Study of Dapagliflozin on Mitochondrial Dysfunction and Impaired Insulin Signaling/Action (DAPA MITO)

• ClinicalTrials.gov Identifier: NCT01439854
• Recruitment Status: Completed
• First Posted: September 23, 2011
• Results First Posted: October 29, 2019
• Last Update Posted: October 29, 2019
• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): The University of Texas Health Science Center at San Antonio

Study Description

Brief 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].

Condition or disease	Intervention/treatment	Phase
Insulin Sensitivity; Multiple Mitochondrial Dysfunctions Syndrome	Drug: Dapagliflozin; Drug: Placebo	Not Applicable

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• 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
• Study Start Date: March 2011
• Actual Primary Completion Date: June 30, 2018
• Actual Study Completion Date: June 30, 2018

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; this arm is control	Drug: Placebo; Patients are treated with placebo
Experimental: Dapagliflozin; Interventional arm	Drug: Dapagliflozin; Treatment arm, 10 mg per day for 2 weeks

Outcome Measures

Primary Outcome Measures :

1. Change in Insulin Sensitivity [ Time Frame: baseline, two weeks ]
   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

Secondary Outcome Measures :

1. Change in Mitochondrial Function [ Time Frame: baseline, two weeks ]
   The change in mitochondrial function/gene expression at two weeks compared to baseline. This was measured by energy expenditure.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• T2DM
• Drug Naive Or On Oral Therapy

Exclusion Criteria:

• Insulin Treatment
• Major Organ Disease

Contacts and Locations

Locations

United States, Texas

Diabetes Division, UTHSCSA

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Ralph DeFronzo, MD; The University of Texas Health Science Center at San Antonio
• Principal Investigator: Devjit Tripathy, MD; The University of Texas Health Science Center at San Antonio

  Study Documents (Full-Text)

Documents provided by The University of Texas Health Science Center at San Antonio:

Study Protocol and Statistical Analysis Plan  [PDF] August 10, 2016

More Information

Additional Information:

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

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT01439854
• Other Study ID Numbers: 5 R01 DK024092-27/NIH Prot IV; R01DK024092 ( U.S. NIH Grant/Contract )
• First Posted: September 23, 2011
• Results First Posted: October 29, 2019
• Last Update Posted: October 29, 2019
• Last Verified: July 2018

Keywords provided by The University of Texas Health Science Center at San Antonio:

Insulin sensitivity; Mitochondrial function; Glucose toxicity; Glucosuria

Additional relevant MeSH terms:

Insulin Resistance; Hypersensitivity; Immune System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs