Follistatins in glucose regulation in healthy and obese individuals

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.

Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β–Smad3 Pathway

“…Previous studies have shown that circulating FST is higher in patients with T2D than in glucose-tolerant individuals or obese individuals and that activin A levels are similar between these groups (Perakakis et al, 2019;Sylow et al, 2020). However, our results indicated that the level of serum FST was lower in patients with diabetic cardiomyopathy than in healthy individuals, and the in vitro experimental results also verified this finding.…”

Short-term treatment with high dose liraglutide improves lipid and lipoprotein profile and changes hormonal mediators of lipid metabolism in obese patients with no overt type 2 diabetes mellitus: a randomized, placebo-controlled, cross-over, double-blind clinical trial

“…Follistatin is mainly secreted by the liver and its inactivation in hyperglycemic mice improves glucose homeostasis by reducing insulin resistance [18]. We have recently demonstrated that glucose or the concomitant insulin release during OGTT reduces follistatin levels, suggesting the presence of a feedback loop mechanism controlling the effects of follistatin on glucose metabolism [16]. In line with these findings, we have also reported a reduction of follistatin in morbidly obese patients early after bariatric surgery, which predicts the improvement in insulin sensitivity observed later in these patients.…”

Remission of Type 2 Diabetes Mellitus after Bariatric Surgery: Fact or Fiction?

“…Apart from adaptations in post-prandial gut peptide responses, additional humoral mechanisms may contribute to the restoration of insulin sensitivity following surgery. Perakakis et al have recently shown that reduced circulating follistatin levels 3 months after RYGB or VSG are able to predict improvements in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c) and insulin resistance 12 months post-operatively, both in individuals with and without T2DM [34]. Additional factors with a presumed weight-loss-independent role in metabolic improvement post-surgery include increased glucose utilization from the intestine, and alterations of gut microbiota [35].…”