Study of Dapagliflozin on Mitochondrial Dysfunction and Impaired Insulin Signaling/Action
Study of Dapagliflozin on Mitochondrial Dysfunction and Impaired Insulin Signaling/Action
The purpose of this study is to examine the effect of the chronic treatment of type 2
 diabetes (T2DM) with dapagliflozin on: (1) mitochondrial gene function/expression and insulin
 signaling/action and (2) oral glucose tolerance and beta cell function. Dapagliflozin is a
 potent, highly specific inhibitor of renal glucose transport [SGLT2].
"Glucotoxicity" has been implicated as a cause of insulin resistance and impaired beta cell
 function in T2DM. Abundant support for the glucotoxicity hypothesis has been provided by in
 vivo and in vitro studies in animals, but a rigorous test of this hypothesis in man is
 lacking. The investigators propose to test the glucotoxicity hypothesis by chronically
 reducing the plasma glucose in type 2 diabetic subjects (T2DM) with an inhibitor of renal
 glucose transport, dapaglifozin, and examining the effect of restoration of normoglycemia on
 mitochondrial function and insulin signaling/sensitivity. Lastly, the investigators will test
 the "glucolipotoxicity" hypothesis, which states that the toxic effects of elevated plasma
 FFA on insulin sensitive tissues (i.e., muscle) are magnified in the presence of concurrent
 hyperglycemia. Thus, high glucose levels increase malonyl CoA, which inhibits CPT I, leading
 to accumulation of FACoA/DAG, which impair mitochondrial function and inhibit insulin action.
Inclusion Criteria:

 -  T2DM

 -  Drug Naive Or On Oral Therapy

 Exclusion Criteria:

 -  Insulin Treatment

 -  Major Organ Disease