Association between single nucleotide polymorphisms within genes encoding sirtuin families and diabetic nephropathy in Japanese subjects with type 2 diabetes

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Abstract

Background

Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy.

Methods

We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran–Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association.

Results

We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy ( P < 0.05), and subsequent haplotype analysis revealed that a haplotype consisting of the 11 SNPs within SIRT1 locus had a stronger association ( P = 0.0028).

Conclusion

These results indicate that SIRT1 may play a role in susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes.

Electronic supplementary material

The online version of this article (doi:10.1007/s10157-011-0418-0) contains supplementary material, which is available to authorized users.

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Most cited references 18

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Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

Jill Milne, Philip Lambert, Simon Schenk … (2007)

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

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Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.

Maria Barbosa, F C Goetz, Elizabeth Seaquist … (1989)

Diabetic nephropathy develops in less than half of all patients with diabetes. To study heredity as a possible risk factor for diabetic kidney disease, we examined the concordance rates for diabetic nephropathy in two sets of families in which both probands and siblings had diabetes mellitus. In one set, the probands (n = 11) had no evidence of diabetic nephropathy, with normal creatinine clearance and a urinary albumin excretion rate below 45 mg per day. In the other set, the probands (n = 26) had undergone kidney transplantation because of diabetic nephropathy. Evidence of nephropathy was found in 2 of the 12 diabetic siblings of the probands without nephropathy (17 percent). Of the 29 diabetic siblings of probands with diabetic nephropathy, 24 (83 percent) had evidence of nephropathy (P less than 0.001), including 12 with end-stage renal disease. No significant differences were noted between the sibling groups with respect to the duration of diabetes, blood pressure, glycemic control, or glycosylated hemoglobin levels. Logistic regression analysis found nephropathy in the proband to be the only factor significantly predictive of the renal status of the diabetic sibling. We conclude that diabetic nephropathy occurs in familial clusters. This is consistent with the hypothesis that heredity helps to determine susceptibility to diabetic nephropathy. However, this study cannot rule out the possible influences of environmental factors shared by siblings.

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Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases.

Leonard Guarente, Shin-ichiro Imai (2010)

Since the discovery of NAD-dependent deacetylase activity of the silent information regulator-2 (SIR2) family ('sirtuins'), many exciting connections between protein deacetylation and energy metabolism have been revealed. The importance of sirtuins in the regulation of many fundamental biological responses to various nutritional and environmental stimuli has been firmly established. Sirtuins have also emerged as critical regulators for aging and longevity in model organisms. Their absolute requirement of NAD has revived an enthusiasm in the study of mammalian biosynthesis of NAD. Sirtuin-targeted pharmaceutical and nutriceutical interventions against age-associated diseases are also on the horizon. This review summarizes the recent progress in sirtuin research (particularly in mammalian sirtuin biology) and re-evaluates the connection between sirtuins, metabolism, and age-associated diseases (e.g., type-2 diabetes) to set a basis for the next ten years of sirtuin research. Copyright 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

: +81-45-5039595 , +81-45-5039567 , smaeda@src.riken.jp

Journal

Journal ID (nlm-ta): Clin Exp Nephrol

Title: Clinical and Experimental Nephrology

Publisher: Springer Japan (Japan )

ISSN (Print): 1342-1751

ISSN (Electronic): 1437-7799

Publication date (Electronic): 18 February 2011

Publication date PMC-release: 18 February 2011

Publication date (Print): June 2011

Volume: 15

Issue: 3

Pages: 381-390

Affiliations

[1 ]Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan

[2 ]Division of Endocrinology and Metabolism, Kanazawa Medical University, Ishikawa, Japan

[3 ]Department of Medicine, Shiga University of Medical Science, Otsu, Shiga Japan

[4 ]The Diabetes Center, Tokyo Women’s Medical University, Tokyo, Japan

[5 ]Division of Nephrology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa Japan

[6 ]Kawai Clinic, Ibaraki, Japan

[7 ]Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan

[8 ]Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639 Japan

Article

Publisher ID: 418

DOI: 10.1007/s10157-011-0418-0

PMC ID: 3110272

PubMed ID: 21331741

SO-VID: c915e783-3cb5-483e-acd5-8a28d0e7a80c

History

Date received : 21 July 2010

Date accepted : 19 January 2011

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ScienceOpen disciplines: Nephrology

Keywords: association study,single nucleotide polymorphism (snp),sirt1,diabetic nephropathy

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ScienceOpen disciplines: Nephrology

Keywords: association study, single nucleotide polymorphism (snp), sirt1, diabetic nephropathy

Association between single nucleotide polymorphisms within genes encoding sirtuin families and diabetic nephropathy in Japanese subjects with type 2 diabetes

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Abstract

Background

Methods

Results

Conclusion

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Karger: Nephrology

Most cited references 18

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.

Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases.

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