Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes

Objective Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and beta-cell function after therapy in AA Y-T2D.Methods In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 +/- 2.1 years (mean +/- SD), 68% female, body mass index (BMI) 40.1 +/- 7.9 kg/m2, duration of diagnosis 1.8 +/- 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. beta-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test.Results At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 +/- 1.3 vs -0.6 +/- 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 +/- 0.68 vs -0.05 +/- 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 +/- 9.4 vs Met: 0.04 +/- 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI.Conclusion Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance beta-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.