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Acta Diabetologica

, Volume 50, Issue 3, pp 401–408 | Cite as

PPARG2 Pro12Ala and ADAMTS9 rs4607103 as “insulin resistance loci” and “insulin secretion loci” in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4

  • M. Trombetta
  • S. Bonetti
  • M. L. Boselli
  • R. Miccoli
  • E. Trabetti
  • G. Malerba
  • P. F. Pignatti
  • E. Bonora
  • S. Del Prato
  • R. C. Bonadonna
Original Article

Abstract

We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (p < 0.01) in the GENFIEV study and in both cohorts combined. The rs1801282 genotype was associated with IS both in the GENFIEV study (p < 0.03) and in the VNDS (p < 0.03), whereas rs4607103 did so in the VNDS only (p = 0.01). In a Mendelian randomization design, both HOMA-IR (instrumental variables: rs1801282, rs4607103) and βF (instrumental variable: rs4607103) were related to T2DM (p < 0.03–0.01 and p < 0.03, respectively). PPARG2 and ADAMTS9 variants are both associated with T2DM and with insulin resistance, whereas only ADAMTS9 may be related to βF. Thus, at least in Italians, they may be considered bona fide “insulin resistance genes”.

Keywords

Type 2 diabetes Insulin resistance PPARG ADAMTS9 

Notes

Acknowledgments

This study was supported in part by an EFSD/Novartis grant (to RCB), research grants of University of Verona (to RCB and EB), and a grant of the Società Italiana di Diabetologia for the GENFIEV Study (to SDP). The superb technical help of Monica Zardini and Federica Moschetta is gratefully acknowledged (Department of Medicine, University of Verona, Verona, Italy). PPARG2 and ADAMTS9 genotyping was performed with XBead Reader of the Center of Functional Genomics of University of Verona, under the supervision of Massimo Delledonne and Alberto Ferrarini, whose contributions are gratefully acknowledged.

Conflict of interest

None of the authors declared any conflict of interest.

Supplementary material

592_2012_443_MOESM1_ESM.doc (224 kb)
Supplementary material 1 (DOC 223 kb)

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Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • M. Trombetta
    • 1
    • 2
  • S. Bonetti
    • 1
  • M. L. Boselli
    • 1
  • R. Miccoli
    • 3
  • E. Trabetti
    • 4
  • G. Malerba
    • 4
  • P. F. Pignatti
    • 4
  • E. Bonora
    • 1
    • 2
  • S. Del Prato
    • 3
  • R. C. Bonadonna
    • 1
    • 2
  1. 1.Division of Endocrinology and Metabolism, Department of Medicine, Ospedale Civile MaggioreUniversity of VeronaVeronaItaly
  2. 2.Azienda Ospedaliera Universitaria Integrata di VeronaVeronaItaly
  3. 3.Department of Endocrinology and MetabolismUniversity of PisaPisaItaly
  4. 4.Department of Life and Reproduction SciencesUniversity of VeronaVeronaItaly

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