MOTIVATION: The increasing prevalence of metabolic syndrome (MetS) is creating immense concern worldwide. In 2009, the International Diabetes Federation (IDF) announced the new MetS definition. MetS is diagnosed by any 3 of the following 5 indicators being present: increased waist circumference (WC), blood pressure (BP), triglycerides, and fasting glucose values, and decreased high–density lipoprotein cholesterol (HDL–C) concentrations. Psychosocial stress relating to an urban environment or acculturation greatly influences the prevalence of both MetS and target organ damage (TOD). Furthermore, in urban Africans, active coping (AC) responses have been associated more with MetS and the related cardiovascular pathology than avoidance. A further synergistic effect of MetS and AC responses was also revealed in African men, in strong association with both subclinical atherosclerosis and renal impairment. Microalbuminuria was four times higher in Africans with MetS, than in those without any MetS indicators. Furthermore, Africans, especially those utilising AC responses, present with greater carotid intima–media thickness (CIMT) than their Caucasian counterparts, although they exhibit a lipid profile that is anti–atherogenic. OBJECTIVES: The objectives were firstly to indicate and compare differences regarding AC responses in the African and Caucasian men, in accord with the prevalence of MetS indicators. Secondly, the extent to which AC responses and MetS indicators predict endothelial dysfunction was investigated. METHODOLOGY: This comparative target population study is nested in the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study, which was conducted from February until the end of May in both 2008 (Africans) and 2009 (Caucasians), avoiding seasonal changes. The Ethics Committee of the North–West University approved the study, and all volunteers gave written informed consent prior to participation. Procedures were conducted according to the institutional guidelines of the Declaration of Helsinki. The participants included 202 male teachers of which 101 were African and 101 Caucasian. Ambulatory blood pressure (BP) measurements were recorded with the Cardiotens CE120 at 30 minute intervals during the day and 60 minutes at night. Actical accelerometers determined physical activity (PA). Registered clinical psychologists supervised completion of the psychosocial questionnaires, including the Coping Strategy Indicator. Participants fasted overnight; after the last BP recording, disconnection of the Cardiotens CE120 and Actical followed. A fasting 8 hour overnight collected urine sample was obtained from each participant. Anthropometric measurements followed, after which a registered nurse commenced blood sampling. The SonoSite Micromaxx was used for the scanning of CIMT. MetS indicators (glucose, triglyceride, and HDL–C), together with gamma glutamyl transferase, cotinine, and ultrahigh–sensitivity C–reactive protein (hs–CRP), were analyzed with Konelab 20i. The albumin–to–creatinine ratio and CIMT determined TOD. Participants were stratified according to ethnicity and median splits of AC response scores (high AC and low AC). Diabetic medication users (n= 8), and participants with renal impairment (n= 2) or HIV positive (n= 13), were excluded from analyses. 2×2 ANCOVA’s determined significant interactions for ethnicity and AC. Partial correlations between MetS indicators and TOD were performed within each ethnic and AC group, independent of age, alcohol consumption and PA. Regression analyses were performed for four models, firstly with microalbuminuria and secondly with CIMT as dependent variables. Significant values were noted as p 0.05, r 0.35, and adjusted R2 0.25. RESULTS: Caucasian men were physically more active than African men, whilst BP, alcohol consumption and hs–CRP levels were significantly higher in African men. Psychological variables revealed higher avoidance scores in Caucasian men and higher social support scores in African men. More MetS indicators exceeded the IDF cut–off points in high AC African men (14.71%) than in their Caucasian counterparts (3.33%). Furthermore, more MetS indicators predicted endothelial dysfunction in African men, especially the high AC responders. CONCLUSION: The following hypotheses were accepted: high AC responses in urban African men were associated with a higher prevalence of MetS indicators than in their Caucasian counterparts, while MetS indicators were associated with a marker of TOD in urban high AC African men, but not in their Caucasian counterparts. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2011.

MOTIVATION: The increasing prevalence of metabolic syndrome (MetS) is creating immense concern worldwide. In 2009, the International Diabetes Federation (IDF) announced the new MetS definition. MetS is diagnosed by any 3 of the following 5 indicators being present: increased waist circumference (WC), blood pressure (BP), triglycerides, and fasting glucose values, and decreased high–density lipoprotein cholesterol (HDL–C) concentrations. Psychosocial stress relating to an urban environment or acculturation greatly influences the prevalence of both MetS and target organ damage (TOD). Furthermore, in urban Africans, active coping (AC) responses have been associated more with MetS and the related cardiovascular pathology than avoidance. A further synergistic effect of MetS and AC responses was also revealed in African men, in strong association with both subclinical atherosclerosis and renal impairment. Microalbuminuria was four times higher in Africans with MetS, than in those without any MetS indicators. Furthermore, Africans, especially those utilising AC responses, present with greater carotid intima–media thickness (CIMT) than their Caucasian counterparts, although they exhibit a lipid profile that is anti–atherogenic. OBJECTIVES: The objectives were firstly to indicate and compare differences regarding AC responses in the African and Caucasian men, in accord with the prevalence of MetS indicators. Secondly, the extent to which AC responses and MetS indicators predict endothelial dysfunction was investigated. METHODOLOGY: This comparative target population study is nested in the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study, which was conducted from February until the end of May in both 2008 (Africans) and 2009 (Caucasians), avoiding seasonal changes. The Ethics Committee of the North–West University approved the study, and all volunteers gave written informed consent prior to participation. Procedures were conducted according to the institutional guidelines of the Declaration of Helsinki. The participants included 202 male teachers of which 101 were African and 101 Caucasian. Ambulatory blood pressure (BP) measurements were recorded with the Cardiotens CE120 at 30 minute intervals during the day and 60 minutes at night. Actical accelerometers determined physical activity (PA). Registered clinical psychologists supervised completion of the psychosocial questionnaires, including the Coping Strategy Indicator. Participants fasted overnight; after the last BP recording, disconnection of the Cardiotens CE120 and Actical followed. A fasting 8 hour overnight collected urine sample was obtained from each participant. Anthropometric measurements followed, after which a registered nurse commenced blood sampling. The SonoSite Micromaxx was used for the scanning of CIMT. MetS indicators (glucose, triglyceride, and HDL–C), together with gamma glutamyl transferase, cotinine, and ultrahigh–sensitivity C–reactive protein (hs–CRP), were analyzed with Konelab 20i. The albumin–to–creatinine ratio and CIMT determined TOD. Participants were stratified according to ethnicity and median splits of AC response scores (high AC and low AC). Diabetic medication users (n= 8), and participants with renal impairment (n= 2) or HIV positive (n= 13), were excluded from analyses. 2×2 ANCOVA’s determined significant interactions for ethnicity and AC. Partial correlations between MetS indicators and TOD were performed within each ethnic and AC group, independent of age, alcohol consumption and PA. Regression analyses were performed for four models, firstly with microalbuminuria and secondly with CIMT as dependent variables. Significant values were noted as p 0.05, r 0.35, and adjusted R2 0.25. RESULTS: Caucasian men were physically more active than African men, whilst BP, alcohol consumption and hs–CRP levels were significantly higher in African men. Psychological variables revealed higher avoidance scores in Caucasian men and higher social support scores in African men. More MetS indicators exceeded the IDF cut–off points in high AC African men (14.71%) than in their Caucasian counterparts (3.33%). Furthermore, more MetS indicators predicted endothelial dysfunction in African men, especially the high AC responders. CONCLUSION: The following hypotheses were accepted: high AC responses in urban African men were associated with a higher prevalence of MetS indicators than in their Caucasian counterparts, while MetS indicators were associated with a marker of TOD in urban high AC African men, but not in their Caucasian counterparts. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2011.

Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.

Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.