Circulating Follistatin and Activin A and Their Regulation by Insulin in Obesity and Type 2 Diabetes

Abstract

Background Circulating follistatin (Fst) binds activin A and thereby regulates biological functions such as muscle growth and β-cell survival. However, Fst and activin A’s implication in metabolic regulation is unclear. Objective To investigate circulating Fst and activin A in obesity and type 2 diabetes (T2D) and determine their association with metabolic parameters. Further, to examine regulation of Fst and activin A by insulin and the influence of obesity and T2D hereon. Methods Plasma Fst and activin A levels were analyzed in obese T2D patients (N = 10) closely matched to glucose-tolerant lean (N = 12) and obese (N = 10) individuals in the fasted state and following a 4-h hyperinsulinemic–euglycemic clamp (40 mU·m–2·min–1) combined with indirect calorimetry. Results Circulating Fst was ~30% higher in patients with T2D compared with both lean and obese nondiabetic individuals (P < .001), while plasma activin A was unaltered. In the total cohort, fasting plasma Fst correlated positively with fasting plasma glucose, serum insulin and C-peptide levels, homeostasis model assessment of insulin resistance, and hepatic and adipose tissue insulin resistance after adjusting for age, gender and group (all r > 0.47; P < .05). However, in the individual groups these correlations only achieved significance in patients with T2D (not plasma glucose). Acute hyperinsulinemia at euglycemia reduced circulating Fst by ~30% (P < .001) and this response was intact in patients with T2D. Insulin inhibited FST expression in human hepatocytes after 2 h and even further after 48 h. Conclusions Elevated circulating Fst, but not activin A, is strongly associated with measures of insulin resistance in patients with T2D. However, the ability of insulin to suppress circulating Fst is preserved in T2D.

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.…”

“…In addition, although FST correlates with insulin resistance in patients with T2D, the effect of insulin on reducing circulating FST is preserved in obese individuals and patients with T2D. Moreover, with an increasing insulin exposure time, FST mRNA levels in human hepatocytes decrease gradually (Sylow et al, 2020). Therefore, the decline in the level of FST in diabetic cardiomyopathy might be explained by prolonged exposure to insulin.…”

Deciphering the Causal Relationships Between Low Back Pain Complications, Metabolic Factors, and Comorbidities

“…Elevated circulating levels of follistatin are observed in obese patients with T2DM accompanied by insulin resistance. 41 , 88 Follistatin was shown to ameliorate fibrosis and improve kidney function in chronic kidney disease, 89 suggesting its application in disorders accompanied by elevated blood pressure, such as chronic kidney disease, obesity, and T2DM. 90 In our ABN analysis, elevated follistatin plasma levels contribute to hypertension development, which affects ECW levels, and thus indirectly correlates with LBP disability ( Figure 2 ).…”

Factors mediating exercise‐induced organ crosstalk

“…Except for ERFE, [137][138][139][140] the circulating levels of IL-6, FGF21, FST, irisin, GDF15, CHI3L1 and ANGPTL4, have been reported to be increased in insulin resistant conditions such as obesity, 33,57,141 T2D, 33,83,84,120,[142][143][144][145][146] polycystic ovary syndrome 147 and non-alcoholic fatty liver disease. 141,148 However, as described, the production and release of these exerkines are also highly induced in response to acute exercise after which insulin sensitivity is enhanced.…”