Please read the abstract in the section, 00front, of this document / Dissertation (MSc)--University of Pretoria, 2003. / Clinical Epidemiology / MSc / unrestricted

The principal objective of this study was to develop an alternative non-genetic rat model for type 2 diabetes (T2D). Six-week-old male Sprague-Dawley rats (190.56 ± 23.60g) were randomly divided into six groups namely: Normal Control (NC), Diabetic/Streptozotocin Control (STZ), Fructose-10 (FR10+STZ), Fructose-20 (FR20+STZ), Fructose-30 (FR30+STZ) and Fructose-40 (FR40+STZ) and were fed a normal rat pellet diet ad libitum for 2 weeks. During this period, the two control groups received normal drinking water whilst the fructose groups received 10, 20, 30 and 40% fructose in drinking water ad libitum respectively. After two weeks of dietary manipulation, all groups except the NC group received a single injection (i.p.) of streptozotocin (STZ) (40mg/kg BW) dissolved in citrate buffer (pH 4.4). The NC group received only a vehicle buffer injection (i.p.). One week after the STZ injection, animals with non-fasting blood glucose >300 mg/dl were considered as diabetic. Three weeks after the STZ injection, the animals in FR20+STZ, FR30+STZ and FR40+STZ were eliminated from the study due to the severity of diabetes and the FR10+STZ group was selected for the remainder of the 11 weeks experimental period. The significantly (p < 0.05) higher fluid intake, blood glucose, serum lipids, liver glycogen, liver function enzymes and insulin resistance (HOMA-IR) and significantly (p < 0.05) lower body weight, oral glucose tolerance, number of pancreatic β-cells and pancreatic β-cell functions (HOMA-beta) of FR10 group demonstrate that the 10% fructose-fed followed by 40 mg/kg of BW STZ injected rat can be an excellent alternative model for T2D. To validate this newly-developed model, an acute intervention trial study was conducted to investigate the anti-diabetic effects of L-Carnitine and white mulberry leaf tea extracts in the newly developed animal model of type 2 diabetes (T2D). Male Sprague-Dawley rats (mean BW 191.88g±16.40g) were randomly divided into 5 groups namely: Normal Control (NC), Diabetic/Streptozotocin control (FR10+STZ), Mulberry Tea Low (FR10+STZ+MTL, 0.25%), Mulberry Tea High (FR10+STZ+MTH, 0.5%), and L-Carnitine (FR10+STZ+CARN). In first three weeks, T2D was induced in all other groups except NC group by using above-mentioned procedure. Mulberry tea was supplied ad libitum and L-carnitine was administered to the FR10+STZ+CARN group at a concentration of 500mg/kg BW once daily during week 4-8 of the intervention trial. The FR10+STZ+CARN group had significantly (p < 0.05) lower total cholesterol, triglycerides, total proteins and fluid intake compared to the diabetic control (FR10+STZ). The NFBG non-significantly reduced in FR10+STZ+CARN group compared to the FR10+STZ group, whereas MT did not. FR10+STZ+MTL had significantly higher serum triglycerides level compared to the NC group, and significantly higher HDL-cholesterol and fluid intake compared to the FR10+STZ group. FR10+STZ+CARN and FR10+STZ+MT groups had significantly lower total proteins compared to NC and FR10+STZ groups, but significantly lower albumin compared to NC group only. The data of the this section of the study suggest that CARN may be effective in normalizing lipid profiles rather than blood glucose in diabetic rats which may aid in the reversal of insulin resistance. On the other hand, MT used in this study did not display any significantly beneficial anti-diabetic effects at least in this experimental condition. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2011.

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Diabetes causes early structural changes to the glomerular basement membrane (GBM), which alters its function and leads to loss of protein in urine. Formation of advanced glycation endproducts (AGEs) is one mechanism proposed to be responsible for the structural changes to the GBM. AGEs are thought to affect blood flow i.e. glomerular filtration rate (GFR) and vascular permeability which over time manifests as overt proteinuria. The gradual loss of minute amounts of protein (albumin) is referred to as microalbuminuria (MA). Microalbuminuria is a dynamic process, with patients regressing to normoalbuminuria more often than progressing to overt proteinuria. Microalbuminuria is not specific to patients with diabetic nephropathy (DN) and new markers specific to DN are being sought. A prospective study was undertaken at the Inkosi Albert Luthuli Central Hospital (IALCH) to evaluate the relationship of serum glycated albumin, urinary and serum components of capillary basement membrane and DN in South African Black and Indian patients with type 1 diabetes. The study was undertaken with sampling of blood and urine at baseline, 6-months, 1 year and 2-year follow-up. Serum glycated albumin, urinary type IV collagen and plasma fibronectin were measured at each visit. Since correlations could be performed only at each time point individually, generalised estimating equation (GEE) regression models were constructed in SPSS (15.0) with time specified as a factor in order to take account of relationships among variables over time. The results of this study showed that serum percentage glycated albumin (PGA), plasma fibronectin (FN) and urinary type IV collagen were not better predictors of incipient impaired renal function than MA. Although previous authors have variously reported serum GA, plasma FN and urinary type IV collagen to be predictive of impaired renal function, these studies were conducted mainly in patients with overt DN. The present study suggest that markers of overt renal dysfunction are not necessarily useful predictors of incipient DN. Differences in predictive relationships point to a different disease processes in the two ethnic groups. Of particular note was the lack of a predictive relationship of either fasting plasma glucose (FPG) or glycated haemoglobin (HbA1c) with any of isotope GFR, estimated GFR and proteinuria in Black patients. The most significant finding of this study showed that combination of serum creatinine and MA provided broadest range of predictors of isotope GFR, estimated GFR and proteinuria. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2010.

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The C57 BL/KsJ db/db mouse is obese, hyperglycemic, hyperinsulinemic and serves as a model for noninsulin dependent diabetes mellitus (NIDDM). This study reports a dysfunction in the pituitary-thyroid axis and apparent peripheral resistence to thyroid hormones due to a reduction in T3 receptor binding. Diabetic mice have subnormal serum T4 concentrations and supranormal T3 concentrations which are most pronounced between 8 and 10 weeks of age. Thyroid glands of diabetic animals appear hypoactive histologically. Serum TSH concentrations approximate those found in normal mice. In vitro studies show that thryroid glands from diabetic animals are responsive to TSH. Pituitary glands from the same animals hypersecrete TSH and are responsive to TRH. Ultrastructural analysis of pituitary thyrotropes from diabetic mice indicate that these cells are hypersecretory and may be under chronic stimulation by TRH. Diet restriction maintains diabetic mice at a normal total body weight but these animals still possess abnormally large fat deposits. The thyroid hormone profile of these mice appears normal as does the histological appearance of the thyroid gland. Similarly, the blockade of peripheral deiodination by daily injection of iopanoic acid returns the thyroid hormone profile to normal.

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The aim of the present study was to develop an alternative non-obese non-genetic rat model of type 2 diabetes (T2D). Six-week-old male Sprague-Dawley rats were randomly divided into six groups, namely: Normal Control (NC), Diabetic Control (DBC), Caffeine 5 mg/kg BW + STZ (CAF5), Caffeine 10 mg/kg BW + STZ (CAF10), Caffeine 20 mg/kg BW + STZ (CAF20) and Caffeine 40 mg/kg BW + STZ (CAF40) and were fed a commercially available rat pellet diet and normal drinking water ad libitum throughout the 13 weeks experimental period. After a one week acclimatization period, diabetes was induced in the animals in DBC and all CAF groups with an injection (i.p.) of the respective dosages of caffeine (mg/kg BW) 15 min before the injection (i.p.) of STZ (65 mg/kg BW) when normal saline was injected to the DBC group instead of caffeine. The NC group received normal saline and citrate buffer instead of caffeine and STZ, respectively. One week after the STZ injection, animals with non-fasting blood glucose > 300 mg/dl were considered as diabetic. Three weeks after the STZ injection, the animals in the CAF5 and CAF10 groups were eliminated from the study due to the severity of diabetes and the experiment was continued with the remainder groups for a 13 weeks period. At the end of the experimental period the rats were euthanized and blood and organ samples were collected for subsequent analysis. The data of daily food and fluid intake, weekly body weight and blood glucose, oral glucose tolerance test, serum insulin, fructosamine, lipid profile, organ specific and antioxidative enzymes, anti-diabetic drug response tests, and liver, heart, kidney and pancreas histopathology suggest that the CAF20 group can be a new and alternative non-obese non-genetic chemically-induced model for T2D and can be therefore used for both chronic and acute research studies as well as pharmacological screening of new anti-diabetic drugs. / Thesis (M.Sc.)-University of KwaZulu-Natal, Durban, 2013.