Potatoes are often thought of as high GI. It is known that cooking and cooling affect GI and that these effects may be mediated through the physicochemical properties of their starch. As part of a Canadian initiative to develop low GI potatoes, novel potato varieties which differed in starch composition were tested in 2 separate studies. In study 1, we determined the GI of 8 varieties and found that cooling produced a wide range of effects (0-50% reduction in GI). In study 2, four previously tested varieties were re-examined. A significant variety-x-treatment interaction (p<0.01) was observed with cooling reducing GI in some potatoes. Examination of the starch properties and their role in determining GI showed that RDS was positively associated with GI (r2= 0.85, p= 0.001) and SDS (r2=-0.60, p= 0.02) and amylose (r2=-0.99, p=0.007) negatively associated with GI. No relationship between RS and phosphorous content and GI was observed.

Potatoes are often thought of as high GI. It is known that cooking and cooling affect GI and that these effects may be mediated through the physicochemical properties of their starch. As part of a Canadian initiative to develop low GI potatoes, novel potato varieties which differed in starch composition were tested in 2 separate studies. In study 1, we determined the GI of 8 varieties and found that cooling produced a wide range of effects (0-50% reduction in GI). In study 2, four previously tested varieties were re-examined. A significant variety-x-treatment interaction (p<0.01) was observed with cooling reducing GI in some potatoes. Examination of the starch properties and their role in determining GI showed that RDS was positively associated with GI (r2= 0.85, p= 0.001) and SDS (r2=-0.60, p= 0.02) and amylose (r2=-0.99, p=0.007) negatively associated with GI. No relationship between RS and phosphorous content and GI was observed.

The nitric oxide molecule (NO ·) is without doubt one of the most influential on the pathophysiology of the cardiovascular system. Its effects are broad ranging in this system influencing almost all of its components, particularly the vasculature, platelets and the myocardium. The beneficial effects of this molecule not only in inhibiting the development of cardiovascular disease (CVD) but in minimizing the risk of its acute thrombotic complications makes it an obvious target for therapies designed to enhance its effects. Assessing the tissue effects of NO · in platelets and the myocardium has been the main focus of this thesis. Determinants of platelet responsiveness to nitric oxide in diabetic patients with acute coronary syndromes: Effects of glycaemic control Background: We chose to perform our initial experiments in diabetic patients admitted with an acute coronary syndrome (ACS). This cohort offered us a unique opportunity to assess NO · bioavailability in a group with one of the highest cardiovascular morbidity and mortality rates. We assessed this via platelet NO · responsiveness, which has been shown from our laboratory to be impaired in ACS but to date had not been assessed specifically in a diabetic group. As hyperglycaemia is a known independent predictor of mortality in this group we chose in our first set of experiments to primarily assess the effects of glycaemic control (acute and chronic) on platelet NO · responsiveness. Study: In diabetic patients admitted with an ACS the relationship between glycaemic control and the main determinants of platelet NO · responsiveness, superoxide (O2-)generation and guanylate cyclase activity were assessed. Secondary hypotheses assessed the effects of acute glycaemic control on other potential modulators of NO · responsiveness such as asymmetric dimethylarginine (ADMA), L-arginine, Larginine/ADMA ratio, platelet activated O2- release and C-reactive protein (CRP). Other values assessed included CK rise, non-esterified fatty acid (NEFA) levels, ADP induced platelet aggregation and neutrophil count. We also assessed the determinants of both platelet SNP response and of O2- levels by a stepwise multivariate analysis; parameters assessed were age, sex, blood sugar level (BSL), statin therapy, insulin therapy, ACE-inhibitor therapy and CK elevation. Conclusions: In diabetic patients admitted with an ACS; 1. Admission BSL was inversely correlated with platelet SNP responsiveness and directly correlated with O2- generation, but not with guanylate cyclase activity. 2. Admission BSL also correlated with CK rise, CRP, neutrophil count and ADP enhanced O2- generation. Admission BSL was inversely correlated with ADMA and L-arginine levels. 3. On multivariate analysis, admission BSL was a significant determinant of O2- levels and an inverse determinant of SNP response; with increasing age also a significant inverse determinant of SNP response. Acute Resolution of hyperglycaemia normalizes platelet responsiveness to nitric oxide in diabetics with acute coronary syndromes Background: We then explored whether improving glycaemic control had any effect on platelet NO · responsiveness. This was performed by randomizing diabetics with ACS to either intravenous infusions or subcutaneous injections of insulin. This experiment was designed to determine possible mechanisms to explain the results of the DIGAMI study, which showed that tight glycaemic control decreased mortality in diabetics admitted with an acute myocardial infarction (AMI). Study: Sixty diabetic patients admitted with an ACS were randomized to aggressive IV insulin therapy or standard subcutaneous insulin therapy over 12 hours. The primary objective of this study, was to assess the acute effects of tight glycaemic control on platelet NO · responsiveness, O2- generation and guanylate cyclase activity. To explore all possible mechanisms of any observed effect δ ADMA,L- arginine and Larginine/ADMA ratio, CRP, non esterified fatty acids (NEFA) and platelet aggregation were assessed. Conclusions: In diabetic patients admitted with an ACS; 1. Aggressive glycaemic control resulted in significantly enhanced platelet responsiveness to SNP, related to a reduction in O2- generation. No effect on guanylate cyclase activity was seen. 2. A significant reduction in ADMA and L-arginine levels were observed with intravenous compared to subcutaneous insulin therapy. Effects of an oral glucose load on platelet responsiveness to nitric oxide Background: Elevated BSLs are associated with adverse cardiovascular outcomes in ACS in both diabetic and non-diabetic subjects. Hyperglycaemia is no longer considered an ‘ innocent bystander ’ however, having detrimental mechanistic implications on a number of protective biological systems. Indeed, harmful effects of sudden glucose loads such as post-prandial hyperglycaemia on the cardiovascular system are becoming apparent. While our previous experiments had focused on the impact of hyperglycaemia and its subsequent correction, on NO · bioavailability, our follow up experiments assessed the effect of an oral glucose load in normal subjects and patients with known cardiovascular disease. In light of the previous findings, we assessed the effects of an acute glucose load on platelet NO · responsiveness and vascular reactivity as assessed by applanation tonometry. Study: 8 healthy and 10 ‘ high-risk ’ cardiovascular subjects were enrolled into this study. A 75 gm glucose load was administered and baseline and 2 hour data were assessed. Platelet SNP responsiveness and O2- generation along with augmentation index (AIx) and ADP-induced platelet aggregation were assessed in all subjects. In the ‘ high-risk ’ cohort cGMP generation and insulin levels were also evaluated. Conclusions: In the healthy volunteers; 1. No significant change occurred in any of the variables assessed In the ‘ high-risk ’ cohort 1. 80 % of patients had undiagnosed impaired glucose handling 2. A significant increase in soluble guanylate cyclase activity was associated with an oral glucose load possibly related to an increase in insulin levels Lack of inotropic effect of nitric oxide in rat papillary muscle. Background: Our final set of experiments moved away from platelet studies to the assessment of myocardial contractility. Differing methodologies and animal models have resulted in variable results in the assessment of the inotropic effects of NO · . While the consensus is that NO · donors have a positive inotropic effect in low doses and are negatively inotropic at high doses, this has been difficult to show in the papillary muscle of most animal models. We addressed this issue in the papillary muscle of the Sprague-Dawley rat. Study: The experimental protocol involved the assessment of NO · effects on contractility on the left ventricular muscle of the Sprague-Dawley rat. These studies initially involved assessing the most stable preparation, comparing a 10bpm with a 35bpm protocol. The effect of the NO · donor SNP was then assessed not only on the isolated LV papillary muscle but also in the presence of β -adrenoceptor stimulation and an ischaemic/reperfusion model (15mins of anoxia/ 30 mins of reperfusion). Conclusions: In the left ventricular papillary muscle of the Sprague-Dawley rat 1. A stimulation frequency of 10bpm resulted in a more stable preparation over a 60 minute protocol, compared to 35bpm. 2. The isolated rat papillary muscle had no measurable response to exogenous NO · donors. The inotropic effects of β -adrenoceptor stimulation and ischaemia-reperfusion were NO · -independent in this model. While the field of NO · research is rapidly expanding, we forget that it is only just over 20 years since we were first aware of its existence. From Furchgott and Zawadski ' s ( Furchgott and Zawadzki, 1980 ) initial observation of an endotheliumderived relaxing factor ( EDRF ) to the subsequent studies by Palmer et al. ( Palmer et al., 1987 ) and Ignarro et al. ( Ignarro et al., 1987 ) showing that EDRF was indeed NO ·, many questions remain unanswered in relation to the 1992 ‘ molecule of the year ’. This thesis contributes to our understanding of NO · and its associated bioavalability in a number of tissues, particularly in relation to a high-risk cohort, the hyperglycaemic diabetic with an ACS. / Thesis (Ph.D.)--Medical School, 2004.

Hyperglycaemia in critical care is common and has been linked to increased mortality and morbidity. Tight control of blood glucose concentrations to more normal levels can significantly reduce the negative outcomes associated with hyperglycaemia. However, hypoglycaemia and glycaemic variability have also been independently shown to increase mortality in critically ill patients. Further complicating the matter, critically ill patients exhibit high inter- and intra patient metabolic variability and thus consistent, safe control of glycaemia has proved very difficult. Model-based and model-derived tight glycaemic control methods have shown significant ability to provide very tight control with little or no hypoglycaemia in the intensive care unit (ICU). The model-based control practised in the Christchurch Hospital ICU uses a physiological model that relies on a single, time-varying parameter, SI, to capture the patient-specific glycaemic response to insulin. As an identified parameter, SI is prone to also capturing other, unintended, dynamics that add variability on multiple timescales. The objective of this research was to enable enhanced glycaemic control by addressing this variability of the SI parameter through better modelling and implementation. An improved model of insulin secretion as a function of blood glucose concentration was developed using data collected from a recent study at the Christchurch Hospital ICU. Separate models were identified for non-diabetic patients and diagnosed, or suspected type II diabetic patients, with R2 = 0.61 and 0.69, respectively. The gradients of the functions identified were comparable to data published in a number of other studies on healthy and diabetic subjects. The transcapilliary diffusion (nI) and cellular clearance (nC) rate parameters were optimised using data from published microdialysis studies. Interactions between these key parameters determine maximum interstitial insulin concentrations available for glucose disposal, and thus directly influence SI. The optimal values of these parameters were determined to be nI = nC = 0.0060 1/min. Models of endogenous glucose production (EGP), as functions of blood glucose concentration and time, were assessed. These models proved unsatisfactory due to difficulties in identifying reliable functions with the available data set. Thus, it was determined that EGP should continue to be treated as a population constant, except during real-time glycaemic control, where the value may be adjusted temporarily to ensure valid SI values. The first 24 hours of ICU stay proved to be a period of significantly increased SI variability, both in terms of hour-to-hour changes and longer-term evolution of level. This behaviour was evident for the entire study cohort as a whole and was particularly pronounced during the first 12-18 hours. The subgroup of cardiovascular surgery patients, in which there was sufficient data for analysis, mirrored the results of the whole cohort, but was found to have even lower and more variable SI. Glucocorticoid steroids were also found to be associated with clinically significant reductions in overall level and increases in hour-to-hour variability of SI. To manage variability caused by factors external to the physiological model, the use of several stochastic models was proposed. Using different models for the early part of ICU stay and for different diagnostic subgroups as well as when patients were receiving certain drug therapies would permit control algorithms to reduce the impact of the SI variability on outcome glycaemia. The impact of measurement timing and BG concentration errors on the variability of SI was assessed. Results indicated that the impact of both sources of errors on SI level was unlikely to be clinically significant. The impact of BG sensor errors on hour-to-hour SI variability was more pronounced. Understanding the effect of sensor and timing errors on SI allows their impact to be reduced by using the 5-95 percentile forecast range of stochastic models during glycaemic control. The performance of the model incorporating the proposed insulin kinetic parameters and secretion enhancements was validated for clinical glycaemic control and virtual trial purposes. This validation was conducted by self- and cross validation on a cohort independent to that with which the model was developed. The use of multiple stochastic models to reduce the impact of this extrinsic variability during glycaemic control was validated using virtual trials.

Research shows a large variability in the degree to which adolescents with diabetes adjust to their illness. Adjustment to diabetes is important because it affects the mental health of adolescents, and has been shown to predict both adherence to treatment, and glycaemic control. This thesis proposed that attachment security has the potential to explain some of the variability in adjustment to diabetes. A causal pathway was hypothesised whereby attachment security both directly predicts adjustment to diabetes, and indirectly via choice of coping strategies. In addition, it was hypothesised that attachment security would indirectly predict adherence behaviours and glycaemic control. The relative importance of attachment to parents and peers was compared. The research hypotheses were tested in a sample of 99 adolescents aged 13-18 years, who had been diagnosed with diabetes for at least a year. Measures of attachment security, adjustment to diabetes, coping strategies, treatment adherence and glycaemic control were taken at one time point. The data were analysed using structural equation modelling to test the hypothesised causal pathway. The results suggested that attachment security both directly predicts adjustment to diabetes, and indirectly predicts adjustment to diabetes via avoidance focused coping strategies. Attachment to parents, but not to peers was associated with adjustment to diabetes, and some gender differences were observed. The results also suggested that attachment security indirectly predicts glycaemic control via adjustment to diabetes. There were no significant associations between adherence to treatment and any other variables. Neither attachment security nor adjustment to diabetes were associated with approach focused coping. It is concluded that attachment security may play an important part in both psychological and physical outcomes for adolescents with diabetes, and this has implications for attachment based interventions. The findings are discussed in relation to other theoretical models, and indications for future research are suggested.

MMed, Community Health, Faculty of Health Sciences,University of the Witwatersrand / Introduction: The complications associated with diabetes usually occur over a long period of time and are mainly influenced by poor glycaemic control. Diabetic complications impact on the individual, the healthcare delivery system, and also have high cost implications. A number of studies have shown the management of diabetes to be sub-optimal in primary health care settings. Barriers that impair a patients’ ability to achieve good glycaemic control can be looked at from a patient, health facility and health professional perspectives. Good glycaemic control will not only benefit the individual patient but will also have a positive financial impact on South Africa’s already overstretched healthcare budget. Methods: In this cross sectional analytical study set in three Community Health Centres (CHCs) in the Johannesburg Metropolitan Health District, 418 diabetic patients were selected. An HbA1c test was conducted for every patient and was used to classify patients into a well controlled glycaemic group (HbA1c < 7%) or a poorly controlled group (HbA1c ≥ 7%). Differences between the two groups in terms of their risk factors for poor glycaemic control were investigated. Patient related risk factors studied included, basic demographic, treatment related, clinical, behavioural and lifestyle characteristics. Healthcare professionals and facility managers were interviewed and patient records were reviewed to describe health system challenges to providing optimal care. Univariate and multivariate logistic regression models were used to determine patient related factors influencing glycaemic control. Results: Of 394 patients with a measurable outcome (HbA1c), only 62 (15.7%) had well controlled diabetes. The mean HbA1c was similar across the three CHCs studied (p=0.464). Good glycaemic control was significantly associated with unemployment, shorter duration since diabetes diagnosis, treatment with oral medication alone and normal LDL-cholesterol levels (p<0.05). On multivariate analysis significant predictors of good glycaemic control were found to be a shorter duration since diabetes diagnosis, treatment with oral medication alone, being male, and those who were unemployed. Numerous challenges to providing optimal diabetes care were reported by health professionals including high patient to staff ratios, lack of working equipment as well as a need to improve diabetes management skills. Record review revealed that only a limited number of patients (16%) had ever had HbA1c testing. Conclusions: The majority (84.2%) of patients attending the selected facilities for diabetes care had poor glycaemic control. Management of diabetes in these CHCs is suboptimal. Patients with a shorter duration of diabetes, those who were male, Black African, unemployed and treated with oral medication alone were more likely to have good glycaemic control. Although the study concludes that patient related factors are at the forefront in terms of factors influencing glycaemic control, improved strategies in all spheres can only improve diabetes management at the CHCs.

In order to examine the effects of industry processed pulse powder (navy bean, lentil and chickpea) on postprandial glycaemic response (BG) and subjective appetite (App) before and after a subsequent meal, three randomized, within-subject experiments on healthy young men were conducted. In experiment 1, all navy bean treatments reduced BG at 30 min and navy bean powder suppressed pre-meal App compared to whole wheat flour. In experiment 2, all lentil treatments reduced pre-meal BG compared to whole wheat flour. However, no App differences were observed. In experiment 3, all chickpea treatments reduced pre-meal BG compared to whole wheat flour. However, no App differences were observed. Therefore, navy bean powder, lentil powder and chickpea powder maintain their low GI and satiating effects, regardless of processing. Pulse powder can be used as a value-added food ingredient to moderate glycaemic response and increase satiety.

In order to examine the effects of industry processed pulse powder (navy bean, lentil and chickpea) on postprandial glycaemic response (BG) and subjective appetite (App) before and after a subsequent meal, three randomized, within-subject experiments on healthy young men were conducted. In experiment 1, all navy bean treatments reduced BG at 30 min and navy bean powder suppressed pre-meal App compared to whole wheat flour. In experiment 2, all lentil treatments reduced pre-meal BG compared to whole wheat flour. However, no App differences were observed. In experiment 3, all chickpea treatments reduced pre-meal BG compared to whole wheat flour. However, no App differences were observed. Therefore, navy bean powder, lentil powder and chickpea powder maintain their low GI and satiating effects, regardless of processing. Pulse powder can be used as a value-added food ingredient to moderate glycaemic response and increase satiety.

Hyperglycaemia is prevalent in critical care and increases the risks of further complications and mortality. Glycaemic control has shown benefits in reducing mortality. However, due in parts to excessive metabolic variability, many studies have found it difficult to reproduce these results. Out-of-Hospital Cardiac Arrest (OHCA) patients have low survival rates and often experience hyperglycaemia. However, these patients belongs to one group who has shown benefit from accurate glycaemic control (AGC), but can be highly insulin resistant and variable, particularly on the first two days of stay. Hypothermia is often used to treat post-cardiac arrest patients or out of hospital cardiac arrest (OHCA) and these same patients often simultaneously receive insulin. In general, it leads to a lowering of metabolic rate that induces changes in energy metabolism. However, its impact on metabolism and insulin resistance in critical illness is unknown, although one of the adverse events associated with hypothermic therapy is a decrease in insulin sensitivity and insulin secretion. However, this decrease may not be notable in the cohort that is already highly resistant and variable. Hence, understanding metabolic evolution and variability would enable safer and more accurate glycaemic control using insulin in this cohort. OHCA patients were undergone preliminary analysis during cool and warm, which includes insulin sensitivity (SI), blood glucose (BG), and exogenous insulin and dextrose. Patients were analysed based on overall cohort, sub-cohorts, and 6 and 12 hour time block. Generally, the results show that OHCA patients had very low metabolic activity during cool period but significantly increased over time. In contrast, BG is higher during cool period and decreased over time. The analysis is equally important as the controller development since it provides scientific evidence and understanding of patients’ physiology and metabolic evolution especially during cool and warm. Model-based methods can deliver control that is patient-specific and adaptive to handle highly dynamic patients. A physiological ICING-2 model of the glucose-insulin regulatory system is presented in this thesis. This model has three compartments for glucose utilisation, effective interstitial insulin and its transport, and insulin kinetics in blood plasma, with emphasis on clinical applicability. The predictive control for the model is driven by the patient-specific and time-varying insulin sensitivity parameter. A novel integral-based parameter identification enables fast and accurate real-time model adaptation to individual patients and patient condition. Stochastic models and time-series methods for forecasting future insulin sensitivity are presented in this thesis. These methods can deliver probability intervals to support clinical control interventions. The risk of adverse glycaemic outcomes given observed variability from cohort-specific and patient-specific forecasting methods can be quantified to inform clinical staff. Hypoglycaemia can thus be further avoided with the probability interval guided intervention assessments. Simulation studies of STAR-OHCA control trials on ‘virtual patients’ derived from retrospective clinical data provided a framework to optimise control protocol design in-silico. Comparisons with retrospective control showed substantial improvements in glycaemia within the target 4 - 7 mmol/L range by optimising the infusions of insulin. The simulation environment allowed experimentation with controller parameters to arrive at a protocol that operates within the constraints found earlier during patient analysis. Overall, the research presented takes model-based OHCA glycaemic control from concept to proof-of-concept virtual trials. The thesis employs the full range of models, tools and methods to optimise the protocol design and problem solution.

Magister Scientiae Dentium - MSc(Dent) / Introduction: The relationship between Periodontal Disease and Type II diabetes has been reported in recent literature. More recent studies suggest that further research is required into the relationship of glycaemic control on Periodontitis. The main aetiological factor in Periodontal Disease is plaque; however other secondary factors such as Diabetes Mellitus, neutrophil abnormalities, smoking, socio-economic status, age, stress, Human Immunodeficiency Virus (HIV) infections, pregnancy, sex hormones, osteoporosis and several other conditions play an important causative role (Genco, 1993). Aim: The purpose of this study is to test the hypothesis that the prevalence and severity of periodontal disease is greater for patients with poorly controlled Type II Diabetes Mellitus (DM-2) compared to those with better controlled Type II Diabetes Mellitus. Methods: 'Coloured female patients', who were diagnosed with Type II diabetes were included in the study. Demographic information, medical history and HbA1c levels were recorded by the attending physician in the diabetes unit. Periodontal examination was carried out by a single examiner. This included a plaque index (PI), a gingival index (GI), bleeding on probing (BoP), probing depths (PD) and clinical attachment loss (CAL). These measurements were recorded on Ramfjord teeth. The presence of any one sextant showing PD of ≥ 4 mm or clinical loss of attachment of ≥ 3 mm was diagnosed as periodontitis. Results: Poor glycaemic control was associated with more severe periodontitis. Conclusion: The results of the study showed that it could be justified that the regression approach (correlation) be applied to the complete sample of 63 individuals. Most of these correlation coefficients were positive and significantly different from zero, indicating that 'HbA1c' had a detrimental influence on the periodontal measurements; within the limitations of the study. This link could be indirect in that some other properties of diabetes, and not necessarily 'HbA1c', affected the dental health of diabetics adversely.