Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes

Francisco J. Ortega, Josep M. Mercader, José M. Moreno-Navarrete, Mónica Sabater, Neus Pueyo, Sergio Valdés, Bartomeu Ruiz, Elodie Luche, Deborah Naon, Wifredo Ricart, Patricia Botas, Elias Delgado, Remy Burcelin, Gema Frühbeck, Fatima Bosch, Gertrude Mingrone, Antonio Zorzano, José M. Fernández-Real

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11 Citations (Scopus)

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. © 2012 Springer-Verlag Berlin Heidelberg.
Original languageEnglish
Pages (from-to)523-534
JournalJournal of Molecular Medicine
Volume91
Issue number4
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • Adipose tissue
  • Calgranulin B
  • Gene expression
  • Humans
  • Inflammation
  • Innate immune system
  • Insulin resistance
  • Mice
  • Muscle
  • Obesity
  • Single-nucleotide polymorphism
  • Type 2 diabetes

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