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 i s 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 i s 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
Showing the most recent 10 out of 20 publications
