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

Authors

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 Brychta
Cody Peer
Yi Zeng
William Figg
Fran Cogen
D Elizabeth Estrada
Shaji Chacko
Stephanie T Chung

Language

English

Publication Date

4-19-2024

Journal

The Journal of Clinical Endocrinology & Metabolism

DOI

10.1210/clinem/dgad669

PMID

37967247

PMCID

PMC11031226

PubMedCentral® Posted Date

11-15-2023

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Female, Adolescent, Humans, Male, Metformin, Liraglutide, Diabetes Mellitus, Type 2, Hypoglycemic Agents, Gluconeogenesis, Blood Glucose, Glucose, gluconeogenesis, glucose production, GLP-1 receptor agonist, pediatric, type 2 diabetes, metformin, minority health

Published Open-Access

yes

Recommended Citation

Dietsche, Katrina B; Magge, Sheela N; Dixon, Sydney A; et al., "Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes" (2024). Children’s Nutrition Research Center Staff Publications. 248.
https://digitalcommons.library.tmc.edu/staff_pub/248