Follistatins in glucose regulation of healthy and obese subjects.

AIMS: It has been recently suggested that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3) may be a therapeutic target against type 2 diabetes due to their glucose-regulatory effects in rodents.

MATERIALS AND METHODS: We investigated this hypothesis in humans by studying i) the physiology of a possible glycemia-follistatin feedback loop i.e. whether glucose but not lipid intake (oral or intravenous) can regulate circulating FST and FSTL3 in healthy humans(n=32), ii) 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, glycemia, circulating FST and FSTL3 are all reduced (by 22-33%) after RYGB and sleeve gastrectomy. Importantly, the changes in circulating FST three months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA-IR and HbA1c observed six months postoperatively both in subjects with and without type 2 diabetes.

CONCLUSIONS: Our findings provide evidence for an important role of FST on glucose homeostasis in healthy individuals as well as in severe obesity accompanied by 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 hyperglycemia and insulin resistance. This article is protected by copyright. All rights reserved.