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The genetics of insulin resistance: Where's Waldo?

ABSTRACT: The physiologic hallmarks of type 2 diabetes are insulin resistance in hepatic and peripheral tissues and pancreatic ?-cell dysfunction. Thus, genetic loci underlying susceptibility to type 2 diabetes are likely to map to one of these endophenotypes. Genome-wide association studies have now identified up to 38 susceptibility loci for type 2 diabetes and a number of other loci underlying variation in type 2 diabetes-related quantitative traits. The majority are of unknown biology or map to pancreatic ?-cell dysfunction. A seemingly disproportionate minority map to insulin resistance. We briefly discuss the known insulin resistance loci identified from genome-wide association, and then discuss reasons why additional insulin resistance loci have not been identified. We present alternative views that may partly explain the apparent dearth of insulin resistance loci contributing to genetic susceptibility to type 2 diabetes, rather than focus on traditional issues such as study design and sampling, which have been addressed elsewhere.

SUBMITTER: Watanabe RM

PROVIDER: S-EPMC3001333 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The genetics of insulin resistance: Where's Waldo?

Watanabe Richard M RM

Current diabetes reports 20101201 6

The physiologic hallmarks of type 2 diabetes are insulin resistance in hepatic and peripheral tissues and pancreatic β-cell dysfunction. Thus, genetic loci underlying susceptibility to type 2 diabetes are likely to map to one of these endophenotypes. Genome-wide association studies have now identified up to 38 susceptibility loci for type 2 diabetes and a number of other loci underlying variation in type 2 diabetes-related quantitative traits. The majority are of unknown biology or map to pancre ...[more]

PMID: 20820957

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Project description:DNA in its simplest form is an ensemble of nucleic acids, water, and ions, and the conformation of DNA is dependent on the relative proportions of all three components. When DNA is covalently damaged by endogenous or exogenous reactive species, including those produced by some anticancer drugs, the ensemble undergoes localized changes that affect nucleic acid structure, thermodynamic stability, and the qualitative and quantative arrangement of associated cations and water molecules. Fortunately, the biological effects of low levels of DNA damage are successfully mitigated by a large number of proteins that efficiently recognize and repair DNA damage in the midst of a vast excess of canonical DNA. In this Account, we explore the impact of DNA modifications on the high resolution and dynamic structure of DNA, DNA stability, and the uptake of ions and water and explore how these changes may be sensed by proteins whose function is to initially locate DNA lesions. We discuss modifications on the nucleobases that are located in the major and minor grooves of DNA and include lesions that are observed in vivo, including oxidized bases, as well as some synthetic nucleobases that allow us to probe how the location and nature of different substituents affect the thermodynamics and structure of the DNA ensemble. It is demonstrated that disruption of a cation binding site in the major groove by modification of the N7-position on the purines, which is the major site for DNA alkylation, is enthalpically destabilizing. Accordingly, tethering a cationic charge in the major groove is enthalpically stabilizing. The combined structural and thermodynamic studies provide a detailed picture of how different DNA lesions affect the dynamics of DNA and how modified bases interact with their environment. Our work supports the hypothesis that there is a "thermodynamic signature" to DNA lesions that can be exploited in the initial search that requires differentiation between canonical DNA and DNA with a lesion. The differentiation between a lesion and a cognate lesion that is a substrate for a particular enzyme involves another layer of thermodynamic and kinetic factors.

Dataset Information

The genetics of insulin resistance: Where's Waldo?

Publications

The genetics of insulin resistance: Where's Waldo?

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