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FGF21 contributes to metabolic improvements elicited by combination therapy with exenatide and pioglitazone in patients with type 2 diabetes

Samms, Ricardo J.; Cheng, Christine C.; Fourcaudot, Marcel; Heikkinen, Sami; Khattab, Ahmed; Adams, John; Cersosimo, Eugenio; Triplitt, Curtis; Puckett, Curtis; Tsintzas, Kostas; Adams, Andrew. C.; Abdul-Ghani, Muhammad A.; DeFronzo, Ralph A.; Norton, Luke

Authors

Ricardo J. Samms

Christine C. Cheng

Marcel Fourcaudot

Sami Heikkinen

Ahmed Khattab

John Adams

Eugenio Cersosimo

Curtis Triplitt

Curtis Puckett

Andrew. C. Adams

Muhammad A. Abdul-Ghani

Ralph A. DeFronzo

Luke Norton



Abstract

Fibroblast growth factor 21 (FGF21) is increased acutely by carbohydrate ingestion and is elevated in patients with type 2 diabetes (T2D). However, the physiological significance of increased FGF21 in humans remains largely unknown. We examined whether FGF21 contributed to the metabolic improvements observed following treatment of patients with T2D with either triple (metformin/pioglitazone/exenatide) or conventional (metformin/insulin/glipizide) therapy for 3 yr. Forty-six patients with T2D were randomized to receive either triple or conventional therapy to maintain HbA1c < 6.5%. A 2-h 75-g oral glucose tolerance test (OGTT) was performed at baseline and following 3 years of treatment to assess glucose tolerance, insulin sensitivity, and ?-cell function. Plasma total and bioactive FGF21 levels were quantitated before and during the OGTT at both visits. Patients in both treatment arms experienced significant improvements in glucose control, but insulin sensitivity and ?-cell function were markedly increased after triple therapy. At baseline, FGF21 levels were regulated acutely during the OGTT in both groups. After treatment, fasting total and bioactive FGF21 levels were significantly reduced in patients receiving triple therapy, but there was a relative increase in the proportion of bioactive FGF21 compared with that observed in conventionally treated subjects. Relative to baseline studies, triple therapy treatment also significantly modified FGF21 levels in response to a glucose load. These changes in circulating FGF21 were correlated with markers of improved glucose control and insulin sensitivity. Alterations in the plasma FGF21 profile may contribute to the beneficial metabolic effects of pioglitazone and exenatide in human patients with T2D.NEW & NOTEWORTHY In patients with T2D treated with a combination of metformin/pioglitazone/exenatide (triple therapy), we observed reduced total and bioactive plasma FGF21 levels and a relative increase in the proportion of circulating bioactive FGF21 compared with that in patients treated with metformin and sequential addition of glipizide and basal insulin glargine (conventional therapy). These data suggest that FGF21 may contribute, at least in part, to the glycemic benefits observed following combination therapy in patients with T2D.

Citation

Samms, R. J., Cheng, C. C., Fourcaudot, M., Heikkinen, S., Khattab, A., Adams, J., …Norton, L. (2022). FGF21 contributes to metabolic improvements elicited by combination therapy with exenatide and pioglitazone in patients with type 2 diabetes. AJP - Endocrinology and Metabolism, 323(2), E123-E132. https://doi.org/10.1152/ajpendo.00050.2022

Journal Article Type Article
Acceptance Date Jun 12, 2022
Online Publication Date Jul 14, 2022
Publication Date Aug 1, 2022
Deposit Date Jul 27, 2022
Publicly Available Date Jul 15, 2023
Journal American journal of physiology. Endocrinology and metabolism
Print ISSN 0193-1849
Electronic ISSN 1522-1555
Publisher American Physiological Society
Peer Reviewed Peer Reviewed
Volume 323
Issue 2
Pages E123-E132
DOI https://doi.org/10.1152/ajpendo.00050.2022
Keywords Physiology (medical); Physiology; Endocrinology, Diabetes and Metabolism
Public URL https://nottingham-repository.worktribe.com/output/8955760
Publisher URL https://journals.physiology.org/doi/abs/10.1152/ajpendo.00050.2022