Role of human Kallistatin in glucose and energy homeostasis in mice.

Autor:	Sandforth L; Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Brachs S; Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany., Reinke J; Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany., Willmes D; Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany., Sancar G; Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Seigner J; Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Juarez-Lopez D; Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Sandforth A; Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., McBride JD; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Ma JX; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA., Haufe S; Department of Rehabilitation and Sports Medicine, Hannover Medical School (MHH), Hannover, Germany., Jordan J; Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany; Medical Faculty, University of Cologne, Cologne, Germany., Birkenfeld AL; Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany; Department of Diabetes, Life Sciences & Medicine, Cardiovascular Medicine & Life Sciences, King's College London, UK. Electronic address: andreas.birkenfeld@med.uni-tuebingen.de.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Apr; Vol. 82, pp. 101905. Date of Electronic Publication: 2024 Feb 29.
DOI:	10.1016/j.molmet.2024.101905
Abstrakt:	Objective: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. Methods: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. Results: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. Conclusions: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance. Competing Interests: Declaration of competing interest Jens Jordan receives grants from Novo-Nordisk, Boehringer-Ingelheim, NASA and ESA as well as honoraria from Menarini and Berlin Chemie. He participates in boards of Novo-Nordisk, Theravance, ESH, EFAS and DGLRM and is the co-founder of Eternygen GmbH. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier GmbH.)
Databáze:	MEDLINE
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