Markers of Glucagon Resistance Improve With Reductions in Hepatic Steatosis and Body Weight in Type 2 Diabetes

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

doi:10.1210/jendso/bvad122

Markers of Glucagon Resistance Improve With Reductions in Hepatic Steatosis and Body Weight in Type 2 Diabetes

J Endocr Soc. 2023 Sep 21;7(11):bvad122. doi: 10.1210/jendso/bvad122. eCollection 2023 Oct 9.

Authors

Sasha A S Kjeldsen^{1

2}, Mads N Thomsen³, Mads J Skytte³, Amirsalar Samkani³, Michael M Richter^{1

2}, Jan Frystyk⁴, Faidon Magkos⁵, Elizaveta Hansen⁶, Henrik S Thomsen⁶, Jens J Holst^{7

8}, Sten Madsbad⁹, Steen B Haugaard^{3

10}, Thure Krarup^{3

5}, 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 Endocrinology, Odense University Hospital, Odense, 5000, Denmark.
⁵ Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, 1958, Denmark.
⁶ Department of Radiology, Copenhagen University Hospital-Herlev, Herlev, 2730, 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: Hyperglucagonemia may develop in type 2 diabetes due to obesity-prone hepatic steatosis (glucagon resistance). Markers of glucagon resistance (including the glucagon-alanine index) improve following diet-induced weight loss, but the partial contribution of lowering hepatic steatosis vs body weight is unknown.

Objective: This work aimed to investigate the dependency of body weight loss following a reduction in hepatic steatosis on markers of glucagon resistance in type 2 diabetes.

Methods: A post hoc analysis was conducted from 2 previously published randomized controlled trials. We investigated the effect of weight maintenance (study 1: isocaloric feeding) or weight loss (study 2: hypocaloric feeding), both of which induced reductions in hepatic steatosis, on markers of glucagon sensitivity, including the glucagon-alanine index measured using a validated enzyme-linked immunosorbent assay and metabolomics in 94 individuals (n = 28 in study 1; n = 66 in study 2). Individuals with overweight or obesity with type 2 diabetes were randomly assigned to a 6-week conventional diabetes (CD) or carbohydrate-reduced high-protein (CRHP) diet within both isocaloric and hypocaloric feeding-interventions.

Results: By design, weight loss was greater after hypocaloric compared to isocaloric feeding, but both diets caused similar reductions in hepatic steatosis, allowing us to investigate the effect of reducing hepatic steatosis with or without a clinically relevant weight loss on markers of glucagon resistance. The glucagon-alanine index improved following hypocaloric, but not isocaloric, feeding, independently of macronutrient composition.

Conclusion: Improvements in glucagon resistance may depend on body weight loss in patients with type 2 diabetes.

Keywords: carbohydrate-reduced high-protein diet; metabolic dysfunction-associated steatotic liver; nonalcoholic fatty liver disease; type 2 diabetes; weight loss; weight maintenance.