Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus

Abstract

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]/μIU/μL versus -2.4±3.6 [mg·kg-1·min-1]/μIU/μL, P=0.005; 18.6±4.8 [mg·lean kg-1·min-1]/μIU/μL versus -3.4±5.6 [mg·lean kg-1·min-1]/μIU/μL, 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]/μIU/μL versus -4.5±4.4 [mg·kg-1·min-1]/μIU/μL, P=0.02; 17.6±6.7 [mg·lean kg-1·min-1]/μIU/μL versus -7.0±6.7 [mg·lean kg-1·min-1]/μIU/μL, 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.

Keywords: diabetes mellitus, type 1; insulin resistance; magnetic resonance imaging; metformin; vascular diseases.

Figures

Figure 1A-D:. Phase-Contrast MRI Reveals Abnormal Aortic Function in T1D Youth vs. Controls

Figure 1. Limited to participants who had phase-contrast MRI data at baseline. Phase-contrast derived MRI measures of the ascending and descending aorta are shown, including: (A) Maximal systolic wall shear stress; (B) Time-averaged wall shear stress; (C) Pulse wave velocity; (D) Relative area change (aortic distensibility). All data sets were adjusted for age, sex, and BMI percentile. *p < 0.05; †p < 0.001

Figure 2.. Consort Diagram of Clinical Trial in participants with T1D

*MRI repairs led to smaller sample size for MRI than for other outcomes

Figure 3A and 3B:. Metformin Improves Insulin Sensitivity in Adolescents with Type 1 Diabetes

Figure 3A. Change in M/I (per kg) in response to metformin vs. placebo, in all T1D participants, adjusted for baseline M/I (per kg) and change in M/I (per lean kg) in response to metformin vs. placebo in all T1D participants, adjusted for baseline M/I (per lean kg) Figure 3B. Change in M/I (per kg) and M/I (per lean kg) in response to metformin vs. placebo in n=28 T1D youth with BMI <90th %ile, adjusted for baseline M/I (per kg) or baseline M/I (per lean kg)

Figure 4A, 4B and 4C:. Metformin Improves Weight and Body Composition in T1D Adolescents

Figure 4A Change in weight (kg) in response to metformin vs. placebo, adjusted for baseline weight (kg) Figure 4B Change in BMI (kg/m2) in response to metformin vs. placebo, adjusted for baseline BMI (kg/m2) Figure 4C Change in fat mass (kg) in response to metformin vs. placebo, adjusted for baseline fat mass (kg)

Figure 4A, 4B and 4C:. Metformin Improves Weight and Body Composition in T1D Adolescents

Figure 4A Change in weight (kg) in response to metformin vs. placebo, adjusted for baseline weight (kg) Figure 4B Change in BMI (kg/m2) in response to metformin vs. placebo, adjusted for baseline BMI (kg/m2) Figure 4C Change in fat mass (kg) in response to metformin vs. placebo, adjusted for baseline fat mass (kg)

Figure 5A and 5B:. Metformin Improves Vascular Health in Adolescents with Type 1 Diabetes

Figure 5A Change in AA WSSMAX in response to metformin vs. placebo, adjusted for baseline AA WSSMAX, change in BMI, change in M/I (per lean kg) and change in SBP Figure 5B Change in AA PWV in response to metformin vs. placebo, adjusted for baseline AA PWV, change in BMI, change in M/I (per lean kg) and change in SBP