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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

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Abstract

Aims

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.

Clinical trial registration number

NCT01526720 (http://www.clinicaltrial.gov).

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Abbreviations

VNDS:

Verona Newly Diagnosed Type 2 Diabetes Study

IL-6:

Interleukin-6

IL-10:

Interleukin-10

TNF-α:

Tumor necrosis factor-alpha

hsCRP:

High-sensitivity C-reactive protein

GLP-1:

Glucagon-like peptide-1

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Acknowledgments

The technical help of Monica Zardini and Federica Moschetta (Department of Medicine, University of Verona, Verona, Italy) is gratefully acknowledged.

Funding

This study was supported in part by an EFSD/Novartis grant (to R.C.B.) and by research grants of University of Verona (to R.C.B. and E.B.). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contribution

M.D. researched and analyzed data and co-wrote the manuscript. M.T. researched data and discussed the manuscript. M.L.B., L.S. researched and analyzed data. C.B. and I.P. researched data. E.B. designed the study, edited the manuscript, and provided substantial contribution to the overall discussion. R.C.B. designed the study, researched data, co-wrote, and edited the manuscript. M.D. and R.C.B. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity and the accuracy of the data analysis.

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona - Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126, Verona, Italy

    Marco Dauriz, Maddalena Trombetta, Linda Boselli, Lorenza Santi, Corinna Brangani, Isabella Pichiri & Enzo Bonora

  2. 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

    Riccardo C. Bonadonna

Authors
  1. Marco Dauriz
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  2. Maddalena Trombetta
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  4. Lorenza Santi
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  7. Enzo Bonora
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  8. Riccardo C. Bonadonna
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Corresponding author

Correspondence to Riccardo C. Bonadonna.

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Conflict of interest

The authors declare that they have no conflict of interest to disclose.

Ethical standard

The VNDS was approved by the local Institutional Review Board, and all subjects gave written informed consent upon recruitment.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

Additional information

Managed by Antonio Secchi.

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Dauriz, M., Trombetta, M., Boselli, L. et al. 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. Acta Diabetol 53, 393–402 (2016). https://doi.org/10.1007/s00592-015-0807-z

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  • DOI: https://doi.org/10.1007/s00592-015-0807-z

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