"TAKE TIME" Pioglitazone Reverses Defects in Mitochondrial Biogenesis in Patients With T2DM

NCT ID: NCT00402012

Last Updated: 2015-12-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-11-30
• Study Completion Date: 2007-12-31

Brief Summary

This study is designed to look at the effect of Pioglitazone treatment on the body's ability to burn food in order to produce energy.

Detailed Description

Skeletal muscle mitochondrial defects are a sine qua non of insulin resistance in patients with T2DM. Pioglitazone decreases free fatty acid levels and restores mitochondria number in adipose tissue whereas high fat diet and lipid infusion decreases genes involved in mitochondrial biogenesis. Increased lipid flux from diet or adipose tissue into skeletal muscle might be the cause of decreased mitochondrial biogenesis. The purpose of this study is to determine if 22 weeks treatment with Pioglitazone can increase mitochondrial biogenesis in muscle in 30 uncomplicated T2DM patients that were previously not taking TZD's. This Phase IV, randomized, double-blind, placebo controlled, clinical trial will consist of 3 phases: a screening, a placebo / Pioglitazone phase (12 weeks) and a weight loss period (6-10 weeks). The primary endpoint is to identify the changes in skeletal muscle mitochondria number and gene expression. Secondary endpoints include MRS measured mitochondrial capacity, insulin sensitivity for glucose disposal and insulin suppression of free fatty acids, electron transport chain activity, mitochondrial content and intra hepatic and intra myocellular lipid. Metformin and Sulfonylurea will be used as standardized oral therapy to maintain HbA1C < 7.0. After completing the protocol, patients will be offered a very low calorie liquid diet (800kcal/d) to assist them in losing weight. During this period they will continue on their previously randomized treatment. When patients lose 10% of their body weight, patients will be switched to a weight maintenance diet (meal replacement with 1 can of glucerna at breakfast and lunch with a "healthy" dinner) for 10 days. MRS measured mitochondrial capacity will again be determined to see if weight loss + pioglitazone has more effect on mitochondrial function than pioglitazone alone.

Conditions

Diabetes Mellitus, Type 2

Keywords

Diabetes Mellitus, Type 2

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

1

Group Type: NO_INTERVENTION

No interventions assigned to this group

2

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

During the double-blind, 12 weeks treatment period, subjects will self-administer study medication (pioglitazone or equivalent volume of placebo) 30 mg/day each morning. The dose of pioglitazone will be increased to 45 mg/day after 4 weeks if the fasting plasma glucose is higher than 100mg/dl or the HbA1C is higher than 7%. This dose has proven tolerability, safety and efficacy for type 2 diabetes and has previously been used at the Pennington Center in studies on pioglitazone.

Interventions

Pioglitazone

During the double-blind, 12 weeks treatment period, subjects will self-administer study medication (pioglitazone or equivalent volume of placebo) 30 mg/day each morning. The dose of pioglitazone will be increased to 45 mg/day after 4 weeks if the fasting plasma glucose is higher than 100mg/dl or the HbA1C is higher than 7%. This dose has proven tolerability, safety and efficacy for type 2 diabetes and has previously been used at the Pennington Center in studies on pioglitazone.

Intervention Type: DRUG

Other Intervention Names

TZD

Eligibility Criteria

Inclusion Criteria

• Men and women aged 18-70 with Type 2 diabetes as defined by:

• Fasting plasma glucose > 126 mg/dL at entry
• Or a two-hour OGTT glucose > 200mg/dL
• Or current treatment with one or two oral anti-diabetic drugs, except TZD
• Or currently using insulin
• Fasting plasma glucose < 200mg/dL at entry
• BMI >27.0 and <45.0kg/m2
• Adequate contraception for women (including, but not limited to: oral contraception, hysterectomy, tubal ligation, or post-menopausal as defined by > 6 months without a menstrual cycle and FSH > 40 mIU/ml).

Exclusion Criteria

• Significant renal, cardiac, liver, lung, or neurological disease (controlled hypertension is acceptable if baseline bp < 140/90 on medications).
• Prior use of other thiazolidinediones (rosiglitazone [AVANDIATM], pioglitazone [ACTOSTM])
• Use of drugs known to affect energy metabolism or body weight: including, but not limited to: orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc.
• Pregnancy
• Alcohol or other drug abuse
• Unwilling or unable to abstain from caffeine (48h) and tobacco (24h) prior to metabolic rate measurements
• Increased liver function tests at baseline (AST/ALT/GGT/or alkaline phosphatase greater than 2.5 times the upper limit of normal)
• Metal objects that would interfere with the measurement of body composition /MRS such as implanted rods, surgical clips, etc.
• HbA1C of > 10%.
• NYHA class III/IV CHF is an exclusionary cardiac condition.
• history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
• varicose veins
• major surgery on the abdomen, pelvis, or lower extremities within previous 3 months
• cancer (active malignancy with or without concurrent chemotherapy)
• rheumatoid disease
• bypass graft in limb
• known genetic factor (Factor V Leiden, etc) or hypercoagulable state
• diagnosed peripheral arterial or vascular disease, or intermittent claudication
• family history of primary DVT or PE (pulmonary embolism)
• peripheral neuropathy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda Pharmaceuticals North America, Inc.

INDUSTRY

Sponsor Role: collaborator

Pennington Biomedical Research Center

OTHER

Sponsor Role: lead

Responsible Party

Frank Greenway

Clinical Medical Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven R Smith, M.D.

Role: PRINCIPAL_INVESTIGATOR

Pennington Biomedical Research Center

Locations

Pennington Biomedical Research Center

Baton Rouge, Louisiana, United States

Countries

United States

References

Bajpeyi S, Myrland CK, Covington JD, Obanda D, Cefalu WT, Smith SR, Rustan AC, Ravussin E. Lipid in skeletal muscle myotubes is associated to the donors' insulin sensitivity and physical activity phenotypes. Obesity (Silver Spring). 2014 Feb;22(2):426-34. doi: 10.1002/oby.20556. Epub 2013 Sep 10.

Reference Type: DERIVED

PMID: 23818429 (View on PubMed)

Bajpeyi S, Pasarica M, Moro C, Conley K, Jubrias S, Sereda O, Burk DH, Zhang Z, Gupta A, Kjems L, Smith SR. Skeletal muscle mitochondrial capacity and insulin resistance in type 2 diabetes. J Clin Endocrinol Metab. 2011 Apr;96(4):1160-8. doi: 10.1210/jc.2010-1621. Epub 2011 Feb 9.

Reference Type: DERIVED

PMID: 21307136 (View on PubMed)

Costford SR, Bajpeyi S, Pasarica M, Albarado DC, Thomas SC, Xie H, Church TS, Jubrias SA, Conley KE, Smith SR. Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab. 2010 Jan;298(1):E117-26. doi: 10.1152/ajpendo.00318.2009. Epub 2009 Nov 3.

Reference Type: DERIVED

PMID: 19887595 (View on PubMed)

Other Identifiers

PBRC 26027

Identifier Type: -

Identifier Source: org_study_id