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Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11)

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Abstract

Background

Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion.

Aim

In this study, we evaluated the association between the genetic variability of G6PC2 and GCK genes and T2D-related quantitative traits.

Methods

In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within GCK gene and 5 tag-SNPs within G6PC2 gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software.

Results

Two SNPs within GCK gene (rs882019 and rs1303722) were associated to DC in opposite way (both p < 0.004). Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all p < 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (p = 0.033). Haplotype analysis revealed that GCK (AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of G6PC2 (GGAAG) was associated with higher fasting C-peptide levels (p = 0.001), higher PC (β = 6.87, p = 0.022) and the lower 2hPG (p = 0.012).

Conclusion

Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D.

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Acknowledgment

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

Funding

This study was supported in part by a European Foundation for the Study of Diabetes/Novartis grant (to RCB) and by research grants of University of Verona (to RCB and EB).

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Authors and Affiliations

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

    C. Zusi, E. Rinaldi, S. Bonetti, M. L. Boselli, E. Bonora & M. Trombetta

  2. Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy

    E. Trabetti & G. Malerba

  3. Department of Medicine and Surgery, University of Parma, Parma, Italy

    R. C. Bonadonna

  4. Division of Endocrinology and Metabolic Diseases, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    R. C. Bonadonna

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  1. C. Zusi
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  2. E. Rinaldi
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  3. S. Bonetti
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  4. M. L. Boselli
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  8. R. C. Bonadonna
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Contributions

CZ and ER researched and analysed data and cowrote the manuscript. SB genotyped all samples and discussed the article. MLB carried out mathematical modelling of the data. ET and GM discussed the article. RCB developed the mathematical models and designed the study. EB edited the manuscript and provided substantial contribution to the overall manuscript. MT is the guarantor 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.

Corresponding author

Correspondence to M. Trombetta.

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The authors have no potential conflicts of interest to disclose.

Research involving human participants and/or animals

We studied the genetics of a cohort and in the main text is reported that the research was approved by the Human Investigation Committee of the Verona City Hospital and the study was conducted in accordance with the Declaration of Helsinki.

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Written consent was obtained from all study participants after a full explanation of the study.

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C. Zusi and E. Rinaldi these authors contributed equally to this manuscript.

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Zusi, C., Rinaldi, E., Bonetti, S. et al. Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11). J Endocrinol Invest 44, 2567–2574 (2021). https://doi.org/10.1007/s40618-020-01483-3

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