Patients with Insulin Dependent Diabetes Mellitus (IDDM) are currently treated with insulin therapy, which is comprised of two daily insulin injections, before breakfast and supper. Unfortunately, IDDM patients undergoing insulin therapy still suffer from hyperglycemia during the long periods between meals, which leads to development of diabetic complications. Hepatic glucose production is normally suppressed by insulin, and excessive hepatic gluconeogenesis secondary to insulin insufficiency exacerbates the degree of hyperglycemia in IDDM patients. Forkhead (FKHR) is a transcription factor that enhances the expression of gluconeogenic genes in the liver, and its activity is inhibited by insulin. This transcription factor is comprised of a DNA binding """"""""winged-helix"""""""" domain and a """"""""transactivation"""""""" domain. The winged-helix domain alone has been shown to act as a dominant negative regulator of FKHR in gluconeogenic gene expression in hepatocytes. To test the hypothesis that hepatic expression of the dominant negative FKHR mutant can inhibit glucose production in the liver and reduce the severity of hyperglycemia in IDDM, and expression cassette comprised of the FKHR-mutant driven by the G6Pase promoter/enhancer will be delivered to the hepatocytes of diabetic animals, alone or with insulin therapy. The G6Pase promoter is induced by glucose and inhibited by insulin in the liver. With this auto-regulated expression system, the dominant negative FKHR mutant will be expressed in response to an elevation in ambient glucose levels and block glucose production in the liver under diabetic conditions. Conversely, in response to falling blood glucose, rising intracellular concentrations of the FKHR-mutant itself and/or blood insulin levels after insulin therapy, its expression will be suppressed and its inhibitory effects on hepatic gluconeogenesis will be alleviated. It is hypothesized that hepatic expression of the FKHR-mutant under diabetic conditions will enable insulin therapy to be more effective in glycemic control without an increased risk of hypoglycemia. This hypothesis will be rigorously tested in diabetic NOD mice using a gutless adenovirus-mediated gene delivery system that is known to be relatively non-toxic and persistent in immune-competent animals. The research proposed in this project can potentially lead to development of an effective and safe adjuvant treatment to complement insulin therapy and significantly improve glycemic control in patients with IDDM.
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| Altomonte, Jennifer; Harbaran, Sonal; Richter, Anja et al. (2003) Fat depot-specific expression of adiponectin is impaired in Zucker fatty rats. Metabolism 52:958-63 |
| Dong, H; Anthony, K; Morral, N (2002) Challenges for gene therapy of type 1 diabetes. Curr Gene Ther 2:403-14 |
