Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Objective: A gene mutation of the Wnt/β-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/β-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and β-cell function.

Research Design And Methods: We performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer.

Results: Sclerostin levels were higher in IGR compared with NGT (50.8 ± 2.4 vs. 38.7 ± 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = -0.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = -0.52 and r = -0.44, respectively; both P < 0.001). Sclerostin levels were not correlated with β-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r(2) associated with HOMA-IR (r(2) change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r(2) change: 0.059; F change: 4.938; P = 0.033).

Conclusions: Sclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.