Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

Jabeur Methnani
* ORCID logo ,
Taieb Ach
,
Aymen El Hraiech
,
Imed Latiri
,
Ali Bouslama
,
Monia Zaouali
,
Asma omezzine
,
Ezdine Bouhlel
Version 1 : Received: 14 December 2022 / Approved: 15 December 2022 / Online: 15 December 2022 (08:37:28 CET)

How to cite: Methnani, J.; Ach, T.; El Hraiech, A.; Latiri, I.; Bouslama, A.; Zaouali, M.; omezzine, A.; Bouhlel, E. Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?. Preprints 2022, 2022120276. https://doi.org/10.20944/preprints202212.0276.v1 Methnani, J.; Ach, T.; El Hraiech, A.; Latiri, I.; Bouslama, A.; Zaouali, M.; omezzine, A.; Bouhlel, E. Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?. Preprints 2022, 2022120276. https://doi.org/10.20944/preprints202212.0276.v1

Abstract

Metformin, the treatment of first choice in type 2 diabetes (T2D), is known to mainly act by decreasing endogenous glucose production (EGP) in the liver. Paradoxically, in the last decade several reports documented increased EGP after metformin treatment. This increase, was often attributed to pronounced rises in glucagon, consistent with counter-regulatory response to the glucose lowering effect of metformin. However, considering that hyperglucagonemia, but not hypoinsulinemia, is a main driver of EGP in T2D, increased EGP should have been a common finding. This observation, together with the finding that metformin antagonizes glucagon effects on energy expenditure and protein synthesis, concurrently to its effects on EGP and the emerging evidences demonstrating increased branched chain and gluconeogenic amino acids in response to metformin treatment may points to a liver alpha-cell skeletal muscle cross talk similar to that observed in the liver-alpha cell axis. Here, we provide a mechanistic perspective to this latter possibility, based on mechanistic studies of metformin’s transcriptional targets; retaining thus its glucagon antagonistic and presumably anti-gluconeogenic effects on liver and attributing the increase in EGP to renal gluconeogenesis. We finally discuss how increased EGP might reflect an adverse response to metformin treatment, providing support from clinical and epidemiological data.

Keywords

Biguanides; Antihyperglycemic agents; Liver alpha-cell axis; gluconeogenesis; Protein metabolism; insulin sensitivity

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.