Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

This proposal will investigate the underlying mechanisms of enhanced insulin sensitivity and improvement of muscle loss and performance in insulin resistant people by resistance exercise training. Based on the investigator's preliminary data, they hypothesize that the key regulators of health benefits of resistance training are two genes: PGC-1a4 and PPARB;, and that the increased expression of these genes following resistance training facilitates storage of glucose in muscle and enhances its utilization for the energy need of muscle for contraction as well as enhancing muscle mass and performance. The investigators will also determine whether resistance training can reduce the higher oxidative stress in insulin resistant humans and improve their muscle protein quality.

Identification of the molecular regulatory points of exercise benefits is of high national priority because of the opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in the older population associated with sarcopenia. The investigators propose a novel metabolic regulatory role of PGC-1α4 (α4), a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, the investigators hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as well as increasing muscle mass and performance. Based on their novel preliminary data, they will also investigate whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data indicates that RE reduces protein degradation which will be investigated in the current proposal. The investigators will determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein degradation and enhancing synthesis and ameliorating oxidative stress. They will study 48 IR people 50-75 yrs before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with lean IS people. They will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase, glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. They will also measure markers of oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent muscle protein degradation, which they hypothesize is reduced by increased anti-oxidant effect of Rβ with RE training. They also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by enhancing contractile protein synthesis. These studies will render the necessary mechanistic explanation on how RE enhances IS, glycolysis, reduces oxidative stress and promote muscle performance and mass in IR people, thus substantially contributing to health and life span.

Eligibility Criteria:
Inclusion criteria

* age 50-75yrs
* BMI 30-38kg/m2
* hip to waist ratio of \>0.85 in women and 1.0 in men
* fasting glucose ≥100-140mg/dl

Lean Group

* age 50-75 years
* hip to waist ratio of \<0.76 in women and 0.90 in men
* fasting glucose of \<100mg/dl.

Exclusion criteria for the study are as follows:

* Coronary artery disease or heart failure.
* Participation in a structured exercise program \>2 days per week
* A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:

  * Inpatient psychiatric treatment in the past 6 months
  * Presence of a known adrenal disorder
  * Abnormal liver function test results (Transaminase \>2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
  * Abnormal renal function test results (calculated GFR \<60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty
  * Active gastroparesis
  * If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study
  * Uncontrolled thyroid disease (TSH undetectable or \>10 mlU/L); testing required within three months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise
  * Abuse of alcohol or recreational drugs
  * Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis).
  * Uncontrolled arterial hypertension (Resting diastolic blood pressure \>90 mmHg and/or systolic blood pressure \>160 mmHg) at the time of screening.
  * Oral steroids
  * A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol
  * Restrictions on Use of Other Drugs or Treatments:
  * Medications that may impact study end points such as mitochondrial biology eg. beta blockers
  * Anti-hyperglycemic drugs including metformin
  * Any other medication that the investigator believes is a contraindication to the subject's participation.