Serum Levels of Adiponectin are Associated with Diabetic Retinopathy and with Adiponectin Gene Mutations in Caucasian Patients with Diabetes Mellitus Type 2

Abstract

Introduction: Even diabetic patients with excellent glycemic control can develop diabetic complications very early. Possibly, not only the degree of glycemic control, but other factors as well are responsible for the development of diabetic microangiopathy. Since adiponectin represents an adipocyte-specific secretory protein modulating endothelial cell functions, it was the aim of the present study to investigate the role of adiponectin serum levels as well as adiponectin gene polymorphisms in the development of diabetic retinopathy.

Methods: A population based cohort of caucasian patients (n=523) with type 2 diabetes mellitus was recruited from an epidemiological field survey. Serum adiponectin levels were determined by ELISA. Genotypes of the Tyr111His and the Gly15Gly polymorphism were determined by PCR-based RFLP analysis. Diabetic retinopathy was graded by fundus photography.

Results: The data demonstrate, that a) the Tyr111His (T→C) polymorphism influences adiponectin serum levels, b) adiponectin serum levels do correlate with the prevalence of diabetic retinopathy, and c) patients heterozygous for the +45 T→G (Gly15Gly) polymorphism show a lower prevalence of diabetic retinopathy. Furthermore, we could generate the proof of principle that adiponectin is detectable in the fluid of the human vitreous body.

Summary: Adiponectin gene polymorphisms influence adiponectin serum levels and elevated adiponectin serum levels are associated with diabetic retinopathy in patients with diabetes mellitus type 2. Therefore, endothelial cell modulating adiponectin should be further investigated as a candidate gene in the development and progression of retinopathy associated with type 2 diabetes mellitus.

Key words

adipocyte - adiponectin - polymorphism - diabetes mellitus type 2 - diabetic retinopathy

References

• 1 Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
• 2 Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 1996;  271 10697-10703
• 3 Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1.  Biochem Biophys Res Commun. 1996;  221 286-289
• 4 Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma.  J Biochem. 1996;  120 803-812
• 5 Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K. Analysis on an expression profile of genes in the human adipose tissue.  Gene. 1997;  190 227-235
• 6 Shapiro L, Scherer PE. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor.  Current Biology. 1998;  8 335-338
• 7 Okamoto Y, Arita Y, Nishida M. et al . An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular vessel walls.  Horm Metab Res. 2000;  32 47-50
• 8 Ouchi N, Kihara S, Arita Y. et al . Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway.  Circulation. 2000;  102 1296-1301
• 9 Frystyk J, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A. Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications.  Diabetologia. 2005;  48 1911-1918
• 10 Hadjadj S, Aubert R, Fumeron F. et al . Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects.  Diabetologia. 2005;  48 1088-1092
• 11 Schäffler A, Barth N, Palitzsch KD, Drobnik W, Schölmerich J, Schmitz G. Mutation analysis of the human adipocyte-specific apM-1 gene.  Europ J Clin Invest. 2000;  30 879-887
• 12 Zietz B, Barth N, Spiegel D, Schmitz G, Schölmerich J, Schäffler A. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) is associated with higher levels of total cholesterol and LDL-cholesterol in male caucasian patients.  Exp Clin Endocrinol Diabetes. 2000;  110 60-66
• 13 Kohner EM, Porta M. Protocols for screening and treatment of diabetic retinopathy in Europe.  Eur J Ophthal. 1991;  1 45-54
• 14 SPSS Inc . SPSS for Windows 95, V. 12.0 SPSS inc. Chicago 2004
• 15 Bunce C, Wormald R. Leading causes of certification for blindness and partial sight in England and Wales.  BMC Public Health. 2006;  8 58
• 16 Aiello LP, Gardner TW, King GL. et al . Diabetic retinopathy.  Diabetes Care. 1998;  21 143-156
• 17 American Diabetes Association . Diabetic Retinopathy.  Diabetes Care. 1998;  21 157-159
• 18 Sjolie AK, Stephenson J, Aldington S. et al . Retinopathy and vision loss in insulin-dependent diabetes in Europe. The EURODIAB IDDM Complications Study.  Ophthalmology. 1997;  104 252-260
• 19 Sjolie AK, Porta M, Parving HH. et al . The Diabetic Retinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics.  J Renin Angiotensin Aldosterone Syst. 2005;  6 25-32
• 20 Stehouwer CDA, Schaper NC. The pathogenesis of vascular complications of diabetes mellitus: one voice or many?.  Europ J Clin Invest. 1996;  26 535-543
• 21 Sowers JR, Epstein M. Diabetes mellitus and associated hypertension, vascular disease, and nephropathy.  An update. Hypertension. 1995;  26 869-879
• 22 Porte Jr D, Schwartz MW. Diabetes complications: Why is glucose potentially toxic?.  Science. 1996;  272 699-700
• 23 Cester N, Rabini A, Salvolini E. et al . Activation of endothelial cells during insulin-dependent diabetes mellitus: a biochemical and morphological study.  Europ J Clin Invest. 1996;  26 569-573
• 24 Kofoed-Enevoldsen A. The Steno hypothesis and glomerular basement membrane biochemistry in diabetic nephropathy. In: Mogensen, C.E. (ed.): The kidney and hypertension in diabetes. 2nd edition. Boston: Kluwer 1994: 203-212
• 25 Williamson JR, Chang K, Frangos M. et al . Hyperglycemic pseudohypoxia and diabetic complications.  Diabetes. 1993;  42 801-813
• 26 Uhlmann K, Kovacs P, Boettcher Y, Hammes HP, Paschke R. Genetics of diabetic retinopathy.  Exp Clin Endocrinol Diabetes. 2006;  114 275-294
• 27 Holl RW, Lang GE, Grabert M, Heinze E, Lang GK, Debatin KM. Diabetic retinopathy in pediatric patients with type-1 diabetes: effect of diabetes duration, prepubertal and pubertal onset of diabetes, and metabolic control.  J Pediat. 1998;  132 760-762
• 28 Schalkwijk CG, Chaturvedi N, Schram MT. et al . Adiponectin is inversely associated with renal function in type 1 diabetic patients.  J Clin Endocrinol Metab. 2006;  91 129-135
• 29 Yilmaz MI, Sonmez A, Acikel C. et al . Adiponectin may play a part in the pathogenesis of diabetic retinopathy.  Eur J Endocrinol. 2004;  151 135-140
• 30 Rudofsky Jr G, Schlimme M, Schlotterer A. et al . No association of the 94T/G polymorphism in the adiponectin gene with diabetic complications.  Diabetes Obes Metab. 2005;  7 455-459
• 31 Saltiel AR. You are what you secret.  Nature Medicine. 2001;  7 887-888
• 32 Nadler ST, Attie AD. Please pass the chips: Genomic insights into obesity and diabetes.  J Nutr. 2001;  131 2078-2081
• 33 Vidal-Puig A, O’Rahilly S. Obesity and diabetes: an avalance of new information.  Mol Med Today. 2000;  6 221-223
• 34 Groop L. Genetics of the metabolic syndrome.  British J Nutrition. 2000;  83 S39-S48
• 35 Funahashi T, Nakamura T, Shimomura I. et al . Role of adipocytokines on the pathogenesis of athersclerosis in visceral obesity.  Int Medicine. 1999;  38 202-206
• 36 Nadler S, Stoehr JP, Schueler KL. The expression of adipogenic genes is decreased in obesity and diabetes mellitus.  PNAS. 2000;  97 1371-11376
• 37 Zietz B, Leonhardt K, Schäffler A. Candidate genes and polymorphism analysis in type 2 diabetes mellitus.  Med Klin. 2006;  101 605-616

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