title: Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Deidre
authors.initials: D
authors.lastname: Winnier
authors.affiliation: Institute of Neuroscience, National Research Council, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Jan
authors.initials: J
authors.lastname: Bruder
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Marcel
authors.initials: M
authors.lastname: Fourcaudot
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Zuo
authors.initials: Z
authors.lastname: Pengou
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jenkinson
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX Departamento de Clinica Medica, Faculdade de Ciencias Medicas, Obesity and Comorbidities Research Center, Universidade Estadual de Campinas, Campinas, Brazil folli@uthscsa.edu.
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
mesh_terms: D015502:Absorptiometry, Photon; D048868:Adaptor Proteins, Signal Transducing; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D015519:Bone Density / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005215:Fasting / Q000097:blood; D005260:Female; D005819:Genetic Markers; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D011236:Prediabetic State / Q000097:blood*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D007328:Insulin; C422903:SOST protein, human