Effect of a 6-Week Carbohydrate-Reduced High-Protein Diet on Levels of FGF21 and GDF15 in People With Type 2 Diabetes

Michael M Richter; Mads N Thomsen; Mads J Skytte; Sasha A S Kjeldsen; Amirsalar Samkani; Jan Frystyk; Faidon Magkos; Jens J Holst; Sten Madsbad; Thure Krarup; Steen B Haugaard; Nicolai J Wewer Albrechtsen

doi:10.1210/jendso/bvae008

Effect of a 6-Week Carbohydrate-Reduced High-Protein Diet on Levels of FGF21 and GDF15 in People With Type 2 Diabetes

J Endocr Soc. 2024 Jan 24;8(4):bvae008. doi: 10.1210/jendso/bvae008. eCollection 2024 Feb 19.

Authors

Michael M Richter^{1

2}, Mads N Thomsen³, Mads J Skytte^{3

4}, Sasha A S Kjeldsen^{1

2}, Amirsalar Samkani³, Jan Frystyk⁵, Faidon Magkos⁶, Jens J Holst^{7

8}, Sten Madsbad⁹, Thure Krarup^{3

6}, Steen B Haugaard^{3

10}, Nicolai J Wewer Albrechtsen^{1

2}

Affiliations

¹ Department of Clinical Biochemistry, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.
² Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
³ Department of Endocrinology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.
⁴ Department of Forensic Medicine, University of Copenhagen, Copenhagen, 2100, Denmark.
⁵ Department of Endocrinology, Odense University Hospital, Odense, 5000, Denmark.
⁶ Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, 2200, Denmark.
⁷ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
⁸ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark.
⁹ Department of Endocrinology, Copenhagen University Hospital-Hvidovre, Hvidovre, 2650, Denmark.
¹⁰ Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.

Abstract

Context: Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are increased in type 2 diabetes and are potential regulators of metabolism. The effect of changes in caloric intake and macronutrient composition on their circulating levels in patients with type 2 diabetes are unknown.

Objective: To explore the effects of a carbohydrate-reduced high-protein diet with and without a clinically significant weight loss on circulating levels of FGF21 and GDF15 in patients with type 2 diabetes.

Methods: We measured circulating FGF21 and GDF15 in patients with type 2 diabetes who completed 2 previously published diet interventions. Study 1 randomized 28 subjects to an isocaloric diet in a 6 + 6-week crossover trial consisting of, in random order, a carbohydrate-reduced high-protein (CRHP) or a conventional diabetes (CD) diet. Study 2 randomized 72 subjects to a 6-week hypocaloric diet aiming at a ∼6% weight loss induced by either a CRHP or a CD diet. Fasting plasma FGF21 and GDF15 were measured before and after the interventions in a subset of samples (n = 24 in study 1, n = 66 in study 2).

Results: Plasma levels of FGF21 were reduced by 54% in the isocaloric study (P < .05) and 18% in the hypocaloric study (P < .05) in CRHP-treated individuals only. Circulating GDF15 levels increased by 18% (P < .05) following weight loss in combination with a CRHP diet but only in those treated with metformin.

Conclusion: The CRHP diet significantly reduced FGF21 in people with type 2 diabetes independent of weight loss, supporting the role of FGF21 as a "nutrient sensor." Combining metformin treatment with carbohydrate restriction and weight loss may provide additional metabolic improvements due to the rise in circulating GDF15.

Keywords: hepatokines; metformin; nutrients; weight loss; weight maintenance.