Sitagliptin reduces FAP-activity and increases intact FGF21 levels in patients with newly detected glucose abnormalities

Anne K N Pedersen; Camilla Hage; Niels Jessen; Linda Mellbin; Mette Bjerre

doi:10.1016/j.mce.2022.111738

Sitagliptin reduces FAP-activity and increases intact FGF21 levels in patients with newly detected glucose abnormalities

Mol Cell Endocrinol. 2022 Oct 1:556:111738. doi: 10.1016/j.mce.2022.111738. Epub 2022 Aug 1.

Authors

Anne K N Pedersen¹, Camilla Hage², Niels Jessen³, Linda Mellbin⁴, Mette Bjerre⁵

Affiliations

¹ Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: aknp@clin.au.dk.
² Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
³ Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark; Department of Biomedicine, Health, Aarhus University, Denmark; Department of Clinical Pharmacology, Aarhus University Hospital, Denmark.
⁴ Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
⁵ Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

PMID: 35926756
DOI: 10.1016/j.mce.2022.111738

Abstract

Introduction: Fibroblast growth factor 21 (FGF21), a hormone with pleiotropic metabolic effects, is inactivated by fibroblast activation protein (FAP), a member of the dipeptidyl peptidase-IV (DPP-IV) family. We investigate if sitagliptin (DPP-IV inhibitor) inhibits FAP-activity and increases intact FGF21.

Methods: Patients with impaired glucose metabolism were randomized to 100 mg sitagliptin (n = 34) or placebo (n = 37) treatment for 12 weeks. Plasma samples obtained at study entry and at 12-weeks were analysed for FAP-activity, FAP, total FGF21 and intact FGF21.

Results: Sitagliptin significantly inhibited FAP-activity (497 ± 553 vs. 48 ± 712 RFU/min, p < 0.01) and correspondingly increased intact FGF21 (253 ± 182 vs 141 ± 80 ng/L, p < 0.01) compared to placebo in plasma. Sitagliptin dose-dependently inhibited the FAP-activity in vitro. Intact FGF21 was higher in patients obtaining a normal glucose tolerance regardless of treatment (p = 0.03).

Conclusion: A sitagliptin-induced increase of intact FGF21 may contribute to an improved metabolic effect in patients with impaired glucose metabolism.

Keywords: DPP-IV inhibitor; Fibroblast activation protein (FAP); Fibroblast growth factor 21 (FGF21); Sitagliptin.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
Fibroblast Growth Factors / metabolism
Glucose
Humans
Sitagliptin Phosphate* / pharmacology
Sitagliptin Phosphate* / therapeutic use

Substances

Dipeptidyl-Peptidase IV Inhibitors
fibroblast growth factor 21
Fibroblast Growth Factors
Glucose
Sitagliptin Phosphate