Studies of the interaction between diabetes family history, exercise, adiposity and metabolic health

Barwell, Nicholas Dominic (2010) Studies of the interaction between diabetes family history, exercise, adiposity and metabolic health. PhD thesis, University of Glasgow.

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The rising tide of obesity and type 2 diabetes has been recognised to have reached epidemic proportions. There is a significant burden of mortality and morbidity associated with the development of these conditions and current estimates suggest that the burden of disease in the next two decades is likely to place considerable strain upon healthcare systems, particularly in the developing world. The development of insulin resistance is a key contributor to the pathogenesis of type 2 diabetes, however the origin of insulin resistance is complex and it is currently unclear precisely how the inter-related components of this metabolic dysfunction are triggered. Obesity is also implicated in the pathogenesis of insulin resistance and represents a risk factor which is potentially modifiable by lifestyle interventions such as exercise and weight loss. Observational and prospective studies have also shown the benefits of lifestyle intervention in reducing the incidence of diabetes in those judged to be at greater risk.

People with a parental history of type 2 diabetes have an increased lifetime risk of diabetes and frequently display metabolic abnormalities which, despite persisting normoglycaemia, are evidence of a ‘pre-diabetic’ state and which may themselves carry increased morbidity and mortality. Observational studies suggest a greater difference in insulin sensitivity between active and sedentary offspring, compared to the difference between active and sedentary individuals with no diabetes family history. This is thought to represent an interaction between positive energy balance, a sedentary lifestyle and a ‘thrifty genotype’. These observations suggest that individuals with a parental history of diabetes are more susceptible to the deleterious health effects of a sedentary lifestyle, but that they may be more responsive to an increase in physical activity. Exercise interventions can be expected to have positive effects upon metabolic health and adiposity however, the individual response to exercise is extremely variable. Other factors such as lifestyle alteration have been implicated in the difference between the observed and predicted response to exercise. Therefore, the aim of this thesis was to examine the physical, metabolic and lifestyle differences between sedentary pre-menopausal women with a parent with type 2 diabetes and matched control subjects with no family history of the condition. In particular, this thesis aimed to explore the effect of an aerobic exercise intervention on metabolic health and body composition, whether the response to exercise is dependent upon a familial history of diabetes and the processes by which exercise might induce any observed changes.

In order to explore the impact of a sedentary lifestyle on women with, and without a family history of type 2 diabetes, thirty four pre-menopausal, sedentary women with a parental history of diabetes (Offspring) and thirty six matched women without a familial history of diabetes (Controls) were recruited. Assessments of body composition, insulin sensitivity, adipose tissue-derived hormone concentration, substrate utilisation, endothelial function by carotid-radial pulse wave velocity, cardiorespiratory fitness, diet and habitual physical activity were performed. Twenty eight Offspring subjects and thirty four matched Controls participated in a seven-week aerobic exercise intervention, training at 65-80 % of predicted maximal heart rate with incremental increases in training duration on a weekly basis. The previously described assessments were performed before and 15-24 hours after the intervention and in a subgroup of 19 Controls and 17 Offspring subjects, further assessments of insulin sensitivity, adipose tissue-derived hormone concentration, substrate utilisation and endothelial function were performed after a further three day period without exercise. In order to determine potential mediators of exercise-induced fat loss fifty five women participated in measurements of substrate utilisation, body composition, endothelial function, insulin sensitivity, cardiorespiratory fitness, dietary intake and habitual physical activity prior to, and after the seven week exercise intervention.

The findings from these studies confirmed that sedentary women with a family history of type 2 diabetes displayed lower insulin sensitivity than those without a parental history of diabetes. In addition, insulin resistance in this group appears to be related to a greater sensitivity to the influence of adipose tissue, particularly circulating non-esterified fatty acids and adipose tissue-derived inflammatory cytokines. In Offspring alone, baseline insulin sensitivity was associated with plasma adiponectin concentration and negatively associated with circulating non-esterified fatty acid concentration. These associations may represent physiological attempts to compensate for developing insulin resistance. Offspring also displayed an augmented metabolic response to the exercise intervention in comparison to Controls. This study showed a 23% increase in post-intervention insulin sensitivity in Offspring with no significant increase in insulin sensitivity in Controls despite a similar improvement in cardiorespiratory fitness and adherence to the exercise regime. Improved post-intervention insulin sensitivity was accompanied by reduced circulating leptin, increased fat and decreased carbohydrate oxidation in both fasting and post-glucose states. No change in diet was observed but Offspring appeared to increase their level of habitual physical activity. The magnitude of change in insulin sensitivity was associated with a parental history of diabetes, but stronger associations were observed between baseline insulin resistance and an ability to reduce circulating leptin in response to exercise. Wide individual variation in fat mass change was observed in the response to exercise, and as expected the strongest predictor of exercise-mediated fat mass reduction was the net energy cost of the intervention. However, a change in fasting respiratory exchange ratio (RER), suggesting an increase in fat oxidation was also independently associated with reduced fat mass.

The combined findings of this thesis suggest that sedentary pre-menopausal daughters of people with type 2 diabetes are more insulin resistant and that this state is, in part, a consequence of heightened sensitivity to fatty acid and inflammatory cytokine release from adipose tissue. However, it would also appear that they represent a high-risk group who are susceptible to the insulin-sensitising effects of exercise and that this may be mediated by a metabolic pathway which involves reductions in circulating leptin concentrations. Finally, the ability to lose fat mass in response to exercise is related to the energy deficit incurred by the activity but also by an individual’s ability to shift fasting substrate utilisation towards fat oxidation. Public health strategies have traditionally focused upon lifestyle interventions which are directed at the population in general. However, awareness of the risks conferred by obesity and familial history of type 2 diabetes and the potential benefits of intervention may suggest that targeting public health resources towards these high-risk groups is a more appropriate and effective strategy.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Insulin resistance, exercise, adiposity, metabolic health, offspring, leptin, fat loss,
Subjects: R Medicine > RZ Other systems of medicine
R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC1200 Sports Medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Malkova, Dr. Dalia and Gill, Dr. Jason
Date of Award: 2010
Depositing User: Dr Nicholas Dominic Barwell
Unique ID: glathesis:2010-2072
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 05 Oct 2010
Last Modified: 10 Dec 2012 13:51

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