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Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men

International Journal of Obesity volume 32, pages 407–412 (2008)Cite this article

Abstract

Objective:

Our previous study using the Goto–Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects.

Subjects and methods:

Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m−2), 199 obese subjects with normal glucose tolerance (NGT, BMI⩾30 kg m−2) and 188 control subjects (NGT, BMI⩽26 kg m−2), were genotyped.

Results:

A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMI⩾30 kg m−2 (P=0.003 and 0.005). The significance was borderline in T2D patients with BMI<30 kg m−2 (P=0.051 and 0.084) and disappeared in T2D patients with BMI⩽26 kg m−2. Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P=0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects.

Conclusions:

The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.

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References

  1. Freeman H, Cox RD . Type 2 diabetes: a cocktail of genetic discovery. Hum Mol Genet 2006; 15 (Suppl 2): R202–R209.

    Article  CAS  PubMed  Google Scholar 

  2. Farooqi IS, O'rahilly S . Genetics of obesity in human. Endocr Rev 2006; 361: 1095–1105.

    Google Scholar 

  3. Hanoune J, Defer N . Regulation and role of adenylyl cyclase isoforms. Annu Rev Pharmacol Toxicol 2001; 41: 145–174.

    Article  CAS  PubMed  Google Scholar 

  4. Galli J, Li LS, Glaser A, Ostenson CG, Jiao H, Fakhrai-Rad H et al. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet 1996; 12: 31–37.

    Article  CAS  PubMed  Google Scholar 

  5. Abdel-Halim SM, Guenifi A, Efendic S, Ostenson CG . Both somatostatin and insulin responses to glucose are impaired in the perfused pancreas of the spontaneously noninsulin-dependent diabetic GK (Goto–Kakizaki) rats. Acta Physiol Scand 1993; 148: 219–226.

    Article  CAS  PubMed  Google Scholar 

  6. Abdel-Halim SM, Guenifi A, Luthman H, Grill V, Efendic S, Ostenson CG . Impact of diabetic inheritance on glucose tolerance and insulin secretion in spontaneously diabetic GK–Wistar rats. Diabetes 1994; 43: 281–288.

    Article  CAS  PubMed  Google Scholar 

  7. Abdel-Halim SM, Ostenson CG, Andersson A, Jansson L, Efendic S . A defective stimulus-secretion coupling rather than glucotoxicity mediates the impaired insulin secretion in the mildly diabetic F1 hybrids of GK–Wistar rats. Diabetes 1995; 44: 1280–1284.

    Article  CAS  PubMed  Google Scholar 

  8. Abdel-Halim SM, Guenifi A, He B, Yang B, Mustafa M, Hojeberg B et al. Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes. Diabetes 1998; 47: 498–504.

    Article  CAS  PubMed  Google Scholar 

  9. Abdel-Halim SM, Guenifi A, Khan A, Larsson O, Berggren PO, Ostenson CG et al. Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP. Diabetes 1996; 45: 934–940.

    Article  PubMed  Google Scholar 

  10. Begin-Heick N . Liver β-adrenergic receptors, G proteins, and adenylyl cyclase activity in obesity–diabetes syndromes. Am J Physiol 1994; 94: C1664–C1672.

    Article  Google Scholar 

  11. Carlsson S, Persson PG, Alvarsson M, Efendic S, Norman A, Svanström L et al. Weight history, glucose tolerance and insulin levels in middle-aged Swedish men. Am J Epidemiol 1998; 148: 539–545.

    Article  CAS  PubMed  Google Scholar 

  12. Grill V, Persson G, Carlsson S, Norman A, Alvarsson M, Ostensson CG et al. Family history of diabetes in middle-aged Swedish men is a gender unrelated factor, which is associated with insulinopenia in newly diagnosed diabetic subjects. Diabetologia 1999; 42: 15–23.

    Article  CAS  PubMed  Google Scholar 

  13. Agardh EE, Ahlbom A, Andersson T, Efendic S, Grill V, Hallqvist J et al. Work stress and low sense of coherence is associated with type 2 diabetes in middle-aged Swedish women. Diabetes care 2003; 5: 719–724.

    Article  Google Scholar 

  14. Alberti KG, Zimmet P . Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Med 1998; 15: 539.

    Article  CAS  PubMed  Google Scholar 

  15. Begin-Heick N . Liver β-adrenergic receptors, G proteins, and adenylyl cyclase activity in obesity–diabetes syndromes. Am J Physiol 1994; 94: C1664–C1672.

    Article  Google Scholar 

  16. Wheeler MB, Lu M, Dillon JS, Leng XH, Chen C, Boyd III AE . Functional expression of the rat glucagon-like peptide-I receptor, evidence for coupling to both adenylyl cyclase and phospholipase-C. Endocrinology 1993; 133: 57–62.

    Article  CAS  PubMed  Google Scholar 

  17. Dillon JS, Lu M, Bowen S, Homan LL . The recombinant rat glucagon-like peptide-1 receptor, expressed in an alpha-cell line, is coupled to adenylyl cyclase activation and intracellular calcium release. Exp Clin Endocrinol Diabetes 2005; 113: 182–189.

    Article  CAS  PubMed  Google Scholar 

  18. Miguel JC, Abdel-Wahab YH, Green BD, Mathias PC, Flatt PR . Cooperative enhancement of insulinotropic action of GLP-1 by acetylcholine uncovers paradoxical inhibitory effect of beta cell muscarinic receptor activation on adenylate cyclase activity. Biochem Pharmacol 2003; 65: 283–292.

    Article  CAS  PubMed  Google Scholar 

  19. Furman B, Pyne N . Modulation of cyclic nucleotides and cyclic nucleotide phosphodiesterases in pancreatic islet β-cells and intestinal L-cells as targets for treating diabetes mellitus. Curr Opin Invest Drugs 2006; 7: 898–905.

    CAS  Google Scholar 

  20. Gault VA, O'Harte FP, Harriott P, Mooney MH, Green BD, Flatt PR . Effects of the novel (pro3) GIP antagonist and exendin (9-39) amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin. Diabetologia 2003; 46: 222–230.

    Article  CAS  PubMed  Google Scholar 

  21. Efendic S . Catecholamines and metabolism of human adipose tissue. 3. Comparison between the regulation of lipolysis in omental and subcutaneous adipose tissue. Acta Med Scand 1970; 187: 477–483.

    Article  CAS  PubMed  Google Scholar 

  22. Collins S, Cao W, Robidoux J . Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Mol Endocrinol 2004; 18: 2123–2131.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Drs Oluf Pedersen and Torben Hansen for valuable discussion and comment, Dr Ralf Morgenstern for the support with DASH instrument, Ms Yvonne Strömberg for excellent laboratory assistance and all subjects for participating in the present study. The work was supported by Novo Nordic Consortium, Swedish Research Council, Novo Nordisk Scandinavia, Glaxo Smith Kline, Vetenskapligt arbete inom diabetologi foundation, Loo and Hans Osterman foundation and Swedish Diabetes Association.

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Authors and Affiliations

  1. Department of Molecular Medicine and Surgery, Rolf Luft Center for Diabetes Research, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden

    S Nordman, A Abulaiti, A Hilding, E-C Långberg, C-G Östenson, S Efendic & H F Gu

  2. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    K Humphreys

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  1. S Nordman
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Correspondence to H F Gu.

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Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo)

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Nordman, S., Abulaiti, A., Hilding, A. et al. Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men. Int J Obes 32, 407–412 (2008). https://doi.org/10.1038/sj.ijo.0803742

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