Identifying the relationship between fat oxidation and insulin resistance (IR) may provide vital clues to the mechanisms behind the development of metabolic disease in prepubertal children. The purpose of this study was to examine the association of fat oxidation with insulin resistance (IR) and insulin sensitivity (SI) in prepubertal children. A total of 34 prepubertal 7-9 year olds (18 females, 16 males, 13 non-Caucasian, 21 Caucasian, 8.0±0.8 years, 36.5±12.1 kg) were observed. Subjects participated in indirect calorimetry to obtain respiratory quotient (RQ) and a blood test to obtain fasting insulin and glucose to calculate IR by homeostatic model assessment (HOMA). A subset (n=16) participated in Frequently Sampled Intravenous Glucose Tolerance Testing (FSIGTT) to obtain insulin sensitivity. Pearson correlations between RQ and IR and RQ and SI were performed. Partial correlations with respect to physical activity, breastfeeding, and birth weight were also performed. A general linear model was used to examine RQ with IR, and separately SI with respect to physical activity, breastfeeding, birth weight, race and sex. Respiratory quotient and IR were significantly associated when adjusted for physical activity, sex and race and breastfeeding, sex and race. In regards to birth weight, RQ and IR were significantly associated when adjusted for breastfeeding, birth weight, and race, but not when breastfeeding was removed from the model. The results of this study suggest lack of physical activity and breastfeeding may be the most influential risk for factors in the development of IR via a mechanism of impaired fat oxidation. Further research is needed to examine the role of physical activity, breastfeeding, and birth weight on fat oxidation and the development of insulin resistance in prepubertal children, however, the results of this study support the promotion of physical activity, breastfeeding, and good maternal nutrition.

Despite clear recommendations on the minimal amount of physical activity for achieving health benefits and reducing risk of chronic disease, the majority of people in the Western world remain sedentary. As a 'lack of time' has been identified as one of the main barriers to becoming and remaining physically active, in the past decade research has focused on high-intensity interval training (HIT) as a time-efficient alternative to aerobic exercise. Although initial studies convincingly demonstrated equal or better health benefits with various HIT protocols compared to much larger volumes of aerobic exercise, these HIT protocols tend to be very strenuous and as such are unlikely to be adhered to by sedentary populations. Furthermore, most HIT protocols are not as time-efficient as sometimes claimed, with the total time per exercise session generally exceeding 20-30 minutes. This thesis aimed to characterise the effects of a novel reduced-exertion HIT (ReHIT) protocol, requiring a maximum of 2 x 20 s all-out sprint efforts in a 10 min training session, upon insulin sensitivity, aerobic capacity, glycogen utilisation and associated acute metabolic responses. The ReHIT exercise bouts were well tolerated by participants, but were associated with a substantial disturbance of physiological homeostasis including muscle glycogen degradation, lactate accumulation, excursions in plasma volume, post-exercise oxygen consumption, respiratory exchange ratio and heart rate, as well as a skeletal muscle signalling response through AMPK, and increases in skeletal muscle GLUT4 and PGC1α mRNA expression (Chapter 4 and 5). The combined training studies (n=49) provide some support for improvements in key disease biomarkers following ReHIT, with improvements in insulin sensitivity observed in men, and increased aerobic capacity observed in men and women (Chapter 7). These observations highlight a potential regulatory role for glycogen in exercise-induced adaptation. However, the mean improvements in insulin sensitivity in men were not consistent between the two training studies (Chapter 2 and 6), and there was a high level of variability observed between individuals (Chapter 6 and 7). Therefore, the impact of ReHIT on insulin sensitivity needs to be further explored in the context of a randomised controlled trial, and the mechanisms underpinning the large variability in adaptive response need to be characterised.

<p>In this thesis, different aspects of the insulin resistance syndrome in relation to plasminogen activator inhibitor-1 (PAI-1) activity are investigated in a longitudinal population-based study. Participants were men investigated at ages 50 and 70 with follow-up data on mortality.</p><p>High PAI-1 activity was associated with low insulin sensitivity, high concentrations of serum triglycerides, high body mass index and high waist/hip ratio, independently of each other and of potential confounders. Low birth weight predicted high blood pressure, insulin resistance, truncal obesity and high PAI-1 activity but not the abdominal obesity or dyslipidaemia present in the insulin resistance syndrome. Increased physical activity level between 50 and 70 years of age, in the absence of active intervention, was associated with improved glucose, insulin, proinsulin and lipoprotein metabolism. Insulin and proinsulin seemed to be important factors that mediate much of the association between a sedentary lifestyle and increased risk of cardiovascular disease. The reported dietary intake of both mono- and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas saturated fatty acid intake displayed no association. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters were partly influenced by factors related with the insulin resistance syndrome.</p><p>This thesis provides further knowledge to the epidemiological view of the interrelations of the insulin resistance syndrome, PAI-1, birth weight, and lifestyle factors as physical activity and dietary habits. PAI-1 is a part of the insulin resistance syndrome and is associated both with modifiable and non-modifiable factors related with this syndrome.</p>

<p>Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases.</p><p>In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated.</p><p>In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium.</p><p>In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.</p>

Background Excess adipose tissue and low physical activity are two major determinants for chronic diseases such as type 2 diabetes and cardiovascular disease.  Understanding these relationships requires accurate and precise measures of body composition and physical activity, and most existing observational studies lack such measures. Paper I to III in this thesis addresses the validity of measures of physical activity and abdominal adipose mass. In paper IV and V, we explore the relationships between obesity and physical activity on metabolic health in non-pregnant and pregnant women and their offspring. Methods and Results Two hundred men and women representative of the Northern Sweden EPIC cohort were recruited for Paper I. A questionnaire on physical activity (PAQ) was validated against objectively measured physical activity energy expenditure (PAEE). A categorical physical activity index (Cambridge index) calculated from PAQ showed strongest correlation with PAEE (r=0.33 p&lt;0.05). In Paper II, abdominal adiposity were assessed in 29 adult men and women using anthropometric measurements, dual energy x-ray absorptiometry (DXA) and ultrasound and were compared to computed tomography (CT). Waist circumference showed the highest correlation with CT-assessed visceral (r=0.85, p&lt;0.0001) and subcutaneous adipose tissue (r=0.86, p&lt;0.0001). Adipose thickness was best assessed with ultrasound. In Paper III, the validity of a wrist-worn triaxial accelerometer was assessed in 32 pregnant and 74 non-pregnant women using double-labeled water method (DLW) as the criterion measure. The output from the accelerometer explained 24% (p &lt;0.001) of the variation in PAEE in non-pregnant and 11% (p&lt;0.05) in the pregnant women. In Paper IV, 35 pregnant and 73 non-pregnant women underwent a 75g oral glucose tolerance test and habitual energy expenditure and physical activity was assessed objectively. Total physical activity was inversely associated with early insulin response in both pregnant (r=-0.47, p=0.007) and non-pregnant (r=-0.36, p=0.004) women. In, Paper V, 32 women and their offspring (n=33) were studied 4 months post-partum. Body composition was quantified using DXA in the women and air-displacement plethysmography  in the infants. Mid-pregnancy weight gain was significantly associated with infant fat mass (r=0.41, p=0.022), whereas late-pregnancy weight gain associated to infant fat-free mass (r=0.37, p=0.04). Conclusion This work describes new methods as well as conventional anthropometric estimates and a questionnaire, that provide relatively strong estimates of body composition and physical activity which could be used in larger studies. Pregnant women were shown to have more sedentary behavior than non-pregnant but physical activity appeared to have equal effect on glucose homeostasis in both groups, which may help guide lifestyle interventions in pregnancy. The impact of weight gain during the different trimesters seems to differentially affect the offspring’s body composition in early infancy, which might give us clues to when different aspects of fetal development and growth occur and how modifiable lifestyle behaviors might be intervened upon to improve long-term health. / Embargo

In this thesis, different aspects of the insulin resistance syndrome in relation to plasminogen activator inhibitor-1 (PAI-1) activity are investigated in a longitudinal population-based study. Participants were men investigated at ages 50 and 70 with follow-up data on mortality. High PAI-1 activity was associated with low insulin sensitivity, high concentrations of serum triglycerides, high body mass index and high waist/hip ratio, independently of each other and of potential confounders. Low birth weight predicted high blood pressure, insulin resistance, truncal obesity and high PAI-1 activity but not the abdominal obesity or dyslipidaemia present in the insulin resistance syndrome. Increased physical activity level between 50 and 70 years of age, in the absence of active intervention, was associated with improved glucose, insulin, proinsulin and lipoprotein metabolism. Insulin and proinsulin seemed to be important factors that mediate much of the association between a sedentary lifestyle and increased risk of cardiovascular disease. The reported dietary intake of both mono- and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas saturated fatty acid intake displayed no association. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters were partly influenced by factors related with the insulin resistance syndrome. This thesis provides further knowledge to the epidemiological view of the interrelations of the insulin resistance syndrome, PAI-1, birth weight, and lifestyle factors as physical activity and dietary habits. PAI-1 is a part of the insulin resistance syndrome and is associated both with modifiable and non-modifiable factors related with this syndrome.

Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases. In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated. In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium. In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.

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PI3K signaling in pancreatic β cells has been shown to be important in modulating β cell mass and function under basal condition. Evidence suggests that a specific group of insulin promoter-expressing neurons also modulates glucose metabolism and energy homeostasis through their PI3K signaling. Thus we hypothesize that PI3K activation via PTEN deletion under the control of rat insulin promoter (RIP) in pancreatic β cells and RIP-expressing neurons will protect against hyperglycemia and diabetes in experimentally induced mouse models of type 2 diabetes. In Chapter IV, we showed that RIP-mediated PTEN deletion in pancreatic β cells led to PI3K activation and subsequent increased β cell mass and function, thus protected the mice from high fat diet (HFD)-induced diabetes. Furthermore in the absence of global leptin signaling, β cell-specific PTEN deletion maintained β cell function in the setting of severe insulin resistance, therefore prevented diabetes development. Interestingly, RIP-mediated PTEN deletion also resulted in increased peripheral insulin sensitivity due to PI3K activation in central nervous system. In Chapter V, we showed this increased insulin sensitivity was maintained after HFD feeding, which also contributed to the protection against diabetes. These mice also showed increased visceral adipogenesis and subcutaneous adiposity on HFD, which were dramatically attenuated in the absence of leptin signaling, indicated the essential role of peripheral leptin action in mediating the insulin sensitive phenotype from neuronal RIP PTEN deletion. Finally, we demonstrated that the insulin sensitizing phenotype in these mice was not mediated through ventromedial hypothalamic nuclei (VMH), such that VMH-specific PTEN deletion did not alter energy homeostasis or glucose metabolism. Together, the data from this thesis points to an inhibitory role of PTEN in both central nervous system and pancreatic β cells in glycemic control. Therefore, PTEN may represent a potential target for diabetes prevention and treatment.

PI3K signaling in pancreatic β cells has been shown to be important in modulating β cell mass and function under basal condition. Evidence suggests that a specific group of insulin promoter-expressing neurons also modulates glucose metabolism and energy homeostasis through their PI3K signaling. Thus we hypothesize that PI3K activation via PTEN deletion under the control of rat insulin promoter (RIP) in pancreatic β cells and RIP-expressing neurons will protect against hyperglycemia and diabetes in experimentally induced mouse models of type 2 diabetes. In Chapter IV, we showed that RIP-mediated PTEN deletion in pancreatic β cells led to PI3K activation and subsequent increased β cell mass and function, thus protected the mice from high fat diet (HFD)-induced diabetes. Furthermore in the absence of global leptin signaling, β cell-specific PTEN deletion maintained β cell function in the setting of severe insulin resistance, therefore prevented diabetes development. Interestingly, RIP-mediated PTEN deletion also resulted in increased peripheral insulin sensitivity due to PI3K activation in central nervous system. In Chapter V, we showed this increased insulin sensitivity was maintained after HFD feeding, which also contributed to the protection against diabetes. These mice also showed increased visceral adipogenesis and subcutaneous adiposity on HFD, which were dramatically attenuated in the absence of leptin signaling, indicated the essential role of peripheral leptin action in mediating the insulin sensitive phenotype from neuronal RIP PTEN deletion. Finally, we demonstrated that the insulin sensitizing phenotype in these mice was not mediated through ventromedial hypothalamic nuclei (VMH), such that VMH-specific PTEN deletion did not alter energy homeostasis or glucose metabolism. Together, the data from this thesis points to an inhibitory role of PTEN in both central nervous system and pancreatic β cells in glycemic control. Therefore, PTEN may represent a potential target for diabetes prevention and treatment.