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

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.

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