Impact of Obesity on Microvascular Insulin Action and Cardiorespiratory Fitness in Type 1 Diabetes

This study will test the hypothesis that in humans with T1D skeletal muscle microvascular insulin resistance predicts a reduction in Cardiorespiratory Fitness (CRF) and obesity exacerbates microvascular insulin resistance, leading to further CRF decline, which is mechanistically linked to increased muscle microvascular endothelial oxidative stress, impaired muscle mitochondrial function, reduced muscle capillary density and decreased satellite cells.

Inclusion criteria

• • Male or female ≥21 and ≤50 years old

• For persons with T1D: Disease duration ≥ 5 years and HbA1c ≤ 8.5% on multiple daily insulin injection or insulin pump
• Body mass index: ≥19 and ≤27 kg/m2 for control and T1D, ≥30 and ≤40 kg/m2 (27.5 to 37.5 for Asian Americans) for obesity and T1D + obesity. BMI is limited to ≤40 kg/m2 (37.5 for Asian Americans) for easier vascular access and cardiac imaging.
• Stable use of non-insulin medications for over 6 months other than estrogen/progesterone containing medications which must be discontinued at least 3 months prior to the study (intrauterine devices may be continued due to limited systemic absorption)

Exclusion criteria

• • Acute or chronic disease other than T1D or obesity

• History of microvascular or macrovascular diabetes complications
• History of diabetic ketoacidosis in the past 24 months
• History of hypoglycemia unawareness
• Recently active (>20 min of moderate/high intensity exercise, 2 times/week)
• Subjects who are smokers or who have quit smoking <5 years
• Subjects with hypertriglyceridemia (>400 mg/dl)
• Current use of vasoactive medications (i.e. calcium channel blockers, angiotensin-converting enzyme or renin inhibitors, angiotensin-receptor blockers, nitrates, alpha- or beta-blockers, or diuretics).
• Females taking oral contraceptives in the past 3 months
• Subjects with a history of significant metabolic, cardiac, cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, or endocrine disease or malignancy
• Pregnant (as evidenced by positive pregnancy test) or nursing women
• Musculoskeletal condition preventing participation in exercise testing or exercise training
• History of gastroparesis
• Pulse oximetry <90%