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

Katrina B. Dietsche, Sheela N. Magge, Sydney A. Dixon, Faith S. Davis, Andrea Krenek, Aruba Chowdhury, Lilian Mabundo, Michael Stagliano, Amber B. Courville, Shanna Yang, Sara Turner, Hongyi Cai, Kannan Kasturi, Arthur S. Sherman, Joon Ha, Eileen Shouppe, Mary Walter, Peter J. Walter, Kong Y. Chen, Robert J. BrychtaCody Peer, Yi Zeng, William Figg, Fran Cogen, D. Elizabeth Estrada, Shaji Chacko, Stephanie T. Chung

Research output: Contribution to journalArticlepeer-review


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 ± 2.1 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. 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 β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

Original languageEnglish
Pages (from-to)1361-1370
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Issue number5
StatePublished - 19 Apr 2024
Externally publishedYes


  • GLP-1 receptor agonist
  • gluconeogenesis
  • glucose production
  • metformin
  • minority health
  • pediatric
  • type 2 diabetes


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