Markers of normoglycemic remission in obese diabetics

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DESCRIPTION (provided by applicant): Obesity in African-Americans (AA) presents a unique model to help identify the markers and mechanisms of associated metabolic disorders. Over half of newly diagnosed AA presenting with severe hyperglycemia and/or unprovoked diabetic ketoacidosis (DKA) display metabolic and immunogenetic features of type 2 diabetes. This variant of type 2 diabetes is referred to as atypical diabetes, Flatbush diabetes, and more recently as ketosis-prone diabetes (KPDM). We have shown that patients with KPDM have markedly decreased insulin secretion and impaired insulin sensitivity, but aggressive management can result in improvement in (-cell function and insulin sensitivity to allow discontinuation of insulin therapy. We also showed that distinctive markers of remission in skeletal muscle are improved expression and insulin-stimulated phosphorylation of Akt2 Ser474 and other key signal transduction kinases and phosphatases. We hypothesize that the correlation between measures of beta-cell function, muscle insulin-stimulated signal transduction and protein expression will identify specific markers indicative of short- and long-term near-normoglycemic remission and/or risk for continued hyperglycemia. The first aim is to identify clinical, metabolic, and immunogenetic markers predictive of short- and long-term near-normoglycemic remission or lack thereof in obese AA with KPDM. Beta-cell function and insulin sensitivity will be measured at initial presentation and again at either near-normoglycemic remission or 12 weeks of insulin therapy. The second aim is to measure insulin-stimulated protein phosphorylation and signal transduction protein expression in the muscle biopsies obtained at presentation and at follow-up. Response to treatment (near-normoglycemic remission or lack thereof) will be correlated with measurements of beta-cell function, insulin sensitivity, muscle insulin-stimulated signaling and protein expression. Because of their unique clinical characteristics, patients with KPDM represent an ideal population in which to identify markers indicative of short- and long-term remission and/or risk for continued hyperglycemia. Identifying such markers will facilitate and guide future therapeutic interventions and may identify patients at risk to develop chronic complications of diabetes