Endocrine Abstracts

Alterations in gene expression are a fundamental component of diabetes. These may be occur as a result of specific genetic alterations that underlie diabetes, due to a lack of insulin signaling as a result of insulin deficiency or insulin resistance, or be secondary to the hyperglycemia and altered metabolic state that occurs in diabetes. To help determine which alterations in diabetes are the result of decreased or absent insulin action in tissues or secondary to the metabolic changes associated with diabetes, we have utilized tissues from mice in which insulin signaling has been eliminated by tissue specific knockout, such as the muscle insulin receptor knockout (MIRKO), liver insulin receptor knockout (LIRKO) and fat insulin receptor (FIRKO) mice. By comparing gene expression profiles of these knockout mice and controls in the basal and streptozotocin-induced untreated-diabetic and insulin-treated diabetic states using microarrays, we have distinguished sets of insulin versus diabetes regulated genes in each tissue. For example, genes of mitochondrial electron transport and oxidative phosphorylation are coordinately down-regulated in muscle of diabetic mice, but are unchanged in muscle of MIRKO mice, indicating that these are secondary alterations due to the diabetic state. By separating these direct and indirect effects of the loss of insulin action, we have identified novel transcriptional regulatory mechanisms activated in diabetes, as well as those directly downstream of insulin action.

A second approach to defining the role of altered gene expression in diabetes has employed comparison of mice with genetically-induced insulin resistance, in this case due to double heterozygosity of the insulin receptor and IRS-1 (DH mice), versus mice on a high fat diet. Both of these models develop phenotypes that are highly dependent on the genetic background of the mouse used to create the model. In general, C57Bl/6 (B6) mice become more insulin resistant and diabetic, whereas 129S6 (129) mice only exhibit mild insulin resistance and no diabetes. By combining gene expression analysis with a genome-wide scan of an F2 intercross, we have been able to identify loci that are related to hyperinsulinemia, hyperglycemia, and hyperleptinemia. For example, gene expression analysis of muscle reveals 141 genes were differentially regulated between B6 and 129 IR/IRS-1 heterozygous mice, whereas 785 genes are differentially expressed between wildtype B6 and 129 mice when maintained on a high fat diet.

Taken together, these two studies illustrate how genetic approaches can be used to dissect insulin and diabetes regulated gene expression and define modifier genes for this disease.