{Reference Type}: Randomized Controlled Trial
{Title}: Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes.
{Author}: Dietsche KB;Magge SN;Dixon SA;Davis FS;Krenek A;Chowdhury A;Mabundo L;Stagliano M;Courville AB;Yang S;Turner S;Cai H;Kasturi K;Sherman AS;Ha J;Shouppe E;Walter M;Walter PJ;Chen KY;Brychta RJ;Peer C;Zeng Y;Figg W;Cogen F;Estrada DE;Chacko S;Chung ST;
{Journal}: J Clin Endocrinol Metab
{Volume}: 109
{Issue}: 5
{Year}: 2024 Apr 19
{Factor}: 6.134
{DOI}: 10.1210/clinem/dgad669
{Abstract}: <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.