<p>The glycaemic responses to various carbohydrate-rich foods are partly dependent on the rate at which the carbohydrate is digested and absorbed. The glycaemic index (GI) is a way of ranking foods according to their glycaemic response and is recommended as a useful tool in identifying starch-rich foods that give the most favourable glycaemic response. This investigation was undertaken to determine whether carbohydrate-rich foods with a low GI and a high content of dietary fibre (DF) could have beneficial metabolic effects in the insulin resistance syndrome. This question was addressed both in single-meal studies and in randomised controlled clinical trials. Starch-rich foods with low GI values incorporated into composite meals resulted in lower postprandial responses of both glucose and insulin than foods with a high GI in meals with an identical macronutrient and DF composition, in subjects with type 2 diabetes. After three weeks on a diet including low GI starchy foods metabolic profile was improved in subjects with type 2 diabetes, compared with a corresponding high GI diet. The glucose and insulin responses throughout the day were lower, the total and low density lipoprotein cholesterol was decreased, and the fibrinolytic activity was normalised. In subjects with impaired insulin sensitivity and diabetes low GI foods rich in soluble DF for breakfast gave a more favourable metabolic profile, with smaller glucose fluctuations from baseline during the day, than a breakfast with high GI foods low in DF. A low GI breakfast high in DF also resulted in lower responses of insulin and C-peptide after breakfast and a lower triacylglycerol response after a standardised lunch. However, none of the tested breakfasts improved the glucose and insulin responses after lunch. Similar results were obtained in obese subjects after including a breakfast with a low GI high in soluble DF for a period of four weeks in comparison with a breakfast with a high GI and low content of DF.</p><p>These results support the therapeutic potential of a diet with a low GI in the treatment of diabetes and also in the treatment of several of the metabolic disturbances related to the insulin resistance syndrome.</p>

<p>During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world.</p><p>The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality.</p><p>The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM).</p><p>The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture. </p><p>It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI. </p><p>The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. </p><p>A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.</p><p>In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.</p>

<p>Congestive heart failure (CHF) is a major cause of morbidity and mortality and the identification of modifiable risk factors is crucial in order to diminish suffering of this common disease. </p><p>The primary aim of this thesis was to investigate novel metabolic risk factors for CHF, with a focus on insulin resistance and inflammation. The secondary aim was to examine the validity of the CHF diagnosis in the Swedish hospital discharge register.</p><p>This thesis was based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, a community-based prospective study started in 1970. The participants were examined at age 50 and 70 and the data was completed with annual updates on mortality and in-hospital morbidity using national registers. </p><p>We showed that insulin resistance predicts CHF incidence independently of established risk factors in both middle-aged and elderly men. The previously described association between obesity and subsequent CHF may be mediated partly by insulin resistance. Moreover, it was established that inflammation, measured as erythrocyte sedimentation rate is a significant predictor of CHF, independent of established risk factors including an interim myocardial infarction. Furthermore, a low beta-carotene level, as well as an increased apolipoprotein B/A-I-ratio was found to predict CHF independently of established risk factors.</p><p>We also showed that the validity of the CHF diagnosis in the Swedish hospital discharge register appears less precise than for other recently investigated cardiovascular diagnoses. However, when including only cases from selected clinics or cases with a primary diagnosis of CHF, the validity is comparable to the above diagnoses. </p><p>In conclusion, insulin resistance and inflammation are strong independent risk factors for the development of CHF, and seem to be involved in the early process leading to CHF. If confirmed, our observations could have large clinical implications as they may offer new approaches in the prevention of CHF.</p>

<p>Many elderly undergo cardiac surgery. The prevalence of malnutrition in elderly is high and increases with comorbidity. This thesis aims to clarify some aspects on performing surgery in elderly concerning nutritional status, nutritional treatment and age-related physiology.</p><p>Study I: 886 patients were assessed preoperatively by body mass index (BMI) and S-albumin and postoperatively for mortality and morbidity.. Low BMI increased the relative hazard for death and low S-albumin increased the risk for infection. BMI and S-albumin are useful in preoperative evaluations</p><p>Study II: we followed energy intake in 31 patients for five postoperative days. Scheduled and unscheduled surgery did not differ in preoperative resting energy expenditure (REE). REE increased by 10-12% postoperatively, more in unscheduled CABG. Nutritional supplementation increased total energy intake. All patients exhibited postoperative energy deficits, less prominent in the supplemented group. There were no differences in protein synthesis or muscle degradation. </p><p>Study III: in 16 patients, .we measured stress hormones and insulin resistance before surgery and for five postoperative days Patients were insulin resistant on the first two days. We saw no clearly adverse or beneficial effects of oral carbohydrate on insulin resistance or stress hormone response. </p><p>Study IV: 73 patients, with early enteral nutrition (EN), were observed until discharge or resumed oral nutrition. EN started within three days in most patients. In a minority, problems occurred (gastric residual volumes, tube dislocation, vomiting, diarrhoea, aspiration pneumonia). In the cardiothoracic ICU individually adjusted early EN is feasible. </p><p>Study V: in 16 patients, splanchnic blood flow (SBF) enhancing treatments (dopexamine (Dpx) or EN) were compared. Dpx increased systemic blood flow, but had only a transient effect on SBF. EN had no effect on systemic blood flow or SBF. Neither Dpx, EN or the combined treatment, exhibited any difference between groups on systemic or splanchnic VO₂ or oxygen extraction ratio. </p>

Obesity is a major health problem in the United States and worldwide. It increases the risk for type-2 diabetes and cardiovascular diseases. A chronic low-grade inflammation occurring in white adipose tissue (WAT) is causally linked to the development of insulin resistance (IR), metabolic syndrome and obesity-associated chronic diseases. The aim of this dissertation research was to elucidate the WAT function in metabolic syndrome using genetic (overexpression of an adipose pro-inflammatory hormone, angiotensinogen) and nutritional manipulations/approaches (caloric restriction and omega-3 fatty acids), with specific emphasis on the role of inflammation. Previous research indicates that WAT renin-angiotensin system (RAS) is overactivated in obesity. However, its role in the pathogenesis of IR is hitherto unknown. Using mice overexpressing angiotensinogen (Agt), the only precursor for the hypertensive hormone angiotensin (Ang) II, in WAT, we showed that adipose-specific RAS overactivation leads to systemic IR. This is at least in part due to Ang II, NADPH oxidase and NF-kB-dependent increases in WAT inflammation. Caloric restriction is the main dietary intervention to treat obesity-associated metabolic disorders. While most health agencies recommend a low-fat diet, energy-restricted high-fat diets (HFR) are also claimed to be effective in this regard. Here, we show that weight loss due to HFR is accompanied by improvements of IR but only partial resolution of WAT inflammation. Further, this diet negatively impacted the adipokine profile supporting the current recommendations for low-fat diets. Dietary interventions targeted at reducing WAT inflammation have not been explored in detail. Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid of marine origin with anti-inflammatory properties. We show that EPA is able to both prevent and reverse high-fat diet-induced IR and hepatic steatosis via modulation of WAT inflammation. In conclusion, primary changes occurring in WAT, such as overexpression of Agt, can lead to WAT inflammation and systemic IR. Moreover, nutritional interventions targeting at reducing adiposity (caloric restriction) and inflammation (EPA) can both lead to improvements in systemic IR. Our findings support the current recommendation of low-fat diets for improvement in metabolic profile and show that dietary modulation of WAT function can be used to improve metabolic derangements in obesity.

<p>Conclusion of this study: These data suggest that 6 weeks of high-fat feeding induces hypertension but does not produce obesity, dyslipidemia and insulin resistance. However, this model may be useful in studying vascular reactivity in hypertension in the absence of insulin resistance.</p>

Skeletal muscle accounts for the largest part of insulin-mediated glucose uptake. Insulin resistance (IR) is the main component of insulin resistance syndrome (IRS) and is an essential cause of a number of cardiovascular risk factors. This thesis investigates the relationships between muscle morphological characteristics and IRS because skeletal muscle is responsible for the majority of glucose uptake. In this population-based sample of 70-year-old men, higher proportion of type I fibers as well as higher capillarization were related to higher insulin sensitivity and higher self-reported physical activity, which were related to a lower prevalence of type IIB fibers. Serum triglycerides, HDL cholesterol and plasminogen activator inhibitor-1 (PAI-1) activity were significantly related to fiber distribution and muscle capillarization and muscle morphology, in part, explained the association between these metabolic risk factors with physical activity level. BMI, glucose intolerance, PAI-1 activity, serum FFA concentration, proportion of type IIB fibers, HDL cholesterol level, drug treatment, physical activity level, and W/H ratio together explained 55% of the variation in the insulin sensitivity index. In addition, almost a twofold improvement of the correlations was seen after correcting for intraindividual variation. Glucose tolerant hypertensive subjects showed a lower capillary supply when compared to controls. Capillary density was negatively correlated to the increase in mean arterial pressure over two decades as well as to supine heart rate 20 years before. Interestingly, supine heart rate showed an independent inverse association to the percentage of type I fibers and a positive correlation to the percentage of type IIB muscle fibers. Capillary density and elevated serum free fatty (FFA) acid values were inversely associated with insulin-mediated blood flow and thus to endothelial dysfunction, which has been linked to IR. In fact, capillary density and serum FFA level together explained 71% of the variation in insulin-mediated leg blood flow changes. In conclusion, these population-based findings support the observations that muscle morphological features and insulin sensitivity are related to each other. Muscle morphology might explain some of the beneficial impact of physical activity on the components of IRS. Accordingly, we suggest that alterations in muscle morphology should be considered as an essential part of the IRS.

The glycaemic responses to various carbohydrate-rich foods are partly dependent on the rate at which the carbohydrate is digested and absorbed. The glycaemic index (GI) is a way of ranking foods according to their glycaemic response and is recommended as a useful tool in identifying starch-rich foods that give the most favourable glycaemic response. This investigation was undertaken to determine whether carbohydrate-rich foods with a low GI and a high content of dietary fibre (DF) could have beneficial metabolic effects in the insulin resistance syndrome. This question was addressed both in single-meal studies and in randomised controlled clinical trials. Starch-rich foods with low GI values incorporated into composite meals resulted in lower postprandial responses of both glucose and insulin than foods with a high GI in meals with an identical macronutrient and DF composition, in subjects with type 2 diabetes. After three weeks on a diet including low GI starchy foods metabolic profile was improved in subjects with type 2 diabetes, compared with a corresponding high GI diet. The glucose and insulin responses throughout the day were lower, the total and low density lipoprotein cholesterol was decreased, and the fibrinolytic activity was normalised. In subjects with impaired insulin sensitivity and diabetes low GI foods rich in soluble DF for breakfast gave a more favourable metabolic profile, with smaller glucose fluctuations from baseline during the day, than a breakfast with high GI foods low in DF. A low GI breakfast high in DF also resulted in lower responses of insulin and C-peptide after breakfast and a lower triacylglycerol response after a standardised lunch. However, none of the tested breakfasts improved the glucose and insulin responses after lunch. Similar results were obtained in obese subjects after including a breakfast with a low GI high in soluble DF for a period of four weeks in comparison with a breakfast with a high GI and low content of DF. These results support the therapeutic potential of a diet with a low GI in the treatment of diabetes and also in the treatment of several of the metabolic disturbances related to the insulin resistance syndrome.

During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world. The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality. The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM). The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture. It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI. The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors. In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.

Congestive heart failure (CHF) is a major cause of morbidity and mortality and the identification of modifiable risk factors is crucial in order to diminish suffering of this common disease. The primary aim of this thesis was to investigate novel metabolic risk factors for CHF, with a focus on insulin resistance and inflammation. The secondary aim was to examine the validity of the CHF diagnosis in the Swedish hospital discharge register. This thesis was based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, a community-based prospective study started in 1970. The participants were examined at age 50 and 70 and the data was completed with annual updates on mortality and in-hospital morbidity using national registers. We showed that insulin resistance predicts CHF incidence independently of established risk factors in both middle-aged and elderly men. The previously described association between obesity and subsequent CHF may be mediated partly by insulin resistance. Moreover, it was established that inflammation, measured as erythrocyte sedimentation rate is a significant predictor of CHF, independent of established risk factors including an interim myocardial infarction. Furthermore, a low beta-carotene level, as well as an increased apolipoprotein B/A-I-ratio was found to predict CHF independently of established risk factors. We also showed that the validity of the CHF diagnosis in the Swedish hospital discharge register appears less precise than for other recently investigated cardiovascular diagnoses. However, when including only cases from selected clinics or cases with a primary diagnosis of CHF, the validity is comparable to the above diagnoses. In conclusion, insulin resistance and inflammation are strong independent risk factors for the development of CHF, and seem to be involved in the early process leading to CHF. If confirmed, our observations could have large clinical implications as they may offer new approaches in the prevention of CHF.