Elevated Circulating Follistatin Is Associated With Diabetic Status and Glycemic Dysregulation in Patients With β‐Thalassemia Major

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Diabetes mellitus (DM) is a frequent and debilitating complication in patients with β-thalassemia major (β-TM), driven by chronic iron overload-induced pancreatic and hepatic dysfunction. Validated biomarkers for early diabetes detection in this population remain limited. Follistatin (FST), a secreted glycoprotein modulating TGF-β/activin signaling and glucose metabolism, has been associated with Type 2 diabetes (T2D), though its relevance to thalassemia-associated diabetes is unexplored. This cross-sectional study examined plasma FST levels and gene expression relative to diabetic status and glycemic control in 134 participants: 80 β-TM/non-diabetic, 34 β-TM/diabetic patients, and 20 healthy controls. Iron modulation effects were explored in HepG2 hepatocytes using ferric ammonium citrate (FAC) or deferoxamine (DFO), and metabolic stress effects were assessed in healthy PBMCs exposed to high glucose or insulin. Plasma FST was significantly elevated in β-TM/diabetic patients versus β-TM/non-diabetic patients or controls (p < 0.001). FST correlated positively with glucose and fructosamine (r = 0.23; p ≤ 0.02), but not with serum ferritin. A stepwise increase in plasma FST was observed across glycemic control subgroups, from 2421 pg/mL in well-controlled to 3831 pg/mL in poorly controlled diabetics (p < 0.0001). FAC upregulated FST mRNA in HepG2 cells, while DFO suppressed it (p < 0.05). Peripheral Blood Mononuclear Cells (PBMCs) FST mRNA was paradoxically lower in β-TM/diabetic patients (p = 0.02), a pattern reproduced in PBMCs under high glucose or insulin, indicating tissue-specific metabolic regulation. Collectively, these findings suggest that elevated plasma FST may reflect a convergence of iron-induced hepatic stress and hyperglycemia-related dysregulation and warrant further cross-sectional investigations as a candidate biomarker in this population.

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