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 β-cell function after therapy in AA Y-T2D.

METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D: age 15.3±2.1y (mean±SD), 68% female, BMI 40.1±7.9kg/m2, duration of diagnosis 1.8±1.3y were randomized to metformin alone (Met) or metformin+liraglutide (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. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2h-OGTT.

RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2h glucose were comparable in both groups, though Met+Lira had higher HbA1c. Met+Lira had a greater decrease from baseline in fasting glucose (-2.0±1.3 vs. -0.6±0.9 mmol/L, P=0.008) and a greater increase in sigma (0.72±0.68 vs. -0.05±0.71, P=0.03). The change in fractional gluconeogenesis was similar between groups (Met+Lira: -0.36±9.4 vs. Met: 0.04±12.3%, P=0.9) and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r=0.63, P=0.003) but not gluconeogenesis or mSI.

CONCLUSIONS: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.