Dynamics of Muscle Mitochondria in Type 2 Diabetes (DYNAMMO T2D) (DYNAMMO-T2D)

Dynamics of Muscle Mitochondria in Type 2 Diabetes (DYNAMMO-T2D)

Insulin promotes the clearance of sugars from the blood into skeletal muscle and fat cells for use as energy; it also promotes storage of excess nutrients as fat. Type 2 diabetes occurs when the cells of the body become resistant to the effects of insulin, and this causes high blood sugar and contributes to a build-up of fat in muscle, pancreas, liver, and the heart. Understanding how insulin resistance occurs will pave the way for new therapies aimed at preventing and treating type 2 diabetes.

Mitochondria are cellular structures that are responsible for turning nutrients from food, into the energy that our cells run on. As a result, mitochondria are known as "the powerhouse of the cell." Mitochondria are dynamic organelles that can move within a cell to the areas where they are needed, and can fuse together to form large, string-like, tubular networks or divide into small spherical structures. The name of this process is "mitochondrial dynamics" and the process keeps the cells healthy. However, when more food is consumed compared to the amount of energy burned, mitochondria may become overloaded and dysfunctional resulting in a leak of partially metabolized nutrients that can interfere with the ability of insulin to communicate within the cell. This may be a way for the cells to prevent further uptake of nutrients until the current supply has been exhausted. However, long term overload of the mitochondria may cause blood sugar levels to rise and lead to the development of type 2 diabetes.

This study will provide information about the relationship between mitochondrial dynamics, insulin resistance and type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance
• Intervention / Treatment: Drug: Intralipid; Drug: Saline

Detailed Description

The traditional view of mitochondria as isolated, spherical, energy producing organelles is undergoing a revolutionary transformation. Emerging data show that mitochondria form a dynamic networked reticulum that is regulated by cycles of fission and fusion. The discovery of a number of proteins that regulate these activities has led to important advances in understanding human disease. Data show that activation of dynamin related protein 1 (Drp1), a protein that controls mitochondrial fission, is reduced following exercise in prediabetes, and the decrease is linked to increased insulin sensitivity and fat oxidation. The proposed research will test the hypothesis that mitochondrial dynamics is a key mechanism of insulin resistance in type 2 diabetes. Translational first-in-man studies will use an acute lipid challenge to investigate the physiological significance of altered skeletal muscle mitochondrial dynamics on insulin sensitivity in humans. The experimental approach harnesses innovative molecular and cellular tools, interfaced with physiologically significant human studies to obtain meaningful data on insulin resistance, and has the potential to generate insights that will lead to new diabetes therapies for future generations.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Pennington Biomedical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy
• Sedentary
• Normal glucose tolerance
• BMI <25 kg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intralipid Infusion, then Saline; Participants in this arm will first receive a lipid infusion. Then 4 weeks later the saline infusion.	Drug: Intralipid; 0.55 ml/kg/h; Other Names: Liposyn; Drug: Saline; 0.55 ml/kg/h for
Sham Comparator: Saline Infusion, then Intralipid; Participants in this arm will first receive a saline infusion. Then 4 weeks later the lipid infusion.	Drug: Intralipid; 0.55 ml/kg/h; Other Names: Liposyn; Drug: Saline; 0.55 ml/kg/h for

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of lipid infusion on mitochondrial fission	Fission will be assessed from quantitative measures of dynamin-related protein-1. The unit of assessment is arbitrary units of blot intensity and is expressed as AU.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of lipid infusion on mitochondrial function	Function will be assessed from oxygen consumption. Unit of assessment is pmol/s/mg of muscle.	5 years
Insulin sensitivity	Insulin sensitivity will be assessed by euglycemic hyperinsulinemic clamp. Units of assessment are mg/kg/min.	5 years

Collaborators and Investigators

• Sponsor: Pennington Biomedical Research Center
• Investigators: Principal Investigator: John P Kirwan, Ph.D., Pennington Biomedical Research Center

Publications and helpful links

General Publications

• Axelrod CL, Fealy CE, Erickson ML, Davuluri G, Fujioka H, Dantas WS, Huang E, Pergola K, Mey JT, King WT, Mulya A, Hsia D, Burguera B, Tandler B, Hoppel CL, Kirwan JP. Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans. Metabolism. 2021 Aug;121:154803. doi: 10.1016/j.metabol.2021.154803. Epub 2021 Jun 4.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Actual): May 1, 2021
• Study Completion (Actual): May 1, 2021

Study Registration Dates

• First Submitted: February 18, 2016
• First Submitted That Met QC Criteria: February 26, 2016
• First Posted (Estimate): March 3, 2016

Study Record Updates

• Last Update Posted (Actual): July 27, 2021
• Last Update Submitted That Met QC Criteria: July 23, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Insulin Resistance; Mitochondrial Dynamics
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: 15-1311

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No