Study of Dapagliflozin on Mitochondrial Dysfunction and Impaired Insulin Signaling/Action
| Status: | Completed |
|---|---|
| Conditions: | Neurology, Endocrine |
| Therapuetic Areas: | Endocrinology, Neurology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 7/12/2018 |
| Start Date: | March 2011 |
| End Date: | June 30, 2018 |
Regulation of Hepatic and Peripheral Glucose Metabolism: Protocol IVA. Effect of Plasma Glucose Reduction by Selective SLGT2 Inhibition on Mitochondrial Dysfunction and Impaired Insulin Signaling/Sensitivity in T2DM
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].
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.
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
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