Effects of Genetic Variation in the Human Retinol Binding Protein-4 Gene (RBP4) on Insulin Resistance and Fat Depot–Specific mRNA Expression
- Peter Kovacs1,
- Michaela Geyer2,
- Janin Berndt1,
- Nora Klöting2,
- Timothy E. Graham3,
- Yvonne Böttcher2,
- Beate Enigk1,
- Anke Tönjes24,
- Dorit Schleinitz1,
- Michael R. Schön5,
- Barbara B. Kahn3,
- Matthias Blüher2 and
- Michael Stumvoll2
- 1Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany
- 2Department of Medicine, University of Leipzig, Leipzig, Germany
- 3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts
- 4Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany
- 5Department of Surgery, University of Leipzig, Leipzig, Germany
- Address correspondence and reprint requests to Michael Stumvoll, MD, Medical Department III, University of Leipzig, Philipp-Rosenthal-Str. 27, D-04103 Leipzig, Germany. E-mail: michael.stumvoll{at}medizin.uni-leipzig.de
Abstract
OBJECTIVE— Serum retinol binding protein 4 (RBP4) is a new liver- and adipocyte-derived signal that may contribute to insulin resistance. Therefore, the RBP4 gene represents a plausible candidate gene involved in susceptibility to type 2 diabetes.
RESEARCH DESIGN AND METHODS— In this study, the RBP4 gene was sequenced in DNA samples from 48 nonrelated Caucasian subjects. Five novel and three known single nucleotide polymorphisms (SNPs) were identified. Furthermore, five recently reported SNPs were genotyped in 90 subjects. Six SNPs, representative of their linkage disequilibrium groups, were then genotyped in 934 diabetic and 716 nondiabetic subjects.
RESULTS— A haplotype of six common SNPs (A-G-G-T-G-C) was significantly increased in 934 case subjects with type 2 diabetes compared with 537 healthy control subjects with normal glucose tolerance (P = 0.02; odds ratio 1.37 [95% CI 1.05–1.79]). Furthermore, in the cohort of 716 nondiabetic Caucasian subjects, carriers of the A-G-G-T-G-C haplotype had significantly higher mean fasting plasma insulin and 2-h plasma glucose than subjects without the haplotype. Two single SNPs (rs10882283 and rs10882273) were also associated with BMI, waist-to-hip ratio, and fasting plasma insulin, and several SNPs were associated with circulating free fatty acids (all adjusted P < 0.05). In addition, subjects carrying a previously reported diabetes-associated haplotype had significantly higher mRNA levels in visceral adipose tissue (adjusted P < 0.05) in a subgroup of nondiabetic subjects (n = 170) with measurements of RBP4 mRNA expression in visceral and subcutaneous fat depots.
CONCLUSIONS— Our data indicate a role of RBP4 genetic variation in susceptibility to type 2 diabetes and insulin resistance, possibly through an effect on RBP4 expression.
- FFA, free fatty acid
- LD, linkage disequilibrium
- RBP4, serum retinol binding protein 4
- SNP, single nucleotide polymorphism
- WHR, waist-to-hip ratio
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 29 August 2007. DOI: 10.2337/db07-1647.
P.K. and M.G. contributed equally to this work.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1647.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted August 23, 2007.
- Received November 24, 2006.
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