Nikolaos Perakakis1, Alexander Kokkinos2, Natia Peradze1, Nicholas Tentolouris2, Wael Ghaly1,3, Dimitrios Tsilingiris2, Andreas Alexandrou4, Christos S Mantzoros1. 1. Division of Endocrinology, Diabetes and Metabolism, Harvard Medical School, Harvard University, Boston, Massachusetts. 2. First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece. 3. Department of Physiology, Fayoum University, Fayoum, Egypt. 4. First Department of Surgery, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
Abstract
AIMS: It has been suggested recently that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose-regulatory effects in rodents. MATERIALS AND METHODS: We investigated this hypothesis in humans by studying the physiology of a possible glycaemia-follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 in healthy humans (n = 32), whether the levels of follistatins change in response to various types of bariatric operation in morbidly obese individuals, with or without type 2 diabetes (n = 41), and whether such changes are associated prospectively with improvement of glucose homeostasis/insulin sensitivity. RESULTS: In healthy individuals, circulating FST decreases after intravenous or oral glucose intake compared to controls, indicating the presence of a negative feedback mechanism. In morbid obesity, insulin resistance, glycaemia, circulating FST and FSTL3 are all reduced (by 22%-33%) after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy. Importantly, the changes in circulating FST 3 months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA-IR and HbA1c observed 6 months postoperatively in individuals with and without type 2 diabetes. CONCLUSIONS: Our findings provide evidence of an important role of FST in glucose homeostasis in healthy individuals as well as in severely obese individuals with insulin resistance and type 2 diabetes. Our data extend recent results from animal studies to humans and support the need for further evaluation of FST inactivation strategies for targeting hyperglycaemia and insulin resistance.
AIMS: It has been suggested recently that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose-regulatory effects in rodents. MATERIALS AND METHODS: We investigated this hypothesis in humans by studying the physiology of a possible glycaemia-follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 in healthy humans (n = 32), whether the levels of follistatins change in response to various types of bariatric operation in morbidly obese individuals, with or without type 2 diabetes (n = 41), and whether such changes are associated prospectively with improvement of glucose homeostasis/insulin sensitivity. RESULTS: In healthy individuals, circulating FST decreases after intravenous or oral glucose intake compared to controls, indicating the presence of a negative feedback mechanism. In morbid obesity, insulin resistance, glycaemia, circulating FST and FSTL3 are all reduced (by 22%-33%) after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy. Importantly, the changes in circulating FST 3 months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA-IR and HbA1c observed 6 months postoperatively in individuals with and without type 2 diabetes. CONCLUSIONS: Our findings provide evidence of an important role of FST in glucose homeostasis in healthy individuals as well as in severely obese individuals with insulin resistance and type 2 diabetes. Our data extend recent results from animal studies to humans and support the need for further evaluation of FST inactivation strategies for targeting hyperglycaemia and insulin resistance.
Authors: Laurent Maïmoun; Thibault Mura; Vincent Attalin; Anne Marie Dupuy; Jean-Paul Cristol; Antoine Avignon; Denis Mariano-Goulart; Ariane Sultan Journal: J Clin Med Date: 2020-04-17 Impact factor: 4.241
Authors: Luis A Garcia; Rocio Zapata-Bustos; Samantha E Day; Baltazar Campos; Yassin Hamzaoui; Linda Wu; Alma D Leon; Judith Krentzel; Richard L Coletta; Eleanna De Filippis; Lori R Roust; Lawrence J Mandarino; Dawn K Coletta Journal: Metabolites Date: 2022-03-02