Study of Dapagliflozin on Mitochondrial Dysfunction and Impaired Insulin Signaling/Action

The University of Texas Health Science Center at San Antonio18 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Insulin Sensitivity Multiple Mitochondrial Dysfunctions Syndrome

Interventions

DapagliflozinDRUG

Treatment arm, 10 mg per day for 2 weeks

PlaceboDRUG

Patients are treated with placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: * T2DM * Drug Naive Or On Oral Therapy Exclusion Criteria: * Insulin Treatment * Major Organ Disease

Locations (1)

Diabetes Division, UTHSCSA

San Antonio, Texas, United States

Outcomes

Primary Outcomes

Change in Insulin Sensitivity

The change in insulin sensitivity and total glucose disposal measured at two weeks with the insulin clamp compared to baseline. This is measured using TGD (whole body tissue glucose disposal)/SSPI (steady state plasma insulin concentration) ratio

Time frame: baseline, two weeks

Secondary Outcomes

Change in Mitochondrial Function

The change in mitochondrial function/gene expression at two weeks compared to baseline. This was measured by energy expenditure.

Time frame: baseline, two weeks

Data from ClinicalTrials.gov

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