabetes over 400 days. A proportion of nontransgenic mice (33%) also developed diabetes. As these were bred from hemizygous pairs this may be the result of epigenetic or environmental factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE132940 | GEO | 2019/10/10

REPOSITORIES: GEO

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Project description:Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 weeks of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between ^2 H_2 O incorporation into islet DNA /in vivo/ and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including IGF2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation. Keywords: time course, mouse strain comparison, effect of obesity, Type 2 diabetes is a disorder that involves an increased demand for insulin brought about by insulin resistance, together with a failure to compensate with sufficient insulin production. Although Insulin resistance occurs in most obese individuals, diabetes is generally forestalled through compensation with increased insulin. This increase in insulin occurs through an expansion of beta-cell mass and/or increased insulin secretion by individual beta-cells. Failure to compensate for insulin resistance leads to type 2 diabetes. One way to understand the pathophysiology of diabetes is to examine the coordinate changes in gene expression that occur in insulin-responsive tissues and pancreatic islets in obese animals that either compensate for insulin resistance or progress to type 2 diabetes. In each case, there are groups of genes that undergo changes in expression in a highly correlated fashion. By identifying groups of correlated transcripts (gene expression modules) during the compensation and development of diabetes, we can gain insight into potential pathways and regulatory networks in obesity-induced diabetes. We study two strains of mice that differ in obesity-induced diabetes susceptibility. In this study, we surveyed gene expression in six tissues of lean and obese C57BL/6 (B6) and BTBR mice aged 4 wks and 10 wks. B6 mice remain essentially non-diabetic at all ages, irrespective of obesity. When obese, BTBR mice become severely diabetic by 10 weeks of age. By analyzing the correlation structure of the genes under three contrast conditions, obesity, strain, and age, we identified gene expression modules associated with the onset of diabetes and provide an interactive co-expression network model of type 2 diabetes. We found a key module that is comprised of cell cycle regulatory genes. In the islet, the expression profile of these transcripts accurately predicts diabetes and is highly correlated with islet cell proliferation.

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Expression of metabolic hormone signalling genes in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes

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