Abstract
Type 2 diabetes (T2D) is characterized by impaired beta cell function and insulin
resistance. T2D susceptibility genes identified by Genome-wide association studies
(GWAS) are likely to have roles in both impaired insulin secretion from the beta cell
as well as insulin resistance. The aim of this study was to use gene expression profiling
to assess the effect of the diabetic milieu on the expression of genes involved in
both insulin secretion and insulin resistance.
We measured the expression of 43 T2D susceptibility genes in the islets, adipose and
liver of leptin-deficient Ob/Ob mice compared with Ob/+ littermates. The same panel of genes were also profiled in cultured rodent adipocytes,
hepatocytes and beta cells in response to high glucose conditions, to distinguish
expression effects due to elevated glycemia from those on the causal pathway to diabetes
or induced by other factors in the diabetic microenviroment.
We found widespread deregulation of these genes in tissues from Ob/Ob mice, with differential regulation of 23 genes in adipose, 18 genes in liver and
one gene (Tcf7l2) in islets of diabetic animals (Ob/Ob) compared to control (Ob/+) animals. However, these expression changes were in most cases not noted in glucose-treated
adipocyte, hepatocyte or beta cell lines, indicating that they may not be an effect
of hyperglycemia alone.
This study indicates that expression changes are apparent with diabetes in both the
insulin producing beta cells, but also in peripheral tissues involved in insulin resistance.
This suggests that incidence or progression of diabetic phenotypes in a mouse model
of diabetes is driven by both secretory and peripheral defects.
Key words
Ob/Ob - gene expression - diabetes
