Clinical studies indicate that there is great variability in the ability of thiazolidinediones, a class of insulin-sensitizing agents, to improve glycemic control in patients with type 2 diabetes. The receptor for thiazolidinediones is peroxisome proliferator activated receptor-gamma (PPARgama), a nuclear receptor that plays an important role in adipogenesis and insulin signaling. We recently identified a common genetic variant in the PPARgamma gene (Pro12Ala PPARgamma2). In vitro studies indicate that this single amino acid substitution has functional consequences. Furthermore, Pro12Ala PPARgamma2 is associated with increased body mass index (BMI) in two Caucasian populations, increased insulin sensitivity in African Americans and Pima Indians, and more rapid weight regain after weight loss in postmenopausal Caucasian women. We hypothesize that inter-individual variability in therapeutic efficacy to thiazolidinediones is due, at least in part, to genetic factors. Specifically, we hypothesize that diabetic subjects who carry the Pro12Ala PPARgamma2 variant will be more insulin sensitive and therefore less responsive to the insulin-sensitizing and glucose lowering effects of rosiglitazone therapy as compared to subjects without the variant. To test this hypothesis, we will perform a prospective rosiglitazone intervention in subjects with type 2 diabetes who either carry or lack the Pro12Ala PPARgamma2 variant. We will compare between the two groups responsivity to rosiglitazone therapy as measured by changes in glycemic control (hemoglobin A1c, fasting blood glucose), lipoprotein profile, insulin sensitivity (euglycemic hyperinsulinemic clamp), and fat metabolism (lipolysis by microdialysis and fat oxidation by indirect calorimetry. Furthermore, to detect novel genes and pathways that predict rosiglitazone responsivity and/or influence insulin sensitivity, we will compare between rosiglitazone responders and nonresponders mRNA expression patterns of several thousand genes in muscle and adipose tissue biopsies using cDNA microarray technology. These studies will define the clinical significance of the Pro12Ala PPARgamma2 variant, and the role of PPARgamma in adipocyte metabolism and insulin signaling in humans more generally. Testing for the Pro12Ala PPARgamma2 may differentiate between patients who will be responsive or unresponsive to thiazolidinedione therapy, which would allow physicians to more rationally prescribe medications based on underlying genetic mechanisms.
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| Snitker, Soren; Watanabe, Richard M; Ani, Ifeanyi et al. (2004) Changes in insulin sensitivity in response to troglitazone do not differ between subjects with and without the common, functional Pro12Ala peroxisome proliferator-activated receptor-gamma2 gene variant: results from the Troglitazone in Prevention of Diabe Diabetes Care 27:1365-8 |
