LAUSR

Background: Cardiovascular disease is the leading cause of mortality in type 1 diabetes mellitus (T1DM) and relates strongly to insulin resistance (IR). Lean and obese adolescents with T1DM have marked IR. Metformin improves surrogate markers of IR in T1DM, but its effect on directly measured IR and vascular health in youth with T1DM is unclear. We hypothesized that adolescents with T1DM have impaired vascular function and that metformin improves this IR and vascular dysfunction. Methods: Adolescents with T1DM and control participants underwent magnetic resonance imaging of the ascending (AA) and descending aorta to assess pulse wave velocity, relative area change, and maximal (WSSMAX) and time-averaged (WSSTA) wall shear stress. Participants with T1DM also underwent assessment of carotid intima-media thickness by ultrasound, brachial distensibility by DynaPulse, fat and lean mass by dual-energy x-ray absorptiometry, fasting laboratories after overnight glycemic control, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate/insulin). Adolescents with T1DM were randomized 1:1 to 3 months of 2000 mg metformin or placebo daily, after which baseline measures were repeated. Results: Forty-eight adolescents with T1DM who were 12 to 21 years of age (40% body mass index [BMI] ≥90th percentile; 56% female) and 24 nondiabetic control participants of similar age, BMI, and sex distribution were enrolled. Adolescents with T1DM demonstrated impaired aortic health compared with control participants, including elevated AA and descending aorta pulse wave velocity, reduced AA and descending aorta relative area change, and elevated AA and descending aorta WSSMAX and WSSTA. Adolescents with T1DM in the metformin versus placebo group had improved glucose infusion rate/insulin (12.2±3.2 [mg·kg−1·min−1]/&mgr;IU/&mgr;L versus −2.4±3.6 [mg·kg−1·min−1]/&mgr;IU/&mgr;L, P=0.005; 18.6±4.8 [mg·lean kg−1·min−1]/&mgr;IU/&mgr;L versus −3.4±5.6 [mg·lean kg−1·min−1]/&mgr;IU/&mgr;L, P=0.005) and reduced weight (−0.5±0.5 kg versus 1.6±0.5 kg; P=0.004), BMI (−0.2±0.15 kg/m2 versus 0.4±0.15 kg/m2; P=0.005), and fat mass (−0.7±0.3 kg versus 0.6±0.4 kg; P=0.01). Glucose infusion rate/insulin also improved in normal-weight participants (11.8±4.4 [mg·kg−1·min−1]/&mgr;IU/&mgr;L versus −4.5±4.4 [mg·kg−1·min−1]/&mgr;IU/&mgr;L, P=0.02; 17.6±6.7 [mg·lean kg−1·min−1]/&mgr;IU/&mgr;L versus −7.0±6.7 [mg·lean kg−1·min−1]/&mgr;IU/&mgr;L, P=0.02). The metformin group had reduced AA WSSMAX (−0.3±0.4 dyne/cm2 versus 1.5±0.5 dyne/cm2; P=0.03), AA pulse wave velocity (−1.1±1.20 m/s versus 4.1±1.6 m/s; P=0.04), and far-wall diastolic carotid intima-media thickness (−0.04±0.01 mm versus −0.00±0.01 mm; P=0.049) versus placebo. Conclusions: Adolescents with T1DM demonstrate IR and impaired vascular health compared with control participants. Metformin improves IR, regardless of baseline BMI, and BMI, weight, fat mass, insulin dose, and aortic and carotid health in adolescents with T1DM. Metformin may hold promise as a cardioprotective intervention in T1DM. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01808690.