Glycemia and gluconeogenesis with metformin and liraglutide: A randomized trial in youth-onset type 2 diabetes

Authors: DIETSCHE, KATRINA - National Institutes Of Health (NIH); MAGGE, SHEELA - Johns Hopkins University School Of Medicine; DIXON, SYDNEY - National Institutes Of Health (NIH); DAVIS, FAITH - National Institutes Of Health (NIH); KRENEK, ANDREA - National Institutes Of Health (NIH); CHOWDHURY, ARUBA - National Institutes Of Health (NIH); MABUNDO, LILIAN - National Institutes Of Health (NIH); STAGLIANO, MICHAEL - National Institutes Of Health (NIH); COURVILLE, AMBER - National Institutes Of Health (NIH); YANG, SHANNA - National Institutes Of Health (NIH); TURNER, SARA - National Institutes Of Health (NIH); CAI, HONGYI - National Institutes Of Health (NIH); KASTURI, KANNAN - Essentia Health; SHERMAN, ARTHUR - National Institutes Of Health (NIH); HA, JOON - Howard University; SHOUPPE, EILEEN - National Institutes Of Health (NIH); WALTER, MARY - National Institutes Of Health (NIH); WALTER, PETER - National Institutes Of Health (NIH); CHEN, KONG - National Institutes Of Health (NIH); BRYCHTA, ROBERT - National Institutes Of Health (NIH); PEER, CODY - National Institutes Of Health (NIH); ZENG, YI - National Institutes Of Health (NIH); FIGG, WILLIAM - National Institutes Of Health (NIH); COGEN, FRAN - Children'S National Medical Center; ESTRADA, D ELIZABETH - Children'S National Medical Center; CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); CHUNG, STEPHANIE - National Institutes Of Health (NIH)

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2023
Publication Date: 11/15/2023
Citation: Dietsche, K.B., Magge, S.N., Dixon, S.A., Davis, F.S., Krenek, A., Chowdhury, A., Mabundo, L., Stagliano, M., Courville, A.B., Yang, S., Turner, S., Cai, H., Kasturi, K., Sherman, A.S., Ha, J., Shouppe, E., Walter, M., Walter, P.J., Chen, K.Y., Brychta, R.J., Peer, C., Zeng, Y., Figg, W., Cogen, F., Estrada, D., Chacko, S., Chung, S.T. 2023. Glycemia and gluconeogenesis with metformin and liraglutide: A randomized trial in youth-onset type 2 diabetes. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgad669.
DOI: https://doi.org/10.1210/clinem/dgad669

Interpretive Summary: Youth-onset type 2 diabetes is a rapidly progressive disease characterized by increased glucose production from the liver, rapid failure of pancreatic cells (B-cell) that produces insulin, and severe insulin resistance. Insulin resistance is a condition when cells in muscles, fat, and liver do not respond efficiently to insulin and are unable to easily take up glucose from circulation. This chronic disease burden is magnified among African American youth who have the highest disease prevalence and burden of metabolic complications. Since increased rates of glucose production from the liver is an important primary pathophysiological factor in youth-onset T2D, the objective of the study was to investigate the effectiveness of combination of metformin with a glucagon like peptide-1 receptor agonists (liraglutide), in reducing glucose production from the liver and improving B-cell function. We showed that Youth-onset type 2 diabetes is associated with dysregulated and high rates of glucose production from the liver and were not suppressed by metformin alone or in combination with liraglutide. Increased glucose clearance was related to improvements in B-cell function. Early combination therapies that will abrogate multiple pathways that contribute to high rates of glucose production and improve B-cell function in Youth-onset type 2 diabetes are needed.

Technical Abstract: 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 B-cell function after therapy in AA Y-T2D. 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. B-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. 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. Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance B-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.