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Metformin Improves the Prerequisites for FGF21 Signaling in Patients With Type 2 Diabetes

Anne Kathrine Nissen Pedersen1, Lars Christian Gormsen2, Søren Nielsen3,4

  • 1Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark.

The Journal of Clinical Endocrinology and Metabolism
|September 30, 2023
PubMed
Abstract

Insights

Metformin treatment in type 2 diabetes patients reduced fibroblast activation protein (FAP) activity and enhanced FGF21 signaling in adipose tissue by upregulating FGFR1c and β-klotho. This suggests improved peripheral FGF21 sensitivity with metformin therapy.

Area of Science:

  • Metabolic regulation
  • Endocrinology
  • Pharmacology

Background:

  • Fibroblast growth factor (FGF) 21 is a key metabolic regulator with therapeutic potential.
  • FGF21 signaling relies on FGFR1c and β-klotho receptors.
  • FGF21 resistance in metabolic diseases is linked to fibroblast activation protein (FAP); metformin's clinical effect on FGF21 is unknown.

Purpose of the Study:

  • To determine the impact of 12-week metformin treatment on the FGF21 signaling pathway in type 2 diabetes (T2D) patients.

Main Methods:

  • A randomized, placebo-controlled trial involving 24 T2D patients treated with metformin or placebo.
  • A control group of 12 healthy individuals received metformin.
  • Analysis of plasma FGF21 and FAP levels, and muscle/fat biopsies for gene and protein expression of FGF21 pathway components.

Main Results:

  • Metformin significantly decreased circulating FAP activity compared to placebo.
  • Adipose tissue showed increased gene and protein expression of β-klotho, FGFR1c, and pFGFR1c.
  • FGF21 mRNA increased in muscle; FGF21 protein was detected in adipose tissue.

Conclusions:

  • Metformin suppresses FAP activity and enhances FGF21 signaling in adipose tissue.
  • Upregulation of FGFR1c and β-klotho by metformin may improve peripheral FGF21 sensitivity in T2D.
  • Findings provide clinical insight into metformin's metabolic effects via the FGF21 pathway.
Keywords:
fibroblast activation protein (FAP)fibroblast growth factor 21 (FGF21)metformintype 2 diabetes (T2D)

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