Elevated circulating levels of certain amino acids (the building blocks of protein) are strongly associated with insulin resistance. This study will investigate the metabolism of these amino acids in individuals with normal glucose metabolism compared to overweight or obese pre-diabetic individuals. The purpose of this study is to determine how elevated levels of the branched-chain amino acids may contribute to the development of insulin resistance and ultimately diabetes. An additional purpose is to determine whether exercise or gastric bypass (GBP) surgery intervention can correct aberrations in branched-chain amino acid metabolism as insulin sensitivity improves. This information will be used to further our understanding of the development of insulin resistance and type 2 diabetes in at-risk populations and potentially improve clinical treatment of such conditions.

Inclusion Criteria:

• Age:

  • Lean and Overweight Pre-diabetic (PD) groups: 40-65 years
  • Obese Gastric Bypass (GBP) patients: 30-65 years

• Body Mass Index (BMI) within desired range for group:

  • Lean group: 18.0 - 24.9
  • Overweight PD group: 25.0 - 35.4
  • GBP group: 35.0 - 50.0

• Fasting Plasma Glucose level within desired range for group:

  • Lean: < 99 mg/dL
  • PD: > 105 - < 126 mg/dL
  • GBP: > 99

• Oral Glucose Tolerance Test, 2-hour Plasma Glucose results within desired range:

  • Lean: < 139 mg/dL
  • PD: 140-199 mg/dL

• Low density (LDL) cholesterol: < 190 mg/dL

• Triglycerides: < 600 mg/dL

• Resting blood pressure: <160/90 mmHg

• Inactive: Exercise < two days/week (GBP and PD only);

• Peak oxygen use: > 14.0 - < 40.0 ml/kg/min (PD only)

• Medications: Stable use of all medications for > three months

• Body Weight < 495 lbs

Exclusion Criteria:

• Smoker: Tobacco use within the last 12 months
• Dieting or intending to diet (excluding intention for gastric bypass procedure in GBP group)- Not weight stable for > six months or weight loss exceeding five pounds in last six months
• Use of potential confounding medications, e.g. Niacin containing drugs
• History of diabetes, heart disease or taking medication for those conditions
• History of hypertension (high blood pressure) not controlled with medication
• Pregnant or intending to become pregnant
• Unwillingness to participate in study visits, submit to skeletal muscle biopsies and all other study testing or continuously participate in the exercise training intervention program for six months if in overweight PD group
• Orthopedic limitations, musculoskeletal disease and/or injury
• Allergic to xylocaine
• Inability to give blood continuously through an intravenous catheter
• Unwillingness to exercise at least three times per week at the Duke Center for Living during staff supervised times (PD only)
• Exercise compliance less than 85% in any 6 week period (missing > 3 exercise sessions in a 6 week period)