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Review
. 2010 Dec;10(6):485-97.
doi: 10.1007/s11892-010-0154-y.

Physiologic characterization of type 2 diabetes-related loci

Niels Grarup  1 , Thomas Sparsø, Torben Hansen
Affiliations
Review

Physiologic characterization of type 2 diabetes-related loci

Niels Grarup et al. Curr Diab Rep. 2010 Dec.

Abstract

For the past two decades, genetics has been widely explored as a tool for unraveling the pathogenesis of diabetes. Many risk alleles for type 2 diabetes and hyperglycemia have been detected in recent years through massive genome-wide association studies and evidence exists that most of these variants influence pancreatic β-cell function. However, risk alleles in five loci seem to have a primary impact on insulin sensitivity. Investigations of more detailed physiologic phenotypes, such as the insulin response to intravenous glucose or the incretion hormones, are now emerging and give indications of more specific pathologic mechanisms for diabetes-related risk variants. Such studies have shed light on the function of some loci but also underlined the complex nature of disease mechanism. In the future, sequencing-based discovery of low-frequency variants with higher impact on intermediate diabetes-related traits is a likely scenario and identification of new pathways involved in type 2 diabetes predisposition will offer opportunities for the development of novel therapeutic and preventative approaches.

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Figures

Fig. 1
Fig. 1
Graphic representation of association with insulin sensitivity (ISI Matsuda) in relation to association with glucose-stimulated insulin release (insulinogenic index) for 36 single nucleotide polymorphisms (SNPs) with a validated impact on diabetes-related traits in 5722 nondiabetic participants of the population-based Inter99 cohort. The effect sizes are expressed as allelic change in fraction of a standard deviation and have been estimated applying a linear regression model adjusted for sex and age. SNPs represented by green dots associate with altered β-cell function using the insulinogenic index (P < 0.05), SNPs shown in red dots associate with altered insulin sensitivity using the Matsuda insulin sensitivity index (ISI Matsuda), and SNPs shown in blue associate with altered β-cell function and altered insulin sensitivity. ISI—insulin sensitivity index
See this image and copyright information in PMC

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