Elevated Circulating Fibroblast Growth Factor 21 in Lean Type 2 Diabetes: Evidence of Metabolic Dysregulation in the Absence of Adiposity

Abstract

Introduction: Lean type 2 diabetes mellitus (T2DM) is a form of diabetes that develops in persons with normal Body Mass Index (BMI) and considerable metabolic impairment. High levels of Fibroblast Growth Factor-21 (FGF21) can indicate disrupted metabolic signaling in this group. The study aimed to assess circulating FGF21 levels in lean T2DM and to examine their association with insulin resistance and hepatic steatosis, both biomarkers of metabolic dysregulation.

Methods: This cross-sectional study included 425 lean adults (body mass index 18.5–22.9 kg/m²), comprising 200 lean T2DM patients and 225 non-diabetic controls. An enzyme-linked immunosorbent assay (ELISA) was used to measure serum FGF21 levels. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and ultrasonography was used to evaluate hepatic steatosis.

Results: Lean T2DM patients had significantly higher levels of glycated hemoglobin (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), fasting glucose, fasting insulin, low-density lipoprotein (LDL) cholesterol, aspartate aminotransferase (AST), and total cholesterol, while high-density lipoprotein (HDL) cholesterol was lower than non-diabetic controls (all p <0.001). In multivariable analyses of the lean T2DM cohort, serum FGF21 was independently associated with HOMA-IR (β = 0.775, p <0.001) and hepatic steatosis (OR = 1.02, 95% CI 1.01-1.03).

Conclusions: Circulating FGF21 levels are elevated in lean T2DM and may reflect compensatory upregulation or altered FGF21 signaling rather than confirmed tissue-level resistance. FGF21 was an independent predictor of insulin resistance and hepatic steatosis, suggesting its potential as a biomarker of metabolic dysfunction in the normal-BMI group.