BACKGROUND. Polycystic ovarian syndrome is one of the commonest endocrinopathies in women of reproductive age. The prevalence of the disease is estimated to be around 5 % in general population (Azziz, 2004). Literature on the prevalence of PCOS in Black women is limited (Knochenhauer, 1998). This syndrome is a diagnostic conundrum due to the phenotypic variability of these women. The PCOS woman also has a greater disposition for impaired glucose homeostasis as well as hyperlipidaemia. OBJECTIVE. The hormonal and metabolic profiles of South African women with PCOS have not been described. Ethnic differences in the prevalence of PCOS have also not been well explored. Our study aims to describe and compare the phenotypic profile of African and Indian women with PCOS and to determine the frequency of insulin resistance and hyperlipidaemia in these women. METHODS. A retrospective audit of all patients attending gynaecology endocrine and infertility clinics over the period June 2005 to June 2009 was carried out. The biochemical and clinical profiles were analysed and a comparative analysis between the two largest groups, Indian and Black women were done. All women that attended these clinics were subjected to a fasting lipogram and fasting serum glucose. An abnormal fasting serum glucose would have necessitated a full glucose tolerance test. RESULTS. A total of 110 patients were analysed in this study. There were 87 Indian patients, 16 Black patients, 5 Coloured patients and 2 White patients. Eighty nine percent of PCOS women studied had an increased body mass index (>25). There was an increased LH:FSH in 66 (75.9%) of Indian women and 13 (81.3%) of Black women. Increased androgens were present in 26 (30.2%) in Indian women and 6 (37.5%) of Black women. An increase in fasting insulin was found in 48 (55.2%) of the Indian women and 5 (31.3%) of the Black women. Twenty five (29.1%) Indian women had an increase in fasting serum glucose compared to 1 (6.3%) in Black women. In the Indian population, 13 (14.9%) were found to have Diabetes Mellitus, and 9 (10.3%) had an impaired glucose tolerance test. In the Black population only 1 patient had impaired glucose tolerance. There were no Black patients with Diabetes Mellitus. No Black women were found to have hyperlipidaemia, however 12 (14.3%) Indian women were affected. None of these differences between the races were statistically significant. The major limitation of the study was the sample size of Black women. This is an ongoing study, and aims to recruit more Black women. This will be able to adequately address the correct perspective regarding the metabolic and cardiovascular abnormalities in these women. CONCLUSION. The prevalence of insulin resistance and hyperlipidaemia in local women with PCOS was 50.9%.and 11.3% respectively. Menstrual irregularities and infertility are the most frequent presenting complaints of women with PCOS. Features of hyperandrogenism are not common presenting complaints in South African women. There are no differences in the hormonal and clinical profile of South African Indian and Black women with PCOS, however, there is a trend toward Indian women having a greater prevalence of glucose abnormalities than Black women. We recommend further studies in the management of the metabolic abnormalities in local women with PCOS, in an attempt to develop a protocol to manage the metabolic complexities of PCOS. / Thesis (M.Med)-University of KwaZulu-Natal, Durban, 2010.

Adrenomedullin (ADM) is a 52 amino acid vasodilator peptide isolated, in 1993, from human pheochromocytoma. It has been demonstrated in the adrenal medulla of several mammalian species, including humans and rats. There have been conflicting results of the tissue distribution in the adrenal cortex. Hypertension is a complex trait with multiple genetic and environmental influences. Furthermore, salt-sensitive hypertension is characterized by a cluster of renal, hormonal, and metabolic derangements that might favour the development of cardiovascular and renal complications. Therefore the objective of this study was to investigate the adrenal distribution of ADM as well as to semi-quantitatively assess the adrenomedullin secretory capacity of the adrenal gland in the rat model of salt sensitive hypertension. Fourty-four male weanling rats were divided into 4 experimental groups and placed on a dietary regimen for 6 weeks viz. Dahl salt sensitive (DSS) rats on a high sodium diet (8% NaCl), DSS on a normal sodium diet (1% NaCl) matched with normotensive Dahl salt resistant (DSR) rats on the same dietary treatments. Blood pressure was monitored by tail-cuff readings and by the end of the six weeks, the DSS rats developed hypertension with tachycardia irrespective of the diet they were fed. The normal sodium diet was found to delay the development of hypertension, whilst the high sodium diet exacerbated the development of hypertension. Kidney weights and heart weights were greater in DSS rats than DSR rats probably due to their renal pathology or cardiac hypertrophy. Adrenomedullin immunopositivity was found predominantly in the adrenal medulla, and to varying degrees in the zona glomerulosa and zona reticularis of the adrenal cortex. The semi-quantitative analysis indicate that there was a 6.3 fold increase in ADM content of DSS rats compared to the DSR rats, where both consumed the 1% NaCI supplemented diet (DSR : 5.98 ± 0.3 vs. DSS : 37.85 ± 0.5, P / Thesis (M.Sc.)-University of Durban-Westville, 2003.

Muscle biopsies were taken at baseline, post eccentric exercise, post aerobic training, and after training followed by eccentric exercise from adults with different health status. In Cell Western analysis of pAkt/Akt ratio suggests that muscle cells isolated from baseline biopsies respond to insulin in a dose dependent manner that tracks with sensitivity to insulin of the host; however, this is uncoupled from glucose disposal in vitro. Nitrotyrosine (NY), a marker of free radical damage, was employed to assess the efficacy of the exercise paradigm. NY immunohistochemistry on muscle cross-sections revealed that eccentric exercise significantly increased damage in older (>55 years of age), but not middle aged (age) subjects, and that training reversed the post eccentric damage significantly in the younger, but not the older group, suggesting distinct adaptation to eccentric exercise. Assessment of total macrophage content by CD68 immunohistochemistry showed that macrophage abundance increased in response to training in the >55 years age group, but not in the training, macrophages increased in response to eccentric exercise in middle aged and decreased in older subjects, showing a disconnect from NY damage. Macrophage phenotypes were assessed in these groups via the M1 marker CD11b, and the M2 marker, CD206. Two dominant populations of macrophages were identified, one of which co-expressed CD11b and CD206, and another which only expressed CD11b. These two populations of macrophages showed the same trends in expression in response to exercise observed with CD68, but did not achieve statistical significance. Bivariate analysis revealed that CD11b/CD206 macrophage densities were correlated with gene activities associated with fibrosis and angiogenesis, whereas CD11b macrophages correlated with gene activities associated with proteostasis and cellular turnover. Lastly, an in vitro model of skeletal muscle cell and macrophage integration was developed to study how macrophage phenotype influences insulin responsiveness. Data suggest that M1 macrophages inhibit insulin stimulated glucose disposal, whereas M2 macrophages enhance this response. Taken together these results suggest a functional distinction between inflammatory (M1) and alternative macrophages (M2) in exercise and insulin resistance that is altered with age.

To determine the influence of muscle mass and absolute work on glucose tolerance and insulin sensitivity following exercise, glucose and insulin responses to an oral glucose tolerance test (OGTT) were analyzed in twelve subjects at baseline and 16 to 18 hrs following three different exercise trials performed on a cycle ergometer: 1) two-legged exercise at 60% of two-leg maximal oxygen uptake (VO2max), 2) one-legged exercise at 60% of the oneleg VO2max, and 3) a second one-leg trial at 60% of one-leg VO2max with work matched to the work obtained during the two-leg trial. Each trial was preceeded by two days of inactivity and a three day diet replication. Analysis of serum glucose concentrations during the post-exercise OGTTs demonstrated that glucose tolerance was unaffected by either the amount of active tissue incorporated in the exercise and/or the amount of work completed by the active tissue. On the other hand, serum insulin concentrations following the two-leg trial decreased 23.5% from 347.62 ±37.98 to 266.05 :L41.62 gU/ml in comparison to the one-leg trial (p < 0.05). The incorporation of a smaller muscle mass which completed an equal amount of absolute work as the larger muscle mass (i.e. one-leg work matched trial) resulted in a large (19%), but nonsignificant reduction in the total insulin compared to the one-leg relative work trial. In addition, total insulin following the two-leg and the one-leg work matched trials were reduced by 19% and 14%, respectively, in comparison to baseline. However, they did not reach statistical significance. The results of this study indicate that the incorporation of a larger muscle mass during an acute bout of aerobic exercise results in a reduction in serum insulin in response to a post-exercise oral glucose challenge. In addition, increasing the absolute work of a muscle mass results in similar reductions in serum insulin regardless of the amount of muscle mass involved in the exercise. While glucose tolerance was unaltered by either the amount of active tissue and/or the amount of work completed by the active tissue. / School of Physical Education

Considerable research has been performed on the effects of exercise and glucose tolerance, however, most of this work has examined aerobic exercise designs. This study examines the immediate post-exercise glucose turnover in eight male subjects exposed to a single bout of running and PRE. Both exercise protocols were designed to be of similar duration and at an intensity representing a typical exercise session. This study was conducted in an effort to offer individuals with NIDDM an alternative to the established aerobic forms of exercise for improved glucose control. Each subject completed two preliminary procedures, which consisted of a maximal graded exercise test and a session where a 1 RM was established on six different Cybex variable resistance machines. Subjects then completed a baseline oral glucose tolerance test (OGTT) in which eight blood samples were analyzed for glucose, insulin, hemoglobin, and hematocrit. Two exercise protocols, separated by 3 to 10 days, consisting of a 40 minute treadmill run at 75% VO2max and a 40 minute, 3 set x 10 repetition based on 75% of the1 RM, were performed and followed 45 minutes later by another OGTT. The results demonstrated that there were no apparent differences in blood glucose or insulin levels post-exercise between the exercise modes. However, the form of exercise did seem to have a varied effect on insulin production. The results of the OGTT demonstrated an explicit difference in the insulin response between the lifting and running trials, with the lifting trial being significantly higher than the resting or running trials. The increased insulin levels observed in the lifting trial may be indicative of increased secretion from the pancreas or that the secreted insulin is simply not being used. The insulin resistance observed in the lifting trial may be due to the muscles inability to respond to insulin or some other metabolic factor(s) released during exercise. Additional studies should be performed on different populations to examine the effects of PRE and running in a effort to better understand the mechanisms responsible for glucose uptake. / School of Physical Education

Motivation: Metabolic syndrome is a constellation of risk factors predisposing to coronary heart disease (CHD) and is classified as a "disease of modern civilization". Characteristics of the metabolic syndrome include abdominal obesity, increased triacylglycerol (TG) concentrations, increased small dense low-density lipoprotein(LDL) particles, decreased high-density lipoprotein cholesterol (HDL-C), hypertension, insulin resistance, inflammation, glucose intolerance and/or type 2 diabetes mellitus. Subjects with metabolic syndrome may be susceptible to oxidative stress due to their prolonged exposure to elevated glucose levels. A variety of natural antioxidants exists (e.g. glutathione, l3-carotene, vitamin C, polyphenols) that may prevent oxidative damage to biological structures. Nuts are rich sources of unsaturated fatty acids, protein, fibre, .micronutrients, phytochemicals and antioxidants. Duet o their high antioxidant content, it can, therefore, be speculated that nuts may play a role in the prevention of oxidative stress in subjects with the metabolic syndrome. Objective: - To investigate the effect of a high walnut and a high unsalted cashew nut diet on the antioxidant status of subjects with metabolic syndrome. Methods: Sixty eight subjects with diagnosed metabolic syndrome (according to the ATP III criteria) were recruited to take part in this parallel, randomized, controlled feeding trial. Subjects were mainly recruited from the North-West University, Potchefstroom Campus and surrounding areas. After a run-in period of three weeks during which the participants followed a prudent diet, subjects were randomly divided into three groups receiving either walnuts or cashew nuts (63- 108g/day)as part of a prudent diet, or continued with the prudent control diet. The intervention was followed for eight weeks. Fasting blood samples were taken at the beginning(after the three week run-in period) and at the end of the intervention. Antioxidant variables including oxygen radical absorbance capacity (ORAC), reduced glutathione (GSH)/oxidized glutathione (GSSG), diacron reactive oxygen metabolites (dRom) were measured at the beginning and the end of the intervention. C-reactive protein (CRP), fibrinogen and plasminogen activator-inhibitor activity (PAI-1a) were also measured as markers of inflammation. The antioxidant capacity and the polyphenol content of the diets and the walnuts and cashew nuts were determined at the end of the intervention. Results: A significant decrease in dRom and significant increases in GSSG, the redox status of glutathione (GSH/GSSG) and ORAC were observed in all three groups from baseline to end. GSH remained unchanged from baseline to end in all three groups. No significant differences in changes in dRom (p = 0.92), GSSG (p = 0.99), GSH/GSSG (p = 0.86), antioxidant capacity (p = 0.10) and GSH (p = 0.34) were observed from baseline to end between groups. The total polyphenol content of the walnut and control diets were similar and significantly higher than the cashew nut diet. The antioxidant capacity of the walnut and cashew nut diets showed a tendency to be higher than the control diet (p = 0.07 and p = 0.06 respectively). CRP, fibrinogen and PAI-1a concentrations did not differ significantly between groups. Conclusion No significant differences between the groups receiving walnuts, cashew nuts or no nuts were observed in GSH, GSSG, GSH/GSSG, dRom or ORAC. Therefore, there seems to be no beneficial effect of the inclusion of walnuts and cashew nuts in the diet on the antioxidant status of the participants. / Thesis (M.Sc. (Dietetics))--North-West University, Potchefstroom Campus, 2006.

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) and tau pathologies, insulin resistance, neuro-inflammation and dysregulation of cholesterol homeostasis, all of which play a role in neuro-degeneration. The main aim of this study was to determine possible relationships between insulin signaling, cholesterol biosynthesis and their effects on Aβ, and inflammatory response in vitro. Insulin treatment increased cholesterol synthesis in human Neuroblastoma SH-SY5Y (SHY) and mouse neuroblastoma 2a (N2a) and N2a transfected with human APP (N2a-APP) by up-regulating biosynthesis enzymes including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3methyl-glutaryl-CoA reductase (HMGCR) through sterol regulatory element binding protein-2 (SREBP2) up-regulation. Aβ caused insulin resistance in N2a-APP cells by phosphorylating IRS-1 at Ser612, inhibiting signaling to downstream targets. Aβ1-42-treated SHY exhibited similar IRS-1 phosphorylation at Ser612 and inflammatory response of JNK activation. Aβ1-42 caused down-regulation of neuro-protective/anti-inflammatory DHCR24, and an increase in HMGCR levels indicating dysregulation of cholesterol homeostasis in SHY cells. Insulin resistance, Aβ toxicity, neuro-inflammation and dysregulation of cholesterol homeostasis appear to be intertwined processes in AD that should be studied simultaneously.

Although insulin resistance of glucose and fat metabolism in type 2 diabetes mellitus (T2DM) is firmly established, that of protein remains controversial for methodological reasons. A hyperinsulinemic (40MU/m2·min) euglycemic (5.5 mmol/L) isoaminoacidemic (postabsorptive concentrations) clamp was combined with [3-3H]glucose and [1-13C]leucine kinetics to concurrently assess protein and glucose metabolism in 10 hyperglycemic men with T2DM and 11 men without (all BMI=29+/-kg/m2), matched also for age, body composition, and waist circumference. In response to hyperinsulinemia, protein turnover and synthesis were stimulated in controls, but not in T2DM. Both insulin-stimulated total and non-oxidative glucose disposal were diminished in T2DM vs. controls. There was a robust positive correlation between the change in synthesis and glucose disposal. Hence, there is an additive effect of T2DM, beyond that of having excess fat, on insulin resistance of whole body protein turnover and synthesis. Furthermore, protein sensitivity to insulin parallels that of glucose, establishing this as an important concern in T2DM management.

Both type 2 diabetes (T2D) and the the metabolic syndrome (MetS) have been shown to increase the risk of cardiovascular disease (CVD). Inflammation and insulin resistance have each been associated with the development of MetS and the onset of T2D as well as the risk of CVD. Inflammation and insulin resistance are therefore suitable targets for public health initiatives and interventions in persons at risk for or living with CVD. Physical inactivity is a major risk factor for CVD as well as MetS and T2D. Conversely, increased physical activity is associated with improved health outcomes for individuals with a high risk for developing CVD. Two possible mechanisms for the deleterious effects of inactivity on health are inflammation and insulin resistance. Researchers have hypothesized that increased adiposity and reduced fitness are partially responsible for the associations between inactivity, inflammation, and insulin resistance. However, these relationships have not been studied extensively in overweight/obese individuals, who are often unfit and sedentary. The purpose of this study was to further examine the relationship between baseline measures of walking activity and sedentary behavior, and inflammation and insulin resistance in a sample of adults with type 2 diabetes and/or metabolic syndrome. This thesis examined baseline data from participants enrolled in either of two studies of patients with T2D (n = 116) or MetS without T2D (n = 126). Participants included low income men and women (not pregnant or nursing) between the ages of 18 and 70 who either show depressed affect (BDI > 11), and were overweight (BMI ≥ 27 kg/m2) and had type 2 diabetes or had at least 3 components of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) classification of the metabolic syndrome (MetS). Structural equation modeling was used to determine if physical inactivity is associated with inflammation or insulin resistance in these conditions. Possible mediational roles of adiposity and low cardiorespiratory fitness were also examined. Additional analyses were conducted to determine if these relationships can be estimated equally in MetS and T2D conditions. Activity was indirectly related to abdominal adiposity via an indirect, positive association with cardiorespiratory fitness. Abdominal adiposity was positively related to both inflammation and insulin resistance. There were no direct associations between activity and inflammation or insulin resistance in this population. Therefore, walking may be negatively related to cardiovascular risk, insofar as it reduces abdominal adiposity.

This study aimed to examine potential mechanisms for glucocorticoid (GC)-induced decreases in glucose clearance, and to determine if a reduction in oxidative stress load via dietary pre-treatment with an antioxidant-rich diet has a positive net effect on glucose tolerance following a sub-chronic treatment with the GC analogue dexamethasone (DEX). Rats fed a diet supplemented with 700IU of -tocopherol for two weeks had improved glucose clearance after five days of DEX-treatment relative to unsupplemented rats as well as decreased markers of oxidative stress. Following an intraperitoneal bolus of insulin, phosphorylation of AMP activated protein kinase (AMPK) was preserved in the supplemented groups despite no significant differences in upstream insulin signalling cascade intermediates between DEX-treated groups. This was corroborated by a similar increase (p<0.05) in phosphorylation of the downstream AMPK substrate acetyl CoA carboxylase. This study demonstrated that -tocopherol supplementation can attenuate GC-induced decreases in glucose clearance in an AMPK-dependent manner. / Nutrition and Metabolism