• Change in skeletal muscle mitochondrial number (electron microscopy + qPCR of mtDNA) and mitochondrial gene expression in T2DM patients treated with pioglitazone (vs. placebo) [ Time Frame: baseline and after intervention ] [ Designated as safety issue: No ]
  

• insulin sensitivity for insulin suppression of free fatty acid and glucose disposal [ Time Frame: baseline and after intervention ] [ Designated as safety issue: No ]
  
• electron transport chain activity; mitochondrial content by MRS (ATP max) [ Time Frame: baseline and after intervention ] [ Designated as safety issue: No ]
  
• intra hepatic and intra myocellular lipid by MRS; mitochondrial content by MRS (ATP max) post weight loss period [ Time Frame: baseline ,after treatment and after weight loss ] [ Designated as safety issue: No ]
  

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