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FP6

EXGENESIS Résumé de rapport

Project ID: 5272
Financé au titre de: FP6-LIFESCIHEALTH
Pays: United Kingdom

Final Report Summary - EXGENESIS (Health benefits of exercise: identification of genes and signalling pathways involved in effects of exercise on insulin resistance, obesity and metabolic syndrome)

Obese humans have a 20-fold increased risk of developing type 2 diabetes compared with lean individuals. The prevalence of obesity is increasing rapidly, with over 20 % of the population in most European Union (EU) Member States now having a BMI > 30. Not surprisingly, type 2 diabetes is also increasing: its prevalence in the EU was estimated at 3 % of the population in 1995, doubling to 6 % by 2010. Diabetes causes debilitating complications, and the total costs to the healthcare systems of 8 major EU Member States were estimated in 2002 to be EUR 29 billion per annum, or EUR 2 800 per patient. While genetic factors increase the risk of developing type 2 diabetes, these cannot explain the rapid increases in its prevalence, which is most likely due to a combination of an ageing population, together with increasing levels of obesity caused by adoption of a sedentary lifestyle with low levels of physical activity, and constant availability of high calorie, refined foods. The EXGENESIS project was unravelling the genes and signalling pathways underlying the increased prevalence of obesity, type 2 diabetes and the metabolic syndrome in individuals who are physically inactive. It provided insights into how regular exercise protects against these conditions. These insights should lead to new treatments, as well as encouraging new policies to promote healthier lifestyles.

The aim of EXGENESIS was to identify the genes and signalling pathways involved in the beneficial effects of exercise on insulin resistance, obesity and the metabolic syndrome. It was already established that regular physical exercise protects the human population against the development of these related metabolic disorders. Our aim was to identify the genes and signalling pathways induced by exercise that accounted for these beneficial effects.

The effects of physical inactivity were investigated by analysing the effects of bed rest in healthy young men. Some of the volunteers, who were retrained after the study, were from groups who are known to be at increased risk of type 2 diabetes due to genetic factors (first-degree relatives of patients with type 2 diabetes) or to environmental factors (subjects born with low birth weight, who may have experienced an adverse intrauterine environment). The bed rest studies showed that all groups and individuals developed severe muscle and liver insulin resistance in response to bed rest, illustrating the significant impact of even a short period of reduced physical activity. Most individuals were able to compensate for this insulin resistance by increasing insulin secretion. Significantly, however, those who were carriers of the TCF7L2 gene variant (which predisposes to type 2 diabetes) were unable to compensate by increasing insulin secretion, rendering these young, non-obese individuals close to a state of overt diabetes. Analyses conducted before and after bed rest identified changes in gene expression that may be responsible for the development of insulin resistance (especially genes involved in mitochondrial function), as well as a number of other genes not previously known to be linked to insulin resistance. Interestingly, many of the gene expression changes were different between the first-degree relatives and low-birth weight individuals compared with the control group, giving clues as to how these groups may respond differently to a lack of physical activity. Exciting on-going studies within the EXGENESIS consortium also suggest that epigenetic changes, i.e. changes in DNA structure that are acquired after conception due to environmental factors, may also influence susceptibility to type 2 diabetes.

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Reported by

UNIVERSITY OF DUNDEE
DD1 4HN DUNDEE
United Kingdom
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