2.12. Candidate Gene Studies on Body Size, Type 2 Diabetes and Related Metabolic Traits, Genetics of ADRA2B, ADIPOQ, ADIPOR1 and ADIPOR2 in the DPS Study Population

Public examination of a doctoral dissertation in the field of clinical nutrition

Doctoral candidate: MSc Niina Siitonen

Time and venue: 2.12.2011 at 12 noon, L1, Canthia, Kuopio Campus

Obesity is a major risk factor for type 2 diabetes (T2DM), and both conditions are increasing rapidly worldwide. Excess adiposity is largely explained by lifestyle related factors, but genetic factors also contribute to an individuals’s susceptibility to gain weight or develop T2DM.

Two entities can be separated in the pathophysiology of T2DM: 1) the compromised response of target tissues to insulin, namely insulin resistance, and 2) the failure of pancreatic beta cells to respond to increased requirement for insulin secretion. The majority of currently known susceptibility genes for T2DM are involved in beta cell function, whereas excess adiposity is a major determinant of insulin resistance.

The aim of the present study was to examine the associations between common genetic variants in biologically plausible candidate genes and traits relating to obesity and T2DM in individuals with impaired glucose tolerance (IGT) who were participating in a randomised lifestyle intervention study, the Finnish Diabetes Prevention Study (DPS). The candidate genes were selected based on their known functions in metabolic pathways and the variants were selected based on previous literature and the haplotype structure of the human genome.

The functional insertion/deletion variant 12Glu9 within the ADRA2B gene, encoding α2B-adrenergic receptor, was associated with acute insulin secretion measured in a subpopulation of the DPS, and with the risk of converting from IGT to T2DM particularly in individuals with central obesity.

Adiponectin is a regulatory molecule secreted by adipose tissue with insulin-sensitising, anti-atherogenic and anti-inflammatory effects. Common single nucleotide polymorphisms (SNPs) within the ADIPOQ gene, encoding adiponectin, were associated with serum adiponectin levels, the risk of T2DM and obesity related traits. Common SNPs in the gene encoding adiponectin receptor 1, ADIPOR1, were associated with various measures of body size in both men and women. In addition, differences in insulin levels according to ADIPOR1 SNPs were seen, particularly in men. Variants in the gene encoding adiponectin receptor 2, ADIPOR2, were associated with the risk of cardiovascular event, and this finding was supported by tissue and allele specific differences seen in the mRNA expression levels.

In summary, these studies suggest that genetic differences in susceptibility to obesity and its comorbidities exist in individuals with an increased risk of T2DM. An interactive effect was seen between ADRA2B and lifestyle, whereas the effects of the adiponectin pathway variants were not modified by lifestyle. The results of these studies partly support the findings of earlier candidate gene studies, but also reveal novel associations.

The doctoral dissertation of Master of Science Niina Siitonen, Heli Tuppurainen, entitled Candidate Gene Studies on Body Size, Type 2 Diabetes and Related Metabolic Traits: Genetics of ADRA2B, ADIPOQ, ADIPOR1 and ADIPOR2 in the DPS Study Population will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Marju Orho-Melander of the University of Lund and the custos will be Professor Matti Uusitupa of the University of Eastern Finland.

Photo available for download at http://www.uef.fi/vaitoskuvat  

For further information, please contact: Niina Siitonen, p. 040 7461567, niina.siitonen@uef.fi

Publishing year: 2011

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