Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex

It is well established that functional exercise capacity and peak oxygen uptake (VO2) are reduced in patients with type 2 diabetes mellitus (T2DM) compared with healthy counterparts. The mechanisms underlying the exercise deficit in T2DM remain largely unknown, but previous work has suggested that reduced exercise blood flow and impaired submaximal VO2 may be contributing factors. Both of these findings are consistent with a peripheral impairment of skeletal muscle oxygen delivery, oxygen utilization, or both. Indeed, dysfunction of skeletal muscle metabolism plays a key role in the pathophysiology of T2DM, and considerable work has described abnormalities of oxidative function in the skeletal muscle of people with T2DM. Given this, it is likely that the causes of exercise intolerance in T2DM may relate to specific defects at the level of the skeletal muscle, particularly given that skeletal muscle blood flow and oxidative capacity are impaired in diabetes. However, to the knowledge of the investigators, no one has related these peripheral muscle abnormalities to the diminished exercise function in this patient group.

The overarching hypothesis for the proposed research is that impaired CVEC in T2DM is the result of preclinical cardiac, vascular dysfunction and skeletal muscle perfusion abnormalities. Exercise training will improve CVEC and will reveal specific reversible therapeutic aspects of this pathology. The investigators will first determine the impairments and then evaluate responses to an established cardiac rehabilitation exercise training program, established to improve fitness in people with and without diabetes. Given the greater CVEC abnormalities observed in women, sex differences will be evaluated for each aim.

Inclusion criteria

• Men and women with and without type 2 diabetes
• BMI 25-40
• Sedentary subjects not participating in a regular exercise program (<one bout of exercise/week)

Exclusion criteria

• Documented cardiovascular disease
• Uncontrolled hypertension: disease systolic blood pressure (SBP) > 150, diastolic blood pressure (DBP)> 110
• Obstructive pulmonary disease or asthma
• Peripheral neuropathy
• Physical impairment that would limit exercise ability
• Subjects taking beta blockers, calcium channel blockers, insulin, or Thiazolidinediones (TZD)
• Current or past smoking within the last 1 years
• Current tobacco use
• Anemia
• Control HbA1c > 5.7, T2DM HbA1c > 9
• Pregnant, nursing or hormonal therapy (other than contraceptives)
• Peri or post-menopausal women
• Type 1 diabetes
• Hepatic or renal disease.
• Peptic ulcer disease.