title: Interleukin-6 as a potential positive modulator of human beta-cell function: an exploratory analysis-the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 6.
abstract: OBJECTIVE
  Recent studies in mouse models of T2D showed that interleukin-6 (IL-6), released from skeletal muscle, is associated with increased glucose-dependent insulin secretion. Few data currently exist exploring the relationship between IL-6 and beta-cell function in humans. We investigated whether IL-6 is positively associated with beta-cell function in newly diagnosed T2D. We extended the same analyses to IL-10, because it regulated similarly to IL-6 in skeletal muscle, and TNF-α and C-reactive protein (CRP), as general biomarkers of inflammation.
  
  
  METHODS
  In 330 VNDS participants, we assessed (1) basal plasma concentrations of IL-6, IL-10, TNF-α, and CRP; (2) beta-cell function, estimated by OGTT minimal modeling and expressed as derivative (DC) and proportional control (PC); (3) insulin sensitivity, by euglycemic insulin clamp.
  
  
  RESULTS
  IL-6 was positively associated with PC in both univariate analysis (p = 0.04) and after adjustment for age, sex, BMI, HbA1c, and M-clamp (p = 0.01). HbA1c was the major independent contributor to the overall variance of PC (16 %), followed by BMI and IL-6 (~2 % each). Similar results were obtained for IL-10 (p = 0.048, univariate; p = 0.04, fully adjusted). TNF-α and CRP were not significantly associated with any component of beta-cell function.
  
  
  CONCLUSIONS
  Our data are the first evidence in human subjects that an endocrine loop involving IL-6 may act as positive modulator of glucose-dependent insulin secretion. Further functional studies are needed to corroborate IL-6 system as a potential druggable target in diabetes.
  
  
  BACKGROUND
  NCT01526720 ( http://www.clinicaltrial.gov ).
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Dauriz
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Trombetta
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Boselli
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Santi
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Corinna
authors.initials: C
authors.lastname: Brangani
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Pichiri
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonora
authors.affiliation: Division of Endocrinology, Department of Clinical and Experimental Medicine, University of Parma School of Medicine and Azienda Ospedaliera Universitaria - Ospedale Maggiore, Via Gramsci 14, 43126, Parma, Italy. bonadonna.riccardo@fastwebnet.it.
authors.forename: Riccardo C
authors.initials: RC
authors.lastname: Bonadonna
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002097:C-Reactive Protein
keywords: Beta-cell function; Inflammation; Interleukin-6; Type 2 diabetes