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Association of a SNP in the IAPP gene and hyperglycemia on β-cell dysfunction in type 2 diabetes: the Toon Genome Study

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Abstract

Objective

In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on β-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels.

Methods

Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on β-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose.

Results

The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR.

Conclusions

The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded.

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References

  1. Halban PA, Polonsky KS, Bowden DW, et al. β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37:1751–8.

    Article  Google Scholar 

  2. Opie EL. The relation of diabetes mellitus to lesion of the pancreas. Hyaline degeneration of the islands of Langerhans. J Exp Med. 1901;5:527–40.

    Article  CAS  Google Scholar 

  3. Ohsawa H, Kanatsuka A, Mizuno Y, et al. Islet amyloid polypeptide-derived amyloid deposition increases along with the duration of type 2 diabetes mellitus. Diabetes Res Clin Pract. 1992;15:17–22.

    Article  CAS  Google Scholar 

  4. Westermark P, Wernstedt C, Wilander E, Hayden DW, O’Brien TD, Johnson KH. Amyloid fibrils in human insulinoma and islets Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA. 1987;84:3881–5.

    Article  CAS  Google Scholar 

  5. Cooper GJS, Willis AC, Clark A, Turner RC, Sim RB, Reid KBM. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA. 1987;84:8628–32.

    Article  CAS  Google Scholar 

  6. Mosselman S, Hoppener JWM, Lips CJM, Jansz HS. The complete islet amyloid polypeptide precursor is encoded by two exons. FEBS Lett. 1989;247:154–8.

    Article  CAS  Google Scholar 

  7. Sanke T, Bell GI, Sample C, Rubenstein AH, Steiner DF. An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. J Biol Chem. 1988;263:17243–6.

    Article  CAS  Google Scholar 

  8. Kanatsuka A, Makino H, Ohsawa H, et al. Secretion of islet amyloid polypeptide in response to glucose. FEBS Lett. 1989;259:199–201.

    Article  CAS  Google Scholar 

  9. Ogawa A, Harris V, McCorkle SK, Unger RH, Luskey KL. Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment. J Clin Invest. 1990;85:973–6.

    Article  CAS  Google Scholar 

  10. Kanatsuka A, Makino H, Yamaguchi T, et al. Islet amyloid polypeptide/amylin in pancreatic β-cell line derived from transgenic mouse insulinoma. Diabetes. 1992;41:1409–14.

    Article  CAS  Google Scholar 

  11. Ohsawa H, Kanatsuka A, Yamaguchi T, Makino H, Yoshida S. Islet amyloid polypeptide inhibits glucose-stimulated insulin secretion from isolated rat pancreatic islets. Biochem Biophys Res Commun. 1989;160:961–7.

    Article  CAS  Google Scholar 

  12. Degano P, Silvestre RA, Salas M, Peiro E. Amylin inhibits glucose-induced insulin secretion in a dose-dependent manner. Study in the perfused rat pancreas. Regul Pept. 1993;43:91–6.

    Article  CAS  Google Scholar 

  13. Yagui K, Yamaguchi T, Kanatsuka A, et al. Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur J Endocrinol. 1995;132:487–96.

    Article  CAS  Google Scholar 

  14. Tokuyama T, Yagui K, Yamaguchi T, et al. Expression of human islet amyloid polypeptide/amylin impairs insulin secretion in mouse pancreatic β cells. Metabolism. 1997;46:1044–51.

    Article  CAS  Google Scholar 

  15. Janson J, Soeller WC, Roche PC, et al. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci USA. 1996;93:7283–8.

    Article  CAS  Google Scholar 

  16. Cook JTE, Patel PP, Clark A, et al. Non-linkage of the islet amyloid polypeptide gene with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1991;34:103–8.

    Article  CAS  Google Scholar 

  17. Nishi M, Bell GI, Steiner DF. Islet amyloid polypeptide (amylin): no evidence of an abnormal precursor sequence in 25 type 2 (non-insulin dependent) diabetic patients. Diabetologia. 1990;33:628–30.

    Article  CAS  Google Scholar 

  18. Zee RYL, Pulido-Perez P, Perez-Fuentes R, Ridker PM, Chasman DI, Romero JR. Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: the Women’s Genome Health Study. Clin Chim Acta. 2011;11:785–7.

    Article  Google Scholar 

  19. Kanatsuka A, Kou S, Makino H. IAPP/amylin and β-cell failure: implication of the risk factors of type 2 diabetes. Diabetol Int. 2018;9:143–57.

    Article  Google Scholar 

  20. Lindstroem P. The physiology of obese-hyperglycemic mice (ob/ob mice). Sci World J. 2007;7:666–85.

    Article  CAS  Google Scholar 

  21. Hoppener JWM, Oosterwijk C, Nieuwenhuis MG, et al. Extensive islet amyloid formation is induced by development of type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia. 1999;42:427–34.

    Article  CAS  Google Scholar 

  22. Soeller WC, Janson J, Hart SE, et al. Islet amyloid-associated diabetes in obese Avy/a mice expressing human islet amyloid polypeptide. Diabetes. 1998;47:743–50.

    Article  CAS  Google Scholar 

  23. Yen TT, Gill AM, Frigeri LG, Barsh GS, Wolff GL. Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. FASEB J. 1994;8:479–88.

    Article  CAS  Google Scholar 

  24. Roostaei T, Nazeri A, Felsky D, et al. for the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer’s disease. Mol Psychiatry. 2017;22:287–95.

    Article  CAS  Google Scholar 

  25. Noumi Y, Kawamura R, Tabara Y, et al. An inverse association between serum resistin levels and n-3 polyunsaturated fatty acids intake was strongest in the SNP-420 G/G genotype in the Japanese cohort: the Toon Genome Study. Clin Endocrinol. 2018;88:51–7.

    Article  CAS  Google Scholar 

  26. Cox DR. Interaction. Int Stat Rev. 1984;52:1–25.

    Article  Google Scholar 

  27. Expert committee on the diagnosis and classification of diabetes mellitus report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20:1183–97.

  28. The guideline for epidemiology study in Japan. The ministry of health, labor and welfare. June 30, 2003 (Japanese).

  29. Matthews DR, Hosker JR, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  CAS  Google Scholar 

  30. Kahn BB. Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell. 1998;92:593–6.

    Article  CAS  Google Scholar 

  31. Polonsky KS. The β-cell in diabetes: from molecular genetics to clinical research. Diabetes. 1995;44:706–17.

    Article  Google Scholar 

  32. Mosselman S, Hoppener JWM, de Wit L, Soeller WC, Lips CJM, Jansz HS. IAPP/amylin gene transcriptional control region: evidence for negative regulation. FEBS Lett. 1990;271:33–6.

    Article  CAS  Google Scholar 

  33. German MS, Moss LG, Wang JH, Rutter WJ. The insulin and islet amyloid polypeptide genes contain similar cell-specific promoter elements that bind identical beta-cell nuclear complexes. Mol Cell Biol. 1992;12:1777–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gurio T, Ryazantsev S, Huang C-J, et al. Evidence for proteotoxicity in β-cells in type 2 diabetes. Toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. Am J Pathol. 2010;176:861–9.

    Article  Google Scholar 

  35. Apostolidou M, Jayasinghe SA, Langen R. Structure of & α-helical membrane-bound human islet amyloid polypeptide and its implications for membrane-mediated misfolding. J Biol Chem. 2008;283:17205–10.

    Article  CAS  Google Scholar 

  36. Patil AM, Xu S, Sheftic SR, Alexanderescu AT. Dynamic & α-helix structure of micelle-bound human amylin. J Biol Chem. 2009;284:11982–91.

    Article  CAS  Google Scholar 

  37. Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest. 2005;115:2047–58.

    Article  CAS  Google Scholar 

  38. Seino S, Shibasaki T, Minami K. Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J Clin Invest. 2011;121:2118–25.

    Article  CAS  Google Scholar 

  39. Wiebe N, Ye F, Crumley ET, Bello A, Stenvinkel P, Tonelli M. Temporal associations among body mass index, fasting insulin, and systemic inflammation. A systematic review and meta-analysis. JAMA Netw Open. 2021;4:e211263.

    Article  Google Scholar 

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Acknowledgements

The authors wish to thank the staffs in the Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan for the support of the Toon Genome Study, the ex-staffs in the Diabetes Research Group, the Second Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan for the suggestions regarding the conduct of this study, and Dr. Jun Ohashi, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, for the suggestions for statistical analyses.

Funding

This study was supported by JSPS KAKENHI, Health Labor Sciences Research Grant, Grants from Ehime University, and the Japan Diabetes Foundation.

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Authors and Affiliations

  1. Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan

    Ryoichi Kawamura, Yasunori Takata, Misaki Takakado, Toshimi Hadate, Yumi Matsushita, Madoka Sano, Hideichi Makino & Haruhiko Osawa

  2. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yasuharu Tabara

  3. Department of Bioscience, Graduate School of Agriculture, Ehime University, Matsuyama, Ehime, Japan

    Koutatsu Maruyama

  4. Diabetes Center, Shiraishi Hospital, Imabari, Ehime, Japan

    Hideichi Makino

  5. Department of Public Health and Epidemiology, Faculty of Medicine, Oita University, Oita, Japan

    Isao Saito

  6. Diabetes Center, Chiba Central Medical Center, 1835-1 Kasori, Wakaba-ku, Chiba, 264-0017, Japan

    Azuma Kanatsuka

Authors
  1. Ryoichi Kawamura
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  2. Yasuharu Tabara
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  3. Yasunori Takata
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  8. Madoka Sano
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  9. Hideichi Makino
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  11. Azuma Kanatsuka
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  12. Haruhiko Osawa
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Corresponding authors

Correspondence to Azuma Kanatsuka or Haruhiko Osawa.

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Conflict of interest

The authors declare no conflict of interest regarding the publication of this paper.

Human rights statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Ehime university hospital and graduate school of medicine, ethics committee, date of approval: 1 April. 2009, approval no. 29-K3, 31-4, and 31-18) and with the Helsinki Declaration of 1964 and later versions.

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Informed consent was obtained from the participants in the study.

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Kawamura, R., Tabara, Y., Takata, Y. et al. Association of a SNP in the IAPP gene and hyperglycemia on β-cell dysfunction in type 2 diabetes: the Toon Genome Study. Diabetol Int 13, 201–208 (2022). https://doi.org/10.1007/s13340-021-00523-4

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  • DOI: https://doi.org/10.1007/s13340-021-00523-4

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