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Diabetes Care 29:464 2006
DOI: 10.2337/diacare.29.02.06.dc05-2020
© 2006 by the American Diabetes Association
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Letters: Observations

The –8503 G/A Polymorphism of the Adiponectin Receptor 1 Gene Is Associated With Insulin Sensitivity Dependent on Adiposity

Konstantinos Kantartzis, MD, Andreas Fritsche, MD, Fausto Machicao, PHD, Hans-Ulrich Häring, MD and Norbert Stefan, MD

Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Tübingen, Germany

Address correspondence to Norbert Stefan, MD, Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: norbert.stefan{at}med.uni-tuebingen.de

Adiponectin has beneficial effects on insulin sensitivity. Unexpectedly, adiponectin knockout mice exhibit no or only mild insulin resistance. Nevertheless, under a high-fat/high-carbohydrate diet, severe insulin resistance was induced in those animals (1). Consistent with this, recent evidence (2) suggests that the relationship of adiponectin with insulin sensitivity is stronger with increasing adiposity. In addition, a haplotype in the adiponectin gene was associated with type 2 diabetes only in obese and morbidly obese subjects but not in lean subjects (3).

Single nucleotide polymorphisms (SNPs) of the genes encoding adiponectin receptor (ADIPOR) 1 and 2 were associated with type 2 diabetes (4) or pre-diabetes phenotypes (5) in some but not in all (6) studies. We found that the –8503 G/A SNP of the ADIPOR1 gene was associated with insulin sensitivity (7). In a very recent study (6) in rather lean subjects with a mean BMI of 21 kg/m2, no associations with insulin sensitivity were found. In our study (7), subjects were more obese (BMI 26 kg/m2). This new information lead us to investigate whether the association of the –8503 G/A SNP of ADIPOR1 with insulin sensitivity is modulated by adiposity. If this was the case, then this may partly explain the inconsistent results regarding SNPs of ADIPOR1 and 2.

Recently reported data (7) from 502 nondiabetic Caucasians were analyzed. Insulin sensitivity was estimated from an oral glucose tolerance test and determined during a euglycemic-hyperinsulinemic clamp (n = 299). Subjects were divided into two groups by the median percentage of body fat (PFAT). In the more obese group (n = 250, PFAT 27–55%), carriers of the –8503 A allele had lower insulin sensitivity estimated from the oral glucose tolerance test using the formula proposed by Matsuda and DeFronzo (8) (G/G, G/A, and A/A: 14.4 ± 0.8, 11.9 ± 0.9, and 9.2 ± 1.7 arbitrary units, respectively, P = 0.003, ANOVA) and determined during the clamp (0.07 ± 0.005, 0.06 ± 0.005, and 0.04 ± 0.01 µmol · kg–1 · min–1 · pmol/l–1, respectively, P = 0.007) compared with homozygous carriers of the G allele, independent of age, sex, and PFAT. In contrast, in the lean group (n = 252, PFAT 7–26%), no significant relationships were found (oral glucose tolerance test: 24.6 ± 1.0, 27.2 ± 1.1, and 23.0 ± 2.4, respectively, P = 0.60; clamp: 0.13 ± 0.006, 0.13 ± 0.007, and 0.12 ± 0.016, respectively, P = 0.84).

In summary, we show that the A allele of the –8503 G/A SNP of the ADIPOR1 gene is associated with less insulin sensitivity only in more obese but not in lean individuals. This finding may be important for further studies on the relationships of genetic variants of ADIPOR1 and possibly of ADIPOR2 with metabolism.

References

  1. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y: Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737, 2002[Medline]
  2. Martin LJ, Woo JG, Daniels SR, Goodman E, Dolan LM: The relationships of adiponectin with insulin and lipids are strengthened with increasing adiposity. J Clin Endocrinol Metab 90:4255–4259, 2005[Abstract/Free Full Text]
  3. Vasseur F, Helbecque N, Lobbens S, Vasseur-Delannoy V, Dina C, Clement K, Boutin P, Kadowaki T, Scherer PE, Froguel P: Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity. Diabetologia 48:892–899, 2005[Medline]
  4. Damcott CM, Ott SH, Pollin TI, Reinhart LJ, Wang J, O’Connell JR, Mitchell BD, Shuldiner AR: Genetic variation in adiponectin receptor 1 and adiponectin receptor 2 is associated with type 2 diabetes in the Old Order Amish. Diabetes 54:2245–2250, 2005[Abstract/Free Full Text]
  5. Wang H, Zhang H, Jia Y, Zhang Z, Craig R, Wang X, Elbein SC: Adiponectin receptor 1 gene (ADIPOR1) as a candidate for type 2 diabetes and insulin resistance. Diabetes 53:2132–2136, 2004[Abstract/Free Full Text]
  6. Hara K, Horikoshi M, Kitazato H, Yamauchi T, Ito C, Noda M, Ohashi J, Froguel P, Tokunaga K, Nagai R, Kadowaki T: Absence of an association between the polymorphisms in the genes encoding adiponectin receptors and type 2 diabetes. Diabetologia 48:1307–1314, 2005[Medline]
  7. Stefan N, Machicao F, Staiger H, Machann J, Schick F, Tschritter O, Spieth C, Weigert C, Fritsche A, Stumvoll M, Haring HU: Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia 48:2282–2291, 2005[Medline]
  8. Matsuda M, DeFronzo R: Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care 22:1462–1470, 1999[Abstract/Free Full Text]

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Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women: A Tagging-Single Nucleotide Polymorphism Haplotype Analysis
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[Abstract] [Full Text] [PDF]

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