title: Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes.
abstract: Calgranulin B (S100A9) was recognized as a candidate type 2 diabetes (T2D) gene in the genomic profiling of muscle from a rodent model of T2D and identifying the human orthologs of genes localized in T2D susceptibility regions. Circulating and S100A9 expressions in muscle and adipose tissue, isolated fat cells, and mouse models were evaluated. A common 5'-upstream single-nucleotide polymorphism (SNP; rs3014866) for S100A9 was analyzed, as well as the effects of weight loss and treatments in vitro with recombinant S100A9. S100a9 expression was increased in muscle of diabetic mice (1.6-fold, p = 0.002), and in muscle from subjects with impaired glucose tolerance (∼4-fold, p = 0.028; n = 34). The rs3014866 SNP was associated with circulating S100A9 and the risk of T2D, having TT carriers at 28 % (p = 0.03) lower risk (n = 1,450). Indeed, increased circulating S100A9 (∼4-fold, p = 0.03; n = 206) and subcutaneous (2-fold, p = 0.01) and omental (1.4-fold, p = 0.04) S100A9 gene expressions (n = 83) in TT carriers run in parallel to decreased fasting glucose and glycated hemoglobin. Accordingly, metformin led to increased S100A9 mRNA in ex vivo-treated adipose tissue explants (n = 5/treatment). Otherwise, obese subjects showed a compensatory increase in circulating and S100A9 expressions in adipose (n = 126), as further demonstrated by decreased levels after diet- (-34 %, p = 0.002; n = 20) and surgery-induced (-58 %, p = 0.02; n = 8) weight loss. Lipopolysaccharide led to increased S100A9 in adipose from mice (n = 5/treatment) while recombinant S100A9 downregulated inflammation in adipocytes (n = 3/treatment). Current findings support the strategy of testing differentially expressed genes in mice and human orthologs associated with T2D. The increased S100A9 reported for obesity and insulin resistance may be envisioned as a compensatory mechanism for inflammation.
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition (UDEN), Institut d'Investigació Biomédica de Girona (IdIBGi), CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03/0010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Ortega
authors.forename: Josep M
authors.initials: JM
authors.lastname: Mercader
authors.forename: José M
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.forename: Mónica
authors.initials: M
authors.lastname: Sabater
authors.forename: Neus
authors.initials: N
authors.lastname: Pueyo
authors.forename: Sergio
authors.initials: S
authors.lastname: Valdés
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Ruiz
authors.forename: Elodie
authors.initials: E
authors.lastname: Luche
authors.forename: Matteo
authors.initials: M
authors.lastname: Serino
authors.forename: Deborah
authors.initials: D
authors.lastname: Naon
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
authors.forename: Patricia
authors.initials: P
authors.lastname: Botas
authors.forename: Elias
authors.initials: E
authors.lastname: Delgado
authors.forename: Remy
authors.initials: R
authors.lastname: Burcelin
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.forename: Gertrude
authors.initials: G
authors.lastname: Mingrone
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Real
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D040502:Calgranulin B / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D040502:Calgranulin B; D008687:Metformin