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

Insulin Sensitivity Clinical Trial

— DAPA MITO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01439854
• Other study ID #: 5 R01 DK024092-27/NIH Prot IV
• Secondary ID: R01DK024092
• Status: Completed
• Phase: N/A
• Start date: March 2011
• Est. completion date: June 30, 2018

Study information

• Verified date: July 2018
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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].

Description:

"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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: June 30, 2018
• Est. primary completion date: June 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• T2DM

• Drug Naive Or On Oral Therapy

Exclusion Criteria:

• Insulin Treatment

• Major Organ Disease

Related Conditions & MeSH terms

• Hypersensitivity
• Insulin Resistance
• Insulin Sensitivity
• Multiple Mitochondrial Dysfunctions Syndrome

Intervention

Drug:
• Dapagliflozin
Treatment arm, 10 mg per day for 2 weeks
• Placebo
Patients are treated with placebo

Locations

Country	Name	City	State
United States	Diabetes Division, UTHSCSA	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	baseline, two weeks
Secondary	Change in Mitochondrial Function	The change in mitochondrial function/gene expression at two weeks compared to baseline. This was measured by energy expenditure.	baseline, two weeks

External Links

•   ADA Diabetes Care 2016 Nov; 39(11): 2036-2041