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

Abstract

OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe 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. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 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 = 20.40; 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 = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-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). CONCLUSIONSSclerostin 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.

MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus

“…Catalano et al (109) showed that sclerostin levels are higher in females with T1DM compared to males and that the duration of the disease was associated with higher levels of sclerostin. Sclerostin levels are also higher in prediabetic subjects (110). These findings suggest that sclerostin expression and/or osteocytes viability and functions could be impaired in diabetes.…”

The Bone Markers Sclerostin, Osteoprotegerin, and Bone-Specific Alkaline Phosphatase Are Related to Insulin Resistance in Children and Adolescents, Independent of Their Association with Growth and Obesity

“…This pathway interacts with insulin secretion and activity, and it has been implicated in various nonskeletal diseases like type 2 diabetes, obesity, early coronary disease, and cancer [8]. Recently, a positive correlation of circulating sclerostin levels with homeostasis model assessment of insulin resistance (HOMA-IR) and a negative association with insulin-mediated total body glucose has been shown in adults with prediabetes, indicating a link to insulin resistance [4]. The role of sclerostin in the early onset of insulin resistance, particularly in children, is unknown so far.…”

“…Considering that childhood obesity is often accompanied by accelerated growth and that bone and adipose tissue are embryologically derived from common precursor cells, bone-derived factors came into focus. Recently, it has been shown that cytokines produced by bone (e.g., osteopontin and osteocalcin) might participate in energy metabolism, insulin resistance, and growth [4]. Some newer bone markers such as sclerostin and osteoprotegerin have been associated with insulin resistance and prediabetes in adults [4].…”

“…Recently, it has been shown that cytokines produced by bone (e.g., osteopontin and osteocalcin) might participate in energy metabolism, insulin resistance, and growth [4]. Some newer bone markers such as sclerostin and osteoprotegerin have been associated with insulin resistance and prediabetes in adults [4]. …”

Sclerostin and Bone Aging: A Mini-Review

“…Indeed, high levels have been shown in obese patients [21] and in type 2 diabetes, likely in relation with fat mass [33], thus raising the possibility of a key role of sclerostin for insulin resistance [34]. Moreover, high levels have been observed in liver diseases [35], indicating a potential role in regulatory mechanisms in other diseases.…”