Thesis submitted in fulfilment of the requirements for the Doctor of Technology: Biomedical Technology In the Faculty of Health and Wellness At the CAPE PENINSULA UNIVERSITY OF TECHNOLOGY, 2012 / Diabetes mellitus is a major health problem not only in urban, but also in the rural areas and is diagnosed by the presence of high glucose levels in the blood. Oxidative stress is known to be actively involved in the onset and progression of diabetes and its complications. Antioxidants have important roles in biological systems by scavenging free radicals which may result in oxidative damage of biological molecules such as lipids, proteins and DNA. Red palm oil, originally from the tropical area of Africa, generally consumed as cooking oil, is known to have some beneficial health effects due to the presence of lipid soluble antioxidants such as carotenoids, tocopherols and tocotrienols. It also contains almost an equal proportion of both saturated and unsaturated fatty acids which makes it distinctive from other vegetable oils. Rooibos, on the other hand, is grown in the Cederberg area of the Western Cape in South Africa and it is commonly consumed as a beverage. It contains a complex profile of water soluble antioxidants (flavonoids) and its health promoting potentials have been reported extensively. Some of the flavonoids present in rooibos include aspalathin, nothofagin, quercetin, rutin and orientin. The objective of this research project was to examine the potential beneficial effects of the dietary intake of red palm oil and rooibos on streptozotocin-induced hyperglycaemia and its influence on the antioxidant status and some biochemical parameters in male Wistar rats. The preliminary phase of this study was designed to investigate the biochemical effects of these two plant products at different dosages following consumption for a period of 7 weeks. The preliminary study did not reveal any adverse effects of the different dosages of red palm oil (1 ml, 2 ml and 4 ml) and rooibos (2%, 4% and 6%) on the experimental rats following dietary intake for 7 weeks. However, these natural products showed an improvement in the antioxidant status of the rats at the different doses. Using a single dose each of both plant products from the preliminary study, the main study was performed to investigate the influence of these two plant products singly and in combination on the blood and liver of streptozotocin-induced hyperglycaemic male Wistar rats. In the main study, streptozotocin (50 mg/kg) dissolved in 0.1 M citrate buffer (pH 4.5) through intramuscular injection was used for the induction of diabetes which was confirmed by the presence of high blood glucose after 72 hours. Red palm oil or rooibos extract alone did not have any effect on the control of blood glucose in the diabetic rats. The dietary intake of the combined treatment with red palm and rooibos had more health promoting effects on the diabetic rats which included a decrease in blood glucose, glycosylated haemoglobin, fructosamine and increased insulin levels. There was a marked increase in liver glycogen levels in all the diabetic groups. Treatment with rooibos alone showed a decrease in glycogen levels in the diabetic rats. The presence of liver enzymes in the serum, commonly used as indicators of liver damage was increased in all the diabetic rats. However, the combined treatment of diabetic rats with red palm oil and rooibos protected the liver from injury. Red palm oil improved high density lipoprotein cholesterol levels (HDL-cholesterol) in the diabetic rats. There was no effect on the activity of glucokinase, the first enzyme in the the glycolytic pathway in both the untreated and treated diabetic rats. However, the activity of pyruvate kinase, the last enzyme in the glycolytic pathway was reduced in all the diabetic groups. The combined treatment with both red palm and rooibos increased the activity of pyruvate kinase. Oxidative stress was confirmed in the diabetic rats with an increase in the plasma thiobarbituric acid reactive substances (TBARS), an indicator of lipid peroxidation. Treatment of diabetic rats with rooibos and the combination of red palm oil and rooibos brought plasma TBARS to a level that was not significantly different from the normal control group. There was a non-significant reduction of total glutathione in the non-treated and treated diabetic groups. A non-significant increase in the activity of liver catalase was observed in all the treated diabetic groups. The activity of superoxide dismutase was significantly decreased in the liver of diabetic rats. Diabetic rats treated with red palm oil, rooibos and the combined treatment showed an increased activity of superoxide dismutase in the liver. Red palm oil and the combined treatment increased the activity of glutathione peroxidase in both the red blood cells and liver of diabetic rats. Red palm oil, rooibos and their combined treatments also improved the plasma antioxidant capacity such as ferric reducing antioxidant power (FRAP) and oxygen reducing absorbance capacity (ORAC) in the diabetic rats. In conclusion, oxidative stress is actively involved in the progression of diabetes mellitus. Red palm oil and rooibos, most especially their combined treatment showed significant beneficial health promoting effects in the diabetic rats. The remarkable effects of the combined treatment of red palm oil and rooibos in the diabetic rats could be due to their antioxidant profiles. Based on the findings from this study, it can be adduced that these plant products could help in the management of diabetes and its complications and therefore, suggested the need for further research studies on antioxidant therapy in the management of diabetes mellitus.

This investigation was concerned with measuring aspects of cardiac function in conscious control, diabetic, hypertensive control, and hypertensive diabetic rats. Preliminary studies were conducted to determine catheter suitability and acute responses to atropine and angiotensin II in conscious animals. The catheter-manometer was tested using a square wave impact and was shown to accurately reproduce a left ventricular pressure pulse. Intravenous atropine caused both heart rate and left ventricular +dP/dt to rise. Intravenously administered angiotensin II caused systolic blood pressure to increase dramatically. In this case heart rate fell and +dP/dt was elevated. Hypertension was induced with deoxycorticosterone acetate (DOCA) and saline drinking water. Rats were first made diabetic with streptozotocin (60 mg/kg; i.v.). One week following this, subcutaneous DOCA (25 mg/kg) was administered twice weekly and all animals received saline drinking water. Following 2 and 5 weeks of DOCA treatment rats were catheterized and resting cardiovascular function was measured. DOCA treatment caused increased systolic and diastolic blood pressures to occur in control and diabetic rats at 2 and 5 weeks. Bradycardia was also observed in DOCA-diabetic and DOCA-control rats at 2 and 5 weeks of treatment. Two and 5 week hypertensive diabetic and control rats exhibited elevated -dP/dt and +dP/dt. The rate of contraction was shown to be proportional to the magnitude of systolic blood pressure in all treatment groups. It is concluded that diabetic rats and control rats did not differ in their response to hypertension after 5 weeks of DOCA treatment. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

It is well established that a cardiomyopathy independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology of diabetic cardiomyopathy is very complex involving many different processes, one of which may be the increased fatty acid utilization, and/or the concomitant decrease in glucose utilization, by the diabetic heart. We compared control and 6-week streptozotocin(STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR X PSP), left ventricular developed pressure (LVDP), rate of pressure rise (+dP/dt) and rate of pressure decline (-dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia and decreased body weight gain as compared to age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts and -dP/dt of control hearts. But, diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. Heart rate, HR X PSP, LVDP and +/-dP/dt were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and adenosine 5'-triphosphate (ATP) levels were similar under all perfusion conditions, therefore eliminating energy stores as the limiting factor in heart function. Results indicate that DCA-induced stimulation of glucose oxidation acutely reversed diabetic cardiac function depression. Therefore, depression of glucose oxidation in the diabetic heart may be contributing to diabetic cardiomyopathy. / Pharmaceutical Sciences, Faculty of / Graduate

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Background: Streptozotocin (STZ) induced diabetes leads to various complications including cardiomyopathy. Recent data suggests transplanted bone marrow stem cells improve cardiac function in diabetic cardiomyopathy. However, whether modified ES, iPS cells, or factors released from these cells can inhibit apoptosis and fibrosis remains completely unknown. The present study was designed to determine the effects of transplanted ES cells overexpressing pancreatic transcription factor 1 a (Ptf1a), a propancreatic endodermal transcription factor, iPS cells, or their respective conditioned media (CM) on diabetic cardiomyopathy. Methods: Experimental diabetes was induced in male Sprague Dawley rats (8-10 weeks old) by intraperitoneal STZ injections (65 mg/kg body weight for 2 consecutive days). Animals were divided into six experimental groups including control, treated with sodium citrate buffer IP, STZ, STZ + ES-Ptf1a cells, STZ + iPS cells, STZ + ES-Ptf1a CM and STZ + iPS CM. Following STZ injections, appropriate cells (1 X 106/mL/injection/day) or CM (2 mL injection/day) were given intravenously for 3 consecutive days. Animals were sacrificed and hearts were harvested at day 28. Histology, TUNEL staining, and Caspase-3 activity were used to assess apoptosis and fibrosis. ERK1/2 phosphorylation was quantified using ELISAs. M-mode echocardiography fractional shortening was used to assess cardiac function. Results: Animals transplanted with ES cells, iPS cells, or both CMs showed a significant (p