<p>Insulin resistance has shown to be a precursor to a number of lifestylerelated chronic diseases and abnormalities in adults and is affected by a number of factors including genetics, age, physical activity and acute exercise, diet, obesity, body fat distribution and medication. Physical activity has shown to have marked effects on improving sensitivity to insulin though various physiological mechanisms, and numerous correlation studies have identified a relationship between these two variables, suggesting the beneficial role of exercise on insulin resistance.&nbsp / This study aimed to identify a relationship between current levels of physical activity, physical fitness and insulin resistance in adults between the ages of 35 and 65 years of age residing in a northern suburb community in Cape Town. A total of 186 volunteers participated in this study ranging from healthy individuals to those with diagnosed chronic conditions. Insulin resistance (determined by the homeostasis model assessment of insulin resistance), physical activity (measured by the Global Physical Activity Questionnaire) and five health-related physical fitness tests were measured. The five components included body composition, determined by body mass index and waist circumference, the 3-minute cardiorespiratory step test, the handgrip&nbsp / muscle strength test, one-minute crunches for muscle endurance and the sit-and-reach flexibility test. Spearman correlation was used to identify the relationships between the homeostasis model assessment of insulin resistance, age, body composition and physical activity and fitness.Results showed that body mass index and waist circumference were the only two variables which produced significant correlations with the homeostasis model assessment of insulin resistance (p &lt / 0.019). No physical activity or fitness data produced significant scores with the homeostasis model assessment of insulin resistance. Body mass index in men was the only significant predictor of HOMA-IR and explained 37% of the variance in insulin resistance, whereas in women, only waist circumference was related to HOMA-IR, but explained less than 16% of the variance. Associations between reported MET-minutes from the Global Physical Activity Questionnaire and the four fitness tests indicated significance with handgrip strength (&rho / = 0.17 / p =0.039), one-minute crunches (&rho / = 0.18 / p = 0.024) and sit-and-reach flexibility (&rho / = 0.17 / 0.034). This study has shown that body composition is an important component in influencing insulin resistance therefore physical activity interventions should be targeted at increasing physical activity levels and reducing body weight.</p>

The primary objective of this research was to explore the impact of glucose ingestion on 2-back task performance (accuracy, discrimination, and reaction times (RT) to target), its relationship to neural activation, using functional magnetic resonance imaging, and potential modulation by insulin resistance (IR) and low density lipoprotein (LDL) in hypertensive but otherwise healthy older adults. While there was no effect of glucose ingestion on task performance or task-relevant neural activation patterns, this study uniquely observed that IR and LDL associated with all 3 measures of 2-back performance and task-relevant neural activation patterns. The left and right precuneus, left cingulate, and left insula were identified as task-associated regions according to our specific target minus nontarget contrast. Of particular importance was the task activation in the right precuneus as it both showed sensitivity to IR and predicted task RTs to targets, suggesting it plays a modulatory role linking IR to task performance.

In recent years, studies have revealed a central role for the intestine in regulation of lipid homeostasis and development of insulin resistance and type-2 diabetes. The function of intestinal Scavenger Receptor Class-B type-I remains unknown, however it is believed to play a role in dietary lipid uptake. Recently, our laboratory demonstrated a correlation between intestinal SR-BI expression and chylomicron secretion. We hypothesized that intestinal SR-BI is involved in chylomicron secretion and contributes to chylomicron oversecretion in insulin resistance. I first characterized chylomicron production in healthy and insulin resistant Syrian golden hamsters. Inhibition of SR-BI resulted in reduced postprandial chylomicron accumulation in plasma, and resistance to diet-induced hyperlipidemia and weight-gain. Lower postprandial triglyceride levels were also observed in SR-BI-/- mice. In summary, these data demonstrate a key role for intestinal SR-BI in chylomicron secretion and control of lipid homeostasis, implicating intestinal SR-BI in chylomicron overproduction in insulin resistant states.

Stress induced hyperglycaemia is prevalent in critical care. Since the landmark paper published by Van den Berghe et al. (2001) a great deal of attention has been paid to intensive insulin therapy in an ICU setting to combat the adverse effects of elevated glucose levels and poor glycaemic control. Glycaemic control protocols have been extensively developed, tested and validated within an ICU setting. However, little research has been conducted on the effects of a glycaemic control protocol in a less acute ward setting. There are many additional challenges presented in a ward setting, such as the variation in meals and levels of activity between patients, from day to day and throughout the day. A simple compartment model is used to describe the nature of insulin and glucose metabolism in patients of the Cardiothoracic Ward (CTW). A stochastic model of the fitted insulin sensitivity parameter is generated for this cohort and validated against cohorts of similar characteristics. The stochastic model is then used to run simulations of predictive control on 7 CTW patients, which shows significantly tighter glucose control than what is obtained with regular clinical procedures. However, the rate of severe hypoglycaemia is an unacceptably high 4.2%. The greatest challenge in maintaining tight glycaemic control in such patients is the consumption of meals at irregular times and of inconsistent quantities. Insulin sensitivity was compared to extensive hourly clinical data of 36 ICU patients. From this data a sepsis score of value 0-4 was generated as gold standard marker of sepsis. Comparing the sepsis score to insulin sensitivity found that insulin sensitivity provides a negative predictive diagnostic for sepsis. High insulin sensitivity of greater than Si = 8 x 10⁻⁵ L mU⁻¹ min⁻¹ rules out sepsis for the majority of patient hours and may be determined non-invasively in real-time from glycaemic control protocol data. Low insulin sensitivity is not an effective diagnostic, as it can equally mark the presence of sepsis or other conditions.

A major cause of morbidity and early death in the Western societies is cardiovascular disease (CVD) secondary to atherosclerotic disease. Metabolic aberrations have been linked to CVD. Particular combinations of these so-called risk markers are common and (central) obesity, Type 2 diabetes, impaired glucose tolerance, hypertension, dyslipidemia, dysfibrinolysis and hyperinsulinemia are often associated. This has been entitled the Insulin Resistance Syndrome (1RS), due to underlying insulin resistance. Moreover, aberrations in circulating levels of androgens and IGF-binding proteins are associated with 1RS. The main hypothesis in this thesis was that increased levels of leptin, the recently discovered adipocyte derived hormone in combination with obesity may be an important factor in the link between 1RS and the development of CVD. The association between leptin levels and variables associated with the Insulin Resistance Syndrome was studied in a healthy sample (n=163) of middle-aged men and women from the northern Sweden MONICA health survey. Central obesity was associated with high levels of leptin and insulin in men and women. In contrast, central obesity was linked to low testosterone levels in men, whereas in women, central obesity was associated with high testosterone but low SHBG levels. Furthermore, in males and postmenopausal women central obesity was a major determinant for circulating leptin. Leptin levels were associated with biochemical androgenicity in non-obese men and women. The direction of this association was dependent on gender and body fat distribution. Specifically, testosterone was inversely associated to leptin in non-obese men and in normal weight women whereas testosterone was positively associated to leptin in non-obese women. In contrast, adiposity and insulin levels, but not testosterone, were associated to leptin in obese men and women. Similarly, leptin was associated to IGFBP-1 and proinsulin in non-obese men and premenopausal women. Hyperleptinemia was significantly associated to high PAI-1 levels in men and in centrally obese women. In a multivariate model, high leptin levels predicted PAI-1 levels in men but not in women. Finally, leptin levels were related to blood pressure in obese men. The impact of hyperleptinemia on future risk for development of CVD was tested in a nested case-referent study based on the MONICA and the Västerbotten Intervention Program surveys. It was found that hyperleptinemia and high total cholesterol levels were associated with increased risk for development of myocardial infarction whereas high levels of apolipoprotein A-l were protective. Hyperleptinemia together with hypertension remained as significant risk markers for hemorrhagic stroke whereas hypertension alone predicted ischemic stroke. The combinations of hyperleptinemia on one hand and low apolipoprotein A- 1 and high blood pressure on the other were associated with a pronounced increased risk for myocardial infarction and hemorrhagic stroke, respectively. In conclusion, hyperleptinemia is independently associated with several risk markers for CVD included in the insulin resistance syndrome. Furthermore, high leptin levels predict the development of CVD. / <p>Härtill 5 uppsatser</p> / digitalisering@umu

Apelin ist ein Adipokin, das Einfluß auf die Glukosehomöostase hat und vermutlich eine wichtige Rolle in der Regulation von Adipositas und den damit assoziierten Erkrankungen einnimmt. Die Effekte von Apelin scheinen metabolisch günstig zu sein. In dieser Arbeit wurden zunächst Apelin-Serumkonzentrationen und metabolische Parameter bei 740 Studienteilnehmern bestimmt und in einer Querschnittsstudie (n=629) sowie in drei Interventionsstudien (n=111) dargestellt. In einer Subgruppe (n=161) wurde die mRNA-Expression von Apelin und dessen Rezeptor APJ im viszeralen und subkutanen Fettgewebe bei Patienten mit Typ-2-Diabetes genauer untersucht. Im Rahmen der Interventionsstuden wurde der Einfluß von 12 Wochen körperlichem Training (n=60), 6 Monaten hypokalorischer Mischkost (n=19) und bariatrischer Chirurgie (n=32) auf den Serum-Apelinspiegel sowie Zusammenhänge mit Gewichtsreduktion, verbesserter Insulinsensitivität und subklinischer Inflammation analysiert. Die höchsten Apelin-Serumkonzentrationen fanden sich beim adipösen Typ-2-Diabetiker. Die Apelin-Serumkonzentration korrelierte aber auch unabhängig vom Bodymassindex signifikant mit Parametern für Insulinresistenz und subklinischer Inflammation. Die Apelin-Expression war in den unterschiedlichen Fettgewebsdepots bei normal glukosetoleranten Patienten gleich, beim Typ-2-Diabetiker mit insgesamt höherer Expression überwog sie im viszeralen Fettgewebe. Nach allen Interventionsstudien kam es zur Abnahme der Apelin-Serumkonzentration und korrelierte auch dann signifikant mit einer verbesserten Insulinsensitivität, wenn es zu keiner Gewichtsreduktion kam. Die Apelinkonzentration im Serum sowie die Expression im Fettgewebe ist nicht nur vom Bodymassindex abhängig, sondern steht im direkten Zusammenhang mit Insulinsensitivität und inflammatorischen Prozessen. Die unterschiedliche fettdepotspezifische Regulation unterstreicht die pathogenetische Bedeutung eines „kranken“ viszeralen Fettgewebes in der Entwicklung von Typ-2-Diabetes, wobei Apelin als metabolisch günstiges Adipokin vermutlich eine kompensatorische Rolle einnimmt.

Background: The augmented whole body glucose uptake response to insulin during the postprandial state is described as meal-induced sensitization (MIS). MIS occurs when the presence of food in the upper gastrointestinal tract (GIT) activates two feeding signals (activation of hepatic parasympathetic nerves and elevation of hepatic glutathione level), and causes insulin to release hepatic insulin sensitizing substance (HISS), which stimulates glucose uptake in peripheral tissues. The impairment of HISS release results in the absence of meal-induced insulin sensitization (AMIS), causing progression to a cluster of metabolic, vascular, and cardiac dysfunction, which we refer to as components of the AMIS syndrome. Objectives: The objective of my doctoral research was to study the manipulation of the HISS-pathway, in age- and diet-induced AMIS models, with exercise ± antioxidants. Also, in a separate project I studied the signaling pathways involved with the HISS action in skeletal muscle. Methods: The 7-day voluntary running was used as exercise intervention to manipulate the HISS pathway in healthy and prediabetic rats. The interaction of an antioxidant cocktail, SAMEC (S-adenosylmethionine + vitamin E + vitamin C), with the effects of exercise on postprandial insulin response was studied. Moreover, in the signaling studies the insulin and 5'-adenosine monophosphate activated protein kinase (AMPK) pathways were examined to test their possible involvement with the HISS action in skeletal muscle. Results: Voluntary running-wheel exercise for 7 days increases the postprandial glucose uptake response to insulin in health and in prediabetes through enhancement/restoration of HISS action. Supplementation with SAMEC during 7 days of exercise does not either harm or add benefits to the positive effects of exercise on insulin sensitivity. Finally, the signaling studies indicate that HISS increases the rate of glycogen synthesis in muscle through an insulin/AMPK-independent pathway.

Despite inconsistent results in the literature, high protein diets are being promoted for the management of metabolic syndrome parameters primarily due to their proposed favorable effects on weight loss. Therefore, lean and fa/fa Zucker rats were given normal and high protein diets with varying protein sources for 12 weeks. A high protein diet with a mixture of animal and plant protein sources was the most effective for improving metabolic syndrome parameters, specifically insulin resistance and hepatic steatosis. A high protein soy diet was the second most effective diet, while a high protein casein diet demonstrated no benefits compared to the other two high protein diets and minimal benefits compared to a normal protein casein diet. Interestingly, high protein diets did not affect body weight regardless of protein source. These findings suggest that the source of protein within a high protein diet is critical for improving metabolic syndrome parameters and that improvements can be observed independent of weight loss.

Insulin resistance is commonly developed in obesity and is a trait of the beginning stage of type 2 diabetes mellitus (DM). It is highly likely that the high plasma fatty acid levels provoke the condition in the obese and insulin resistant state of type 2 DM. Hence, the purpose of this study was to determine if a high concentration of palmitic acid causes insulin resistance and how ceramide content is regulated under the various conditions in the isolated rat soleus muscle. A submaximal insulin stimulus (100 ,aU/ml) increased 3-O-methylglucose transport by -2.7 fold over basal conditions in the soleus (1.90 ± 0.23 µmol•ml"1•hr-1 vs. 5.06 ± 0.38 µmol•ml-1•hr-1, respectively) (P < 0.05). Five hours of palmitic acid preincubation induced a significant decrease in insulin-stimulated glucose transport (3.49 ± 0.11 µmol•ml-1•hr-1) by -31 % (P < 0.05) compared with the control. By contrast, the addition of L-cycloserine, a serine palmitoyltransferase inhibitor, attenuated the palmitic acid response by -20% (4.19 ± 0.27 µmol•ml-1•hr-1) (P < 0.05). A 5 hr preincubation with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an adenosine analogue that increase AMP activated protein kinase, increased glucose transport (3.29 ± 0.1 µmol•ml-1•hr-1) (P < 0.05) compared with the control group. Moreover, regardless if palmitic acid or L-cycloserine were present, insulin-stimulated glucose uptake was normalized (5.30 ± 0.38 µmol•ml-1•hr-1 and 5.56 ± 0.16 µmol•ml"1•hr-1, respectively) after 5 hr AICAR preincubation. We next measured the ceramide content to investigate whether the reduced glucose uptake results from ceramide accumulation in the soleus. The total ceramide mass in the soleus was increased by -35% in palmitic acid-treated group compared with the control group (122.02 ± 2.07 pmol•mg-1 vs. 90.79 + 1.24 pmol•mg 1, respectively) (P<0.05). Both L-cycloserine and AICAR decreased palmitateinduced ceramide synthesis by -20% and -14%, respectively (97.15 + 2.5 pmol•mg-1 and 105.79 ± 1.94 pmol•mg-1, respectively) (P<0.05) compared with the palmitic acid-treated group. We also measured serine palmitoyltransferase (SPT) to determine if AICAR regulates ceramide synthesis by inhibiting SPT. Total SPT protein level increased by -27% (P<0.05) and SPT activity increased by -44% (P<0.05) compared with the control group. By contrast, after muscles were incubated with L-cycloserine for 5 hr, both SPT protein level and enzyme activity were decreased by -17% and -23%, respectively (P<0.05). In adition, 5 hr AICAR treatment blunted palimitic acid-induced SPT protein level and enzyme activity by 11% (P<0.05) and 20% (P<0.05), respectively, compared with the palmitic acid-treated group. In conclusion, these data suggest that short term exposure (5 hr) to high fatty acid levels appears to cause insulin resistance by increasing ceramide accumulation and that AMPK expression (AICAR treatment) can attenuate the problem by regulating SPT levels. / School of Physical Education, Sport, and Exercise Science

Motivation: The metabolic syndrome is characterized by a group of risk factors for cardiovascular disease (CVD) that includes obesity, dyslipidemia, high blood pressure, insulin resistance, glucose intolerance or non-insulin dependant diabetes mellitus, pro-thrombotic state and pro-inflammatory state. The NHANES I11 study showed the prevalence of this syndrome to be 24.0% in men and 23.4% in women in the USA. These figures translate to more than 47 million US residents having the metabolic syndrome. In the THUSA (acronym for Transition and Health in the Urbanization of South Africans) study in South Africa it was found that 12% and 28.4% of men and women, respectively, of the black population of the North West Province had three or more disturbances characterizing this syndrome. Therefore, it is evident that the metabolic syndrome is a health problem not only for developed countries but also for developing countries. As a result, this syndrome has been identified as a target for dietary therapies to reduce the risk of CVD and type 2 diabetes. Epidemiological studies have consistently demonstrated an inverse association between nut consumption and coronary heart disease (CHD) morbidity and mortality in different population groups. Nut consumption may not only offer protection against heart disease, but also increase longevity. Recently, the benefits of nuts consumption were acknowledged by the U.S. Food and Drug Administration when they approved a qualified health claim that eating nuts (1.5 ounces/day ≈ 42.8 g/day) may reduce the risk of CHD. In this regard, the most comprehensively studied mechanism involved the favourable lipid lowering effects of nuts. There is, however, a lack of data in the literature regarding the effect of nuts on the metabolic syndrome. Objective: The main objective of this study was to examine the effects of a high walnut diet and a high unsalted cashew nut diet on markers of the metabolic syndrome in humans. In order to provide a foundational body of evidence for the aforementioned, a secondary objective included conducting a systematic review that investigates the effects of nuts on the lipid profile. Methods: The main project consisted of a controlled feeding trial with a parallel, randomized controlled study design on participants having the metabolic syndrome. Sixty-four subjects having this syndrome (29 men, 35 women) with a mean (±SD) age of 45±10 y and who met with the selection criteria were all fed a 3-week run-in control diet. After this period, participants were grouped according to gender and age and then randomized into three groups, namely, those that received a controlled feeding diet including walnuts (20% energy (E), 60-100g/day; protein:carbohydrate:fat=18:42:40%E). or unsalted cashew nuts (20%E 66- 1 15g/day; protein:carbohydrate:fat=l9:44:37%E) or no nuts (protein:carbohydrate:fat=20:47:33%E) for 8 weeks. The participants' physical activity and weight were maintained for the duration of the study. For the systematic review. human intervention trials that investigated the independent effects of nuts on lipid concentrations were included. Medline and Web of Science databases were searched from the start of the database to August 2004 and supplemented by cross-checking reference lists of relevant publications. These papers received a rating based upon the methodology as it appeared in the publication. No formal statistical analysis was performed due to the large differences in study designs of the dietary intervention trials. The main outcome measures for the systematic review, were percentage differences between treatment and control groups for total blood cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDL-C) and triacyglycerols (TG). Results: Regarding the main objective, we found that both the walnut and unsalted cashew nut intervention diets had no significant effect on the lipid profile, serum fructosamine, insulin, insulin sensitivity, insulin resistance, serum high sensitivity C-reactive protein, blood pressure and serum uric acid concentrations when compared to the control dict. All three groups experienced highly significant increases in serum insulin concentrations when comparing the baseline to end (P<0.05). In turn, insulin resistance increased while insulin sensitivity decreased in all three groups. Plasma glucose concentrations increased significantly in the cashew nut group compared to the control group (P<0.05). By contrast, serum fructosamine was unchanged in the cashew nut group while the control group had significantly increased concentrations of this short-term marker of glycaemic control. The literature search for the systematic review yielded 41 5 publications. After screening, 23 nut studies were included in the review with most of these studies including heart-healthy diets. The majority of the studies were short (4-6 weeks) with only one study lasting 6 months. The number of subjects in most of the studies was sufficient to study the effects on TC and LDL-C but not for HDL-C and TG. The results of three almond (50-100g/day), two peanut (35-68g/day), one pecan nut (72g/day) and four walnut (40-84g/day) studies showed convincing evidence for a lipid lowering effect of TC between 2-1 6% and LDL-C between 2- 19%, when compared to their control diets. Currently, there are indications from inadequately designed intervention studies that hazelnuts (lg/day/kg body weight) and pistachios (20%E) may have a lipid lowering effect. At this stage the evidence for macadamia nuts is less convincing. Furthermore, it is apparent that the components in nuts further reduce TC and LDL-C concentrations beyond the effects predicted by equations based solely on dietary fatty acid profiles. Conclusions: In the controlled feeding trial, subjects displayed no improvement in the markers of the metabolic syndrome after following a walnut or unsalted cashew nut diet compared to a control diet while maintaining body weight (8 weeks). Finally, we suspect that the dramatic increase in insulin resistance may have masked the protective effects of the walnut and cashew nut diets in our subjects with the metabolic syndrome Further research is warranted before a consensus can be reached. From the systematic review it was concluded that the consumption of ≈50-100g (≈1.5-3.5 servings) of nuts five or more times/week as part of a heart-healthy diet with total fat content (high in mono- and /or polyunsaturated fatty acids) of ≈ 35% of energy may significantly decrease TC and LDL-C in normo- and hyperlipidemic individuals. Recommendations: A similar nut controlled feeding trial with some form of calorie restriction, should be done on participants having the metabolic syndrome. Future research should use randomized controlled studies with larger sample sizes and longer duration to investigate the effects of nuts on HDL-C and TG concentrations. Also, studies should investigate the effects on the lipid profile of mixed nuts and those individual nuts not yet considered. In addition, the unique nutrient and non-nutrient composition of nuts requires further research in order to elucidate the possible mechanisms responsible for the LDL-C lowering effect / Thesis (Ph.D. (Nutrition))--North-West University, Potchefstroom Campus, 2005.