Effect of Pioglitazone on Mitochondrial Function in Muscle and Adipose Tissue in Humans (PIO)

Mitochondrial dysfunction in skeletal muscle results in decreased muscle fatty acid oxidation, leading to conversion of fatty acids into triglycerides and its accumulation inside the muscle tissue. Moreover, in adipose tissue mitochondrial dysfunction results in decreased fatty acid oxidation and triglyceride synthesis, leading to increased circulating fatty acid concentrations, which in turn also leads to lipid accumulation inside muscle tissue. Lipid accumulation inside muscle tissue interferes with the insulin signaling pathway and causes insulin resistance. Mitochondrial dysfunction in both tissues has therefore been proposed to play an important role in insulin resistance in humans.

Pioglitazone, a thiazolidinedione, is an FDA approved medication for the treatment of type 2 diabetes. It improves muscle insulin sensitivity at least in part by lowering intramuscular lipid concentrations but the mechanism by which this occurs is unclear. In the present study, we shall therefore test the hypothesis that pioglitazone improves mitochondrial function in muscle and adipose tissue in humans who are insulin resistant.

Study Overview

• Status: Completed
• Conditions: Type II Diabetes Mellitus
• Intervention / Treatment: Other: pioglitazone

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States
    • Tempe, Arizona, United States, 85287
      • Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Both men and women, ages 18-65, any ethnicity.

Description

Inclusion Criteria:

1. Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
2. Subjects may be of either sex with age as described in each protocol. Female subjects must be non-lactating and will be eligible only if they have a negative pregnancy test throughout the study period.
3. Subjects must range in age from 18-65.

4. Subjects must have the following laboratory values:

   • 2-hour OGTT plasma glucose 140-250 mg/dl
   • Hematocrit ≥ 35 vol%
   • Serum creatinine ≤ 1.6 mg/dl
   • AST (SGOT) < 2.5 times upper limit of normal
   • ALT (SGPT) < 2.5 times upper limit of normal
   • PT, PTT within the normal range

Exclusion Criteria:

1. Subjects must not be receiving any medications with known effects on glucose tolerance unless the subject has been on stable dose of such agents for the past three months before entry into the study. Subjects taking systemic glucocorticoids will be excluded. Subjects may be taking a stable dose of estrogens or other hormonal replacement therapy, if the subject has been on these agents for the prior three months.
2. History of clinically significant heart disease, including ischemic heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG) and congestive heart failure
3. History of peripheral vascular disease (history of claudication)
4. History of pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation).
5. History of peripheral edema
6. Uncontrolled hypertension with systolic BP>160 mmHg, diastolic BP>100 mmHg
7. Resting heart rate >100 beats/min
8. Autonomic neuropathy
9. Heavy alcohol consumption (> 2 drinks/day)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pioglitazone group	Other: pioglitazone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Distribution of adipocyte mitochondria	3 months

Secondary Outcome Measures

Outcome Measure	Time Frame
number of adipocyte proteins	3 months
number of mitochondrial proteins	3 months

Collaborators and Investigators

• Sponsor: Arizona State University
• Collaborators: Takeda

Publications and helpful links

General Publications

• Xie X, Sinha S, Yi Z, Langlais PR, Madan M, Bowen BP, Willis W, Meyer C. Role of adipocyte mitochondria in inflammation, lipemia and insulin sensitivity in humans: effects of pioglitazone treatment. Int J Obes (Lond). 2017 Aug 14:10.1038/ijo.2017.192. doi: 10.1038/ijo.2017.192. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2008
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: July 16, 2010
• First Submitted That Met QC Criteria: July 16, 2010
• First Posted (Estimated): July 19, 2010

Study Record Updates

• Last Update Posted (Actual): August 13, 2024
• Last Update Submitted That Met QC Criteria: August 9, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 07-012A