Metformin Improves Insulin Resistance (IR) and Vascular Health in Youth with Type 1 Diabetes (T1D)

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Cardiovascular disease is the leading cause of mortality in T1D and relates to IR. We demonstrated that lean and obese T1D youth have IR and that metformin improves surrogate markers of IR in obese T1D youth. Yet, little is known about vascular health in T1D youth or about the effect of metformin on directly-measured IR or vascular health. In The Effects of MEtformin on cardiovasculaR function in AdoLescents with type 1 Diabetes (EMERALD) study, we hypothesized that T1D youth have impaired vascular function and that metformin decreases IR and improves vascular health. 49 T1D youth ages 12-21 years (40% with BMI ≥ 90%ile; 44% male) and 24 controls of similar age, BMI and sex underwent phase contrast MRI of the ascending (AA) and descending aorta (DA) to determine aortic pulse wave velocity (PWV) and wall shear stress (WSS). T1D youth also had carotid intima-media thickness (cIMT) by ultrasound, DXA scan, fasting labs following overnight IV glycemic control, and a hyperinsulinemic-euglycemic clamp (80 mU/m2/min insulin) to assess IR (glucose infusion rate [mg/kg/min)]/insulin or M/I). T1D youth were then randomized 1:1 to 2g of metformin or placebo daily, and all measures repeated at 3 months. At baseline, T1D youth vs. controls had elevated aortic PWV (AA: 3.7±0.2 vs. 2.5±0.4 m/s, p<0.05; DA: 4.2±0.2 vs. 3.1±0.3 m/s, p=0.02) and WSS (AA: 1.1±0.04 vs. 0.9±0.N/m2, p=0.003; DA: 1.6±0.vs. 1.1±0.07 N/m2, p<0.0001). Compared to the placebo group, T1D youth in the metformin group had no baseline differences but had improvement at 3 months in M/I (12.2±3.2 vs. -2.4±3.6 uIU/uL, p<0.01), AA PWV (-1.1±1.1 vs. 4.1±1.6 m/s, p<0.04), AA WSS (-0.03±0.04 vs. 0.2±0.N/m2, p<0.03) and far wall diastolic cIMT (-0.04±0.01 vs. 0.00±0.01 mm, p=0.04) in baseline-adjusted models. T1D youth have IR and vascular dysfunction compared to controls of similar age, sex and BMI. Metformin mitigated IR and improved aortic and carotid health in T1D youth, and thus may hold promise as a cardiovascular protective intervention. Disclosure K.J. Nadeau: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. M. Sch fer: None. L. Browne: None. A. Baumgartner: None. Y. Garcia Reyes: None. A. Maniatis: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; MannKind Corporation, Dexcom, Inc., Xeris Pharmaceuticals, Inc., Bigfoot Biomedical. S. Nayak: None. L. Pyle: None. M. Cree-Green: None. J.E. Reusch: Research Support; Self; Merck & Co., Inc.. Board Member; Self; American Diabetes Association. Research Support; Self; AstraZeneca. Other Relationship; Self; Sanofi-Aventis.