Dissertations / Theses on the topic 'Diabetes – Complications'

Cystic fibrosis-related diabetes (CFRD) is a secondary form of diabetes, associated with increasing age in subjects with Cystic Fibrosis (CF). With improved life expectancy, CFRD is anticipated to increase in prevalence in addition to its complications. The aim of this study was to investigate the use of HbA1c as an early predictor of disease, as well as investigate microvascular and macrovascular complications in an adult CF cohort attending the All Wales Cystic Fibrosis Centre. The current method of using the conventional oral glucose tolerance test (OGTT) to diagnose CFRD was compared to using glycated haemoglobin (HbA1c). The findings demonstrated that a HbA1c value ≥ 5.5%/36mmol/mol was significantly predictive of the development of dysglycaemia over a 6-year period. The association between HbA1c and development of diabetic retinopathy (DR) was analysed. The study demonstrated 23% of CF patients with CFRD screened for DR had evidence of moderate to severe diabetic retinopathy. They had a higher HbAc1 and longer duration of CFRD compared to those without severe forms of DR. This suggests that microvascular complications are present in CFRD and to a similar extent as in type 1 diabetes mellitus. The prevalence of cardiac autonomic neuropathy (CAN) in CFRD was tested in 71 subjects with CF. CF subjects who were of an older age group demonstrated an inverse correlation with heart rate variability (HRV) during deep breathing (p < 0.05). CF dysglyaemic individuals with severe forms of diabetic retinopathy had reduced HRV during deep breathing compared to subjects with mild or no DR (p < 0.05). The presence of arterial stiffness in CFRD was examined in 65 CF subjects and 31 healthy volunteers. Age, gender and mean arterial pressure were significant predictors of increased augmentation index (AIx) and pulse wave velocity (PWV). Glycaemic control did not influence the arterial stiffness measurement outcomes. The CF group demonstrated a greater Aix than healthy volunteers (HV) (P < 0.05) when other variables were controlled in the analysis, suggesting possible increased inflammatory mechanism leading to increased Aix accounting for these findings. CF dysglycaemic subjects had greater PWV than CFNGT subjects which was only significant at the 10% level. The study findings demonstrate HbA1c has a predictive value in the diagnosis of CFRD based on a positive OGTT. Severe DR is prevalent in CFRD and is associated with a reduction in HRV during deep breathing. Glycaemic control is not predictive of arterial stiffness, in contrast to age, gender and MAP. Thus future consideration of the use of HbA1c may help to predict individuals with underlying dysglycaemia and reduce the risk of the development of associated microvascular complications.

Diabetes mellitus is a group of metabolic diseases characterized in disordered blood glucose levels with many altered genes, proteins and metabolites. The chronic hyperglycemia in diabetes damages organ systems and makes the diabetic patients vulnerable to one or more complications. The onset of diabetes and complications in diabetes are estimated to occur 5 to 10 years before the clinical diagnosis. The early diagnosis of diabetes prevents the damage and pathological progress of diabetes and complications in diabetes. The central hypothesis of this study was that the protein N-glycosylation pathway in diabetes might be influenced by elevated hexosamine flux in diabetes elevating sugar nucleotide levels. This, in turn, might affect the N-glycan branching pathway and result in detectable changes in plasma glycoprotein glycoforms. The aim of the study was to discover potential glyco-biomarkers for diabetes and complication in diabetes. Mass spectrometry based glycomic quantification was performed to look for alterations in N-glycan profiles between normal and diabetic plasma samples. Fucosylated N-glycans and intersected N-glycans were found to be up-regulated in diabetes with statistical significance. The elevated fucosylation in diabetes was verified at the glycosylation site level by quantitative Aleuria aurantia lectin (AAL) pull-down experiments. Fucosylated fetuin-A and α-1-acid glycoprotein were selected as candidate glyco-biomarkers. A lectin ELISA using F(abʹ)2 fragments as capture antibody was developed to validate the fucosylation changes by screening 20 normal and 20 diabetic patient plasma samples. We conclude that the fucosylation level of fetuin-A is a potential glyco-biomarker for diabetes. Additional work is necessary to see whether this glyco-biomarker correlates with any pathological complications of diabetes.

Diabetes mellitus is a chronic disease that affects millions of people in the United States. The purpose of this project was to develop a guideline to help clinical staff provide clear and concise diabetes self-management instructions to patients in a community setting. Orem's self-care deficit theory (SCD) and health belief model (HBM) provided a platform to assess how patients' self-care deficit contributes to illness and the effect of patients' perception of illness. SCD theory and the HBM provided the framework for the development of the guideline to decrease diabetes acute complications through self-management education. The practice-focused question was whether the diabetes treatment guideline would decrease diabetes complication, improve the quality of care received by the diabetic patients, and if the facility would adopt the developed guideline. AGREE II Tool was used to assess the quality of the guideline and the staffs' desire for the adoption of the guideline. Data were collected from questionnaires given to staff members at the practice site in 2 rounds. Six medical staff were asked to critique the initial guideline, and 5 medical professionals were asked to assess the final guideline. Most of the participants' scores indicated strong agreement that full consideration was met. The score in all 6 AGREE II domains was above 90%, and 100% of the participants recommended the guideline to be adopted in the facility. Data analysis indicated the diabetes practice guideline is valid, will enhance the treatment of diabetes, and the practice site employees were eager to adopt the treatment guideline. Findings may be used to increase population health and reduce acute complications from diabetes mellitus.

Diabetes mellitus has been associated with both clinical and experimental cardiac dysfunction. Diabetic cardiomyopathy which is characterized by depressed cardiac contractility is accompanied by a variety of biochemical changes in Ca⁺⁺ metabolism. This cardiomyopathy may occur in the presence of normal coronary arteries and normal blood pressure. However, some studies have shown that hypertension is more prevalent among diabetics and can aggravate the cardiovascular abnormalities associated with diabetes. To understand the mechanisms of diabetic cardiomyopathy and consequences of combined hypertension and diabetes, experiments were designed to measure cardiac tissue responses to various inotropic agents in experimental diabetes. Six weeks following streptozotocin (STZ) administration, Wistar, spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats exhibited the 'classical signs' of diabetes which included: hyperglycemia, hypoinsulinemia, hyperlipidemia (except in WKY), and hypothyroidism. Decreased basal atrial rate and increased basal developed force (BDF) suggest a depressed SA node function and an alteration of Ca⁺⁺ utilization by diabetic ventricles. Decreased post quiescent potentiation (PQP) values (except in WKY) in ventricular tissues suggest a diminished amount of releasable Ca⁺⁺ from sarcoplasmic reticulum (SR). Decreased post stimulation potentiation (PSP) values in SHR papillary muscles (PM) are probably suggestive of a depressed sarcolemmal Na⁺-Ca⁺⁺ exchange function in this tissue. Diabetic rats show subsensitivity to β-adrenergic stimulation in ventricular tissues, supersensitivity and hyperresponsiveness to Ca⁺⁺ and α-adrenergic stimulation (except in WKY) in ventricular tissues and left atria (LA) and supersensitivity to BAY K 8644 in SHR LA and hyperresponsiveness to verapamil in ventricular strips. These alterations may be attributed to a change in receptor number and/or a post receptor alteration. Ryanodine decreased the PQP of Wistar and SHR PM and SHR LA in both controls and diabetics. It especially abolished PQP in SHR diabetic tissues, but had no effect on WKY tissues, which may suggest a difference in the SR function in these tissues. SR with impaired Ca⁺⁺ uptake may contribute to these phenomena in diabetic rats. Ryanodine also diminished (PQP + BDF) of SHR LA and (PQP/BDF) of Wistar and SHR PM, ˙but had no effects on control and other diabetic tissues. It appears that ryanodine has some influence on the Na⁺-Ca⁺⁺ exchange generated by sarcolemma (SL) of certain diabetic tissues. Further experiments are required to clarify this. SHR diabetic rats had greater changes in most of the measurements such as hyperlipidemia, depressed PQP and PSP values, and altered drug responses. This model exhibited very high mortality as compared to Wistar and WKY diabetic rats. As has been shown previously, the combination of hypertension and diabetes exerts a synergistic effect on the cardiac dysfunction in this model, and that altered lipid metabolism, SL and SR function are all involved in the development of cardiomyopathy. WKY diabetic rats, on the other hand, exhibited no significant changes in blood lipids, or in response to phenylephrine or to Ca⁺⁺ (LA) stimulation. Lack of change in these factors may explain the relatively normal cardiac function of this model as measured previously.
Pharmaceutical Sciences, Faculty of
Graduate

Diabetes mellitus (DM) is a metabolic disease resulting from failures in the production or response to the hormone insulin. Much of the pathogenesis and mortality attributed to DM are due to the long-term complications of hyperglycaemia, which is characteristic of the disease. This thesis presents structural and functional studies of two previously uncharacterised human enzymes, dihydrodipicolinate synthase-like protein (DHDPSL) and D-xylulokinase (XK). Both enzymes were revealed to have unexplored associations with DM. DHDPSL is distantly related (~25% sequence identity) to a family of Schiff base-dependent aldolases that include dihydrodipicolinate synthase and N-acetylneuraminate lyase. Despite these distant homologies the biological function of DHDPSL is unknown. It also does not map to any known metabolic pathway in humans, but is targeted to the mitochondrial compartment consistent with the presence of a mitochondrial targeting sequence. There are also strong associations between mutations in the Dhdpsl gene and primary hyperoxaluria type III a rare disorder of endogenous oxalate production. The DHDPSL crystal structure was determined by X-ray crystallography utilising in situ proteolysis of a fusion of DHDPSL with maltose-binding protein for crystallisation. Two apoforms and six Schiff base complexes with potential ligands were analysed at best to 2.0 A�� resolution and with an Rfree of 18.3%. DHDPSL is folded as (a/ss)���-barrel with a C-terminal subdomain and forms a tetramer in the crystal. The structural consequences of the diseaserelevant DHDPSL mutations were analysed and were found to largely affect the C-terminal subdomain. Findings also showed that DHDPSL acts as an oxaloacetate decarboxylase and is therefore likely to be a bifunctional oxaloacetate decarboxylase /4-hydroxy-2-ketoglutarate aldolase present in the liver and kidney mitochondria. Overall, these results revealed the presence of a potentially significant metabolic pathway in mitochondria whereby oxaloacetate can be converted to pyruvate. XK has a potential role in the regulation of de novo lipogenesis in the liver that has gained little previous attention. Excessive hepatic lipid accumulation is linked to impaired insulin response and the development of DM. XK was identified and produced recombinantly in Eschericia coli aided by molecular chaperones. Crystals suitable for structural analysis were obtained after five generations of repeated seeding. Five crystal structures were used to analyse substrate binding, the best of which was determined at 2.0 A�� resolution with an Rfree of 17.8%. XK assumes an actin-like two-domain FGGY sugar kinase fold. The most striking feature revealed by the XK molecular structure was a dramatic domain movement that must accompany catalysis. A competitive inhibitor of XK, 5-deoxy-5-fluoro-D-xylulose (Ki of 25.4 M) was also functionally validated and structurally analysed. A supplemental structural study of a major hypoxic response protein of unknown function, Rv1738, from the causative agent of tuberculosis, Mycobacterium tuberculosis is also described. This study presents the first novel protein structure to be determined by the racemic protein crystallography method. The Rv1738 structure exposes a relationship with a family of ribosome-inhibiting stress-response proteins that may be indicative of its function.

This thesis examined the incidence and temporal trends of Type 1 diabetes diagnosed in Northern Ireland children using data from the Northern Ireland Childhood Diabetes Register (NICDR). Overall, there was evidence of a departure from linearity in incidence with indications that rates are levelling off in recent years. Further analyses also indicated that birth cohort effects were evident in the incidence rates suggesting that exposures in early life may play an aetiological role in this condition. A systematic review and meta-analyses was performed in this thesis to investigate the association of childhood vaccinations and subsequent risk of Type 1 diabetes. Twelve studies investigating a range of vaccinations were included. Results provided no evidence to suggest an association between childhood vaccinations and risk of Type 1 diabetes. A study using data from the Clinical Practice Research Datalink (CPRD) was included in this thesis to report findings on depression and other complications in young people diagnosed with Type 1 diabetes. This study found that rates of depression were significantly higher in cases with diabetes compared to controls without diabetes. Results also showed elevated rates of microvascular complications and significantly higher rates of cardiovascular disease compared to matched controls. Another focus of this thesis was on mortality in individuals with Type 1 diabetes. Population-based studies reporting relative mortality in Type 1 diabetes diagnosed in young people were systematically reviewed. In total, 23 independent studies were included. Associations between relative mortality and study/ country characteristics were explored. In addition to this review, a further two UK-based studies were performed to investigate mortality, one using data from the NICDR and the other using the CPRD. Both studies found excess mortality rates in individuals with Type 1 diabetes when compared, respectively, to the general population and to a group of controls without diabetes.

There is increasing evidence to suggest that genetic factors are involved in the pathogenesis of microvascular complications in diabetes mellitus. Recent studies have suggested that genetic variations in the aldose reductase (ALR2) gene may contribute to the genetic susceptibility to microvascular complications. Aldose reductase is the first and rate-limiting enzyme of the polyol pathway and is implicated in the pathogenesis of diabetic microvascular disease (nephropathy, retinopathy and neuropathy). It has recently been shown that the three polymorphisms of the ALR2 gene are associated with susceptibility to microvascular complications in both TIDM and T2DM. The aim of this study was to investigate the CA dinucleotide repeat polymorphism (5'ALR2) that is located -2100bp and the C-106T substitution in the promoter region of the ALR2 gene, and also the A+ 11842C within intron 8 of the ALR2 gene itself. DNA from 285 Caucasoid patients with TIDM and well-defined microvascular disease and 120 normal healthy controls, as well as 60 Southern Indian patients with T2DM and 43 non diabetic controls were typed. The 5'ALR2 Z-2/X genotype was significantly increased in patients with nephropathy (n=92), retinopathy (n=160) and neuropathy (n=104) compared to those with no microvascular disease after 19 years duration of diabetes (uncomplicated, n=66) (46%, 41%, 42% vs. 24%, respectively). In contrast, the frequency of the Z+2/Y genotype (where Y is not Z-2) was significantly reduced in the patients with nephropathy, retinopathy and neuropathy compared to the uncomplicated (17%, 23%, 23% vs. 52%, respectively). Similar observations were made in the Southern Indian T2DM patients, however no significant differences were found. In the patients with TIDM the C-106 allele was associated with the Z-2 5'ALR2 allele. The C/Z-2 haplotype was present in 32% of the nephropaths, 32% of the retinopaths and 35% of the neuropaths compared to 11.5% of the uncomplicated. The A+ 11842 allele was also associated with the C-1 06 allele in TIDM patients with microvascular disease. The reported mitochondrial polymorphism (mt5178A/C) was not found in this. TIDM population, possibly due to differences in the background frequencies between ethnic groups. Family studies investigating the transmission of the 5'ALR2 and C-106T alleles from parents to offspring with diabetic nephropathy found preferential transmission of the Z-2 allele although this was not statistically significant. Functional studies of the activity of the ORE in TIDM patients with and without microvascular disease showed differences in the mean OREBP binding activity. OREB and OREC were found to have increased activity in response to hyperglycaemia in the complicated patients compared to the uncomplicated and normal controls. In conclusion, these results confirm the role of the aldose reductase gene in the genetic susceptibility to diabetic microvascular complications, and a possible role of the DI7S934 polymorphism in T2DM. These results also provide a novel insight into the role of the ORE of the ALR2 gene in the pathogenesis of diabetic microvascular complications. Further studies are now required to determine the molecular basis of these observations. Hopefully, in the future it will be possible to offer 'high risk' patients therapeutic intervention that will prevent the ravages of the long term complications of diabetes mellitus.

Background: African American (AA) women have a disproportionately higher prevalence of Type 2 Diabetes Mellitus (T2DM) and its related complications than Hispanics and non-Hispanic white women. Cultural practices, stigmatization, discrimination, socio-economic status, historical experiences and geographical locations have all been proposed as factors that influence the prevalence of T2DM in AA women. However, no study has explored how AA women with T2DM perceive their risk of developing diabetes complications, and how their risk perceptions impact their diabetes self -management. Purpose: The purpose of this study was to describe the perceptions that AA women diagnosed with T2DM have of their risks of developing DM complications, how their perceived risk of diabetes complications influences their DM self-management, and how the socio-cultural and economic contexts in which DM management occurs influences AA women's DM self-management behaviors. Method: A qualitative descriptive study was used to provide a comprehensive description of the perception of risk for developing diabetes complications among AA women with T2DM. A purposive sample of 10 AA women with T2DM was selected for the study. Findings: Findings revealed that the risk perception for developing DM complications influenced DM self-management among AA women with T2DM. Sociocultural and economic factors were also found to influence DM self-management among AA women with T2DM. Conclusion: This study revealed numerous factors that were associated with development of diabetes complications among AA with T2DM. However, risk perception stood out to be associated with all the factors.

Mild thiamin deficiency is prevalent in diabetes, and high dose thiamin ameliorates some diabetic complications, but there are no definitive studies addressing thiamin intake, diabetes control and thiamin status in diabetes. Subjects were 113 people with diabetes (58 type 1, 55 type 2), 43 with and 70 without thiamin supplementation. Dietary thiamin was estimated by 24-hour recall, diabetes control by HbA1c. Age, BMI, albumin excretion, activity level and smoking status did not correlate with red cell thiamin (RCT) in either group. RCT correlated with serum thiamin (ST) (p < 0.01). In those unsupplemented, adequate dietary thiamin did not ensure normal RCT, with 15.7 % of subjects below the reference range. Supplementation to intake > 4 mg/d, was significantly associated with normal RCT (p = 0.028), with 97.7% of supplemented subjects having normal RCT. Supplementation was also significantly associated with elevated serum thiamin 24 hours post supplementation, contrary to other reports. HbA1c was not significantly associated with RCT. Conclusions: In diabetes, adequate dietary thiamin does not ensure normal red cell thiamin, but supplementation to > 4 mg/day does, raising questions about actual thiamin requirements in diabetes and supporting evidence that thiamin deficiency in diabetes is not primarily due to dietary deficiency. Diabetes control was not significantly related to thiamin status.

Class of 2007 Abstract
Objectives: To determine the effect of antihypertensive use on renal function and other diabetic complications in adults over the age of 18 with type 2 diabetes mellitus (DM). Methods: A retrospective secondary analysis of the NIH Pima epidemiologic data included 1,828 individuals with type 2 DM were evaluated for antihypertensive use and DM complications. Statistical analysis was done using general linear model regression (GLM) or logistic regression models controlling for age, sex and DM duration. Three groups were established to evaluate antihypertensive use Group 1 those taking antihypertensives to those not taking antihypertensives, Group 2 those taking more than one (multiple) antihypertensives to those only taking one and Group 3 those taking an angiotensin converting enzyme (ACE) inhibitor to those not taking an ACE. Results: Group 1 those taking antihypertensives were significantly worse for all outcome measures than those taking no antihypertensives as evident with: renal function (ACR 43 mg/mmol versus 15.9 mg/mmol (ρ=0.0003) and albuminuria 55.8% versus 37.6% (p=0.0039), retinopathy, neuropathy and CVD. Group 2 those taking multiple antihypertensives had significantly worse renal function (ACR 69.2 mg/mmol versus 34.5 mg/mmol (p=0.0329) and albuminuria 63% versus 52% (p=0.0396)), CVD while retinopathy and neuropathy were not significantly different. Group 3 those taking ACE had significantly worse renal function (ACR 43.8 mg/mmol versus 35.2 mg/mmol (p=0.0329)) while CVD was improved and no difference was observed in retinopathy and neuropathy. Conclusions: Antihypertensive use had little impact on preventing diabetic complications. This is contrary to well- documented literature that supports the use of antihypertensives to slow disease progression and protect renal function.

The research investigated Australian diabetes health professionals’ (DHPs’) knowledge and their intervention, health promotion, and care management of oral health issues which impact upon the person with diabetes. Results identified the need for enhanced provision of diabetes-specific oral health education, clinical resource tools, and the delivery of oral health services. The findings were discussed within the context of the current health system policies and their impact upon DHPs’ management of diabetes related oral health complications.

OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

Master of Public Health
OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

My studies consider the genre of children's literature, specifically picture books, and their treatment of the topic of diabetes. I frame my argument with an examination of diabetes, the psychological effects of diabetes on the child, the need of thorough education about diabetes. I argue for the use of the picture book as an effect tool in educating and socializing the diabetic child. I first explore the implications of diabetes and the long term complications caused by one's poor control of the disease. I then explore the psychological ramifications of a chronic illness on the young child. Next I assert the need to combine the physiological and psychological factors of diabetes into a responsible text for children, one which both serves as an educating tool and a source of comfort in difficult times with the disease. I conclude my studies with critiques of existing materials in the limited genre and compare them to the story I have written for children about diabetes.
Master of Arts

The appropriateness of universal screening for gestational diabetes mellitus (GDM) has been strongly questioned, since it does not satisfy ethical principles for screening.

The aims of these studies were to determine the prevalence of GDM, expressed in terms of impaired glucose tolerance (IGT) and diabetes mellitus (DM), to evaluate different screening models using traditional anamnestic risk factors and repeated random B-glucose, to determine whether GDM increases risks for maternal complications such as preeclampsia, and to determine whether IGT during pregnancy, if left untreated, is associated with increased maternal or neonatal morbidity.

Of 4,918 pregnant non-diabetic women attending maternal health care, 73.5% agreed to have a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed in 1.7%, IGT in 1.3% and DM in 0.4%. Traditional risk factor criteria were fulfilled by 15.8%. Prior GDM and a prior macrosomic infant showed the highest association with GDM. No selective or two-step universal screening model would have detected all cases of GDM. A constructed model comprising prior GDM, a prior LGA/macrosomic infant, or a cut-off random B-glucose level of 8 mmol/l as an indication for OGTT reduced the need for OGTT to 7.3% compared to the selective screening model with traditional risk factors. Such a universal two-step screening model had 100% sensitivity for DM, and 44.7% sensitivity for IGT.

The Swedish Medical Birth Register was used to evaluate GDM as risk factor for preeclampsia. GDM occurred in 0.8% and preeclampsia in 2.9% of 430,852 singleton pregnancies. There is an independent and significant association between GDM and preeclampsia. Obesity is a major confounding factor, but cannot explain the total excess risk.

In a prospective population-based case-control study 213 women with untreated IGT during pregnancy were identified. For each case, four controls were recruited from the same delivery department. The analyses confirmed that maternal and fetal morbidity were increased in the cases in terms of cesarean section rate, pre-term delivery, Erb’s palsy and admission to NICU. There was a marked, independent increase in the proportion of LGA infants (OR 7.3; 95% CI 4.1-12.7). To determine whether treatment has an effect when IGT is diagnosed during pregnancy, a randomized study is required.

Abstract The markers of microvascular complications of type 1 diabetes were evaluated in adolescents in a cross sectional survey of 100 out of 138 eligible patients aged 9-19 years with a duration of diabetes over two years who visited the Paediatric Outpatient Clinic at Oulu University Hospital in 1997-1999, and one hundred healthy controls. Two patients in early or mid-puberty had non-proliferative diabetic retinopathy, but no other signs of microvascular complications. The five patients with persistent microalbuminuria were all girls; one prepubertal, one late pubertal and three postpubertal. Their mean glycated haemoglobin A1c (HbA1c) was higher, but they had a similar duration of diabetes and age distribution to those without microalbuminuria. The adolescent patients were predisposed to higher fasting serum total and low-density lipoprotein cholesterol and triglyceride levels and higher diastolic blood pressure than the control subjects. The proportional total body fat was highest in the girls with diabetes by the end of puberty, while serum leptin levels did not differ between the patients and healthy controls. The patients had low fasting serum insulin levels and high insulin-like growth factor-binding protein 1 levels, related to hypoinsulinaemia. Distal motor nerve function in the lower extremities were already affected before puberty, and distal and proximal nerve function deteriorated as puberty advanced. Ten patients had neurophysiologically confirmed distal diabetic polyneuropathy, and they were older and they had longer duration of diabetes and higher HbA1c than patients without polyneuropathy. Although cardiovascular function was in the main well preserved in the adolescents with type 1 diabetes, the power spectrum analysis of heart rate variability showed attenuated autonomic nervous system reactivity. Taken together these data show that a relatively small proportion of adolescents with type 1 diabetes have signs of microvascular complications. The prevalences of diabetic retinopathy, persistent microalbuminuria and distal diabetic polyneuropathy were 2%, 6% and 10%, respectively. Pubertal maturation seems to promote the progression of early signs of microvascular complications in patients affected by type 1 diabetes.

Thesis (MFamMed)--Stellenbosch University, 2015.
ENGLISH ABSTRACT: Introduction: Diabetes is the most prevalent endocrinology problem encountered in primary care practice. If recent trends showing a dramatic increase in prevalence (believed to be a consequence of a decline in physical activity and excessive caloric intake) continue, then the condition will soon affect nearly 20 million people in the U.S a reflection of the global trend. Effective management requires care that is thoughtful and meticulous, incorporating intensive patient education. Euglycemic control, with the level of glycosylated haemoglobin (HbA1c) kept below 7.0mmol/L, has emerged as a major treatment objective because of its association with a marked reduction in the risk for micro vascular complications. The primary physician is in the unique position to provide comprehensive care to the diabetic patient. Setting: The aim of this study is to evaluate the profile of complications arising due to diabetes mellitus among adult diabetics attending internal medicine outpatient department and family medicine/primary care outpatient department in the Dora Nginza hospital, PE hospital complex. Method: The study is a descriptive retrospective study in which names of patients were collated from clinic records of both clinics, files sought at the records department covering the period between Jan 2007 and Jan 2008 inclusive. Prevalence of statistical variables was generated using frequency tables, bar graphs, cross tabulations and chi square test. Results: Hyperglycemia was the major complication which predominantly was associated with high haemoglobin A1c (HbA1c) levels. However, some hyperglycaemic cases were also found to be associated with normal HbA1c. Complications were found to be more in type 2 diabetics. Patients with hypertension, obesity, smoking and alcohol use were observed to have a higher risk of developing diabetic complications. The findings on retinopathy in this study was inconclusive in view of the fact that patients sent for fundoscopy did not return with documented results from the sister hospital PE provincial hospital. Family Medicine outpatient department overall did better in patient care compared to the Internal Medicine outpatient department. Conclusion: The challenge for the primary care physician is to design a therapeutic program that is safe practical and acceptable to the patient. The ultimate goal of therapy is the prevention of micro vascular and macro vascular complications, consequence of diabetes that makes the condition a major risk factor for cardiovascular disease, stroke, visual impairment, renal failure, impotence, peripheral neuropathy, limb loss and ultimately death. These can be averted through appropriate education of both hospital staff, patients and their care givers. The recommendations made are based on the findings of the study.
AFRIKAANSE OPSOMMING: Nie beskikbaar.

Thesis (M Med (Family Medicine) -- University of Limpopo, 2011.
Introduction The burden of type 2 diabetes mellitus continues to rise and constitutes a real threat especially in the developing world. As for most non-communicable diseases, change of behavior and adoption of healthy lifestyle habits help to prevent and slow down the increase of type 2 diabetes mellitus. Aim of the Study To establish the knowledge, attitudes and practices regarding lifestyle modifications among type 2 diabetic patients attending the diabetic clinic at Mamelodi hospital. Methods: This cross sectional study describes the knowledge, attitudes and practices regarding lifestyle modifications (KAP) among 217 type 2 diabetes mellitus patients attending Mamelodi Hospital, Pretoria, Republic of South Africa. A face-to-face interview using a structured questionnaire was carried out for data collection. Socio-demographic characteristics of the participants and anthropometric measurements were obtained and the body mass index (8MI) of participants were determined. The Knowledge, attitude and practice of participants were assessed. 2 Results: Majority of participants were female 176(81.1 %), while male were 41 (18.9%). This amounted to a female to male ratio of 4:1. Most participants were in the age group 51-60 years 93(42.9%). Majority of them had low level of education 108(49.5%) and low income 206(94.9%). Majority of participants were obese 153(71 %) with more female diabetic patients being obese 120 (78.4%) than male 33 (21.6%). 15 participants (14 females and 1 male) were morbidly obese (BMI~40kg/m2). 108 participants (49.5%) did not have a formal education. No respondent had good knowledge and 92.6% of respondents had poor knowledge of the benefits of exercise, weight loss and healthy diet. Majority of respondents (97.7%) had bad practices in relation to lifestyle modifications. Nevertheless, majority of them (84.3%) had positive attitudes toward lifestyle modifications. Significant positive correlation (r= 0.170, p=0.012) was found between the global knowledge level and attitude level alone, whereas there was no significant correlation found between the global knowledge level and practice level as well as the attitude level and practice level. Conclusion: In conclusion, despite positive attitudes of participants toward healthy lifestyle habits, the knowledge and practices regarding lifestyle modifications among type 2 diabetes mellitus patients attending Mamelodi Hospital were generally low. Nevertheless the positive attitudes of participants should be encouraged and the implementation of a lifestyle intervention program will help improve the knowledge and practices of type 2 diabetes mellitus patients attending Mamelodi Hospital for the better management and control of this current pandemic of type 2 diabetes mellitus.

The isolated perfused working heart was used to study hypertensive- diabetes induced alterations in cardiac function at 6 and 12 weeks after the induction of diabetes. There was no difference in cardiac function between normotensive Wistar and spontaneously hypertensive (SHR) diabetic rats at 6 weeks after diabetes induction. Wistar-Kyoto (WKY) rats were also included as normotensive controls in our 12-week study. Successful induction of diabetes was confirmed by the presence of hyperglycemia, hypoinsulinemia, glycosuria and increased haemoglobin glycosylation in all three diabetic groups. However, quantitation of various parameters of heart function revealed highly significant differences between SHR diabetic animals and all other groups, associated with an increased mortality. Serum lipids were elevated in SHR and Wistar and unaffected in WKY diabetic rats. Furthermore, thyroid hormone levels were not depressed in WKY diabetic rats and could explain the lack of cardiac dysfunction in these animals. The data provide further evidence that the combination of hypertension and diabetes mellitus produces greater myocardial dysfunction than is seen with either disease alone and is associated with a significant mortality. The effects of hydralazine on blood lipids, systolic pressure and cardiac performance were assessed in male Wistar rats, 6 weeks after they were made diabetic with streptozotocin (STZ). When hydralazine was administered for a 6-week period to the diabetic rats, their blood lipids were not significantly different from that of non-diabetic rats despite a low serum insulin. In contrast, blood lipids were elevated in the diabetic rats that were not treated with hydralazine; these animals also had low insulin levels. Cardiac performance was depressed in the untreated diabetic animals, but the cardiac performance of the hydralazine-treated diabetic animals showed a definite improvement which could be partly explained by their normal thyroid status in contrast to the untreated diabetic animals which were slightly hypothyroid. Blood pressure was elevated only in the untreated diabetic animals. Thus hydralazine controlled the high serum lipids and blood pressure and improved cardiac performance in STZ diabetic rats. To examine the influence of sex differences in the STZ model of diabetes, we studied left ventricular function in hearts from 6 week male and female rats. Significantly lower values for +dP/dt occurred in male diabetic rats compared with their own controls or female diabetics at most left atrial filling pressures. Decreases in this value for female diabetic rats compared to their own controls occurred only at high left atrial pressures. It appears that diabetes mellitus produces greater myocardial dysfunction in male diabetic rats.
Pharmaceutical Sciences, Faculty of
Graduate

Diabetes mellitus is a lifelong, incapacitating disease affecting multiple organs. Worldwide prevalence figures estimate that there are 250 million diabetic patients today and that this number will increase by 50% by 2025. The disease is associated with devastating chronic complications including coronary heart disease, stroke and peripheral vascular disease (macrovascular disease) as well as microvascular disorders, leading to damage of kidneys (nephropathy) and eyes (retinopathy). These complications impose an immense burden on the quality of life of the patients and account for more than 10% of health care costs in Europe. Therefore, novel means to prevent the onset and the progression of these devastating diabetic complications are needed. The aim of the work presented in this thesis is to propose novel computational methods to study diabetes complications with a multi-level approach. Diabetes mellitus is a strongly multifactorial disease, and several risks factors (such as genetic, and environmental factors) are combined together in a complex trait, leading to the onset of the disease. Physiological mechanisms that underlie the disease and the onset and progression of the different complications are still mostly unknown. Given the complex nature of diabetes, the study of the complications can be faced with a multi-level modeling approach. In the general scheme for complex disease, such as diabetes, 3 key elements act together to determine the disease status (outcome) of a patient: i) the phenotype, i.e. the set of all metabolic, anthropometric and clinical variables characterizing the patient, ii) the genotype, i.e. the DNA sequence of the patient, iii) the set of interventions on the patient, i.e. therapies and treatments with drugs. All these 3 variables are connected each other through interactions and have a joint effect on the final outcome of the patient. The multi-level approach allows to disjoint the full problem into sub-problems, focusing only on a set of variables and interaction (reflecting a specific level of information) according to available data. In the present work, 3 main levels of study of diabetes complications are considered, and, for each approach, novel methodologies developed during my PhD are proposed. The 3 levels of study considered in the present work are: i) modeling the effect of genotype on the outcome, ii) modeling the effect of phenotype and treatment on the progression of the outcome, iii) modeling the effect of treatment on the phenotype. In the first level of study, diabetes complications are studied from a static point of view, i.e. without considering their progression over time, and the main objective is to identify the genetic biomarkers that allow to predict the disease state of the patients with the final goal to stratify patients according to the risk of developing the disease. Genome Wide Associations Studies (GWAs) are statistical studies aiming at identify those SNPs able to explain the differences observed for a certain outcome (the disease status) between cases (diseased subjects) and controls (healthy subjects) in a study population. Several methods performing univariate and/or multivariate selection have been used in literature for the identification of genetic markers from GWAs data. In this thesis, a novel algorithm for genetic biomarker selection and subjects classification from genome-wide SNP data has been developed. The algorithm is based on the Naïve Bayes classification framework, enriched by three main features: i) bootstrap aggregating of an ensemble of Naïve Bayes classifiers, ii) a novel strategy for ranking and selecting the attributes used by each classifier in the ensemble, iii) a permutation-based procedure for selecting significant biomarkers, based on their marginal utility in the classification process. The algorithm has been validated on the Wellcome Trust Case-Control Consortium on Type 1 Diabetes and its performance compared with the ones of both a standard Naïve Bayes algorithm and HyperLASSO, a penalized logistic regression algorithm from the state-of-the-art in simultaneous genome-wide data analysis. The second level of study is represented by the dynamic analysis of diabetes complications, where the variable “time” plays a major role. In particular, the objective is to model the onset and the progression of diabetes complications over time, using phenotypic and therapeutic information, with the final goal to estimate a probability for the diabetic patient to develop a certain complication, thus optimizing clinical trials and avoiding invasive and expensive tests. So far, several models of diabetes complications are present in literature, but none is able to flexibly integrate accumulating –omics knowledge (i.e. proteomics, metabolomics, genomics) into a clinical macro-level. The most interesting complication models, in fact, are based on Markov Models (also called state transition model) and use phenotypic information to describe the cohort of interest without the possibility to easily integrate additional information. A new in-silico model for simulating the progression of cardiovascular and kidney complications in diabetic patients is presented. The model proposes, as innovative feature, the use of Dynamic Bayesian Networks (DBNs) for modeling the interactions between variables. Compared to Markov Models, which require as many nodes as the number of combinations of variables’ values, DBNs are more advantageous in handling both the structure and possible additional information, since each variable is simply represented by a node in the network. The model was built relying on data from the Diabetes Control and Complications Trial, a multicenter randomized clinical trial designed to compare intensive with conventional therapy with regard to their effects on the development and progression of the early vascular and neurologic. The developed model is able to predict the progression of the main diabetes complications with an accuracy greater than 95% at a population level. The model is suitable to be used as a decision support tool to help clinicians in the therapy design through cost-effectiveness analysis: exploiting the simulations generated through the model, it is possible, for example, to choose the best strategy between two different therapies for treating a specific cohort of patients. To this aim, a user-interface based on the present model is currently under development. The flexible structure of the model will allow to easily add genotypic information in the next feature as a potential mean to improve predictions. The last level of study focuses on the action of a specific drug on a target phenotype, with the final aim to develop rational means to personalize drug therapy and to ensure maximum efficacy with minimal adverse effects. Focusing on cardiovascular diseases as a direct complication of diabetes, aspirin therapy is an important component of cardiovascular prevention for high risk patients. Aspirin performs its preventive action by inhibiting a key enzyme (the prostaglandin-endoperoxide synthase PTGS-1, also known as cyclooxygenase COX-1) in the cascade leading to the production of thromboxane B2 (TxB2), the major factor involved in the platelets aggregation with consequent formation of thrombi. It is known, from literature, that diabetic patients exhibit a different response to aspirin therapy in comparison to healthy subjects, showing a reduced effectiveness of the drug, which is often referred to as ‘aspirin resistance’. Given the lack of a mathematical characterization of these phenomena, the problem was faced using a pharmacodynamics modeling approach, with an explorative intent. Relaying on biological knowledge retrieved from literature, a partially lumped and partially distributed compartmental model was developed, able to describe: i) the kinetics of COX-1 enzyme, from its production within megakaryocytes in bone-marrow to circulating platelets in blood, ii) the pharmacokinetics and pharmacodynamics of aspirin, i.e. its distribution in the body tissues and its interaction with COX-1. The model was tested using data of serum thromboxane TxB2 recovery levels after aspirin withdrawal in healthy subjects. Possible mechanisms to explain the so-called ‘aspirin resistance’ have been finally discussed.
Il diabete mellito rappresenta una delle patologie più diffuse nel mondo e si stima che la sua incidenza aumenterà del 50 % nell’arco di 15 anni, passando da 250 milioni a quasi 400 milioni di malati nel 2025. La patologia comporta l’insorgenza di devastanti complicanze croniche, tra cui disturbi legati al danneggiamento dei vasi sanguigni sia a livello macro-vascolare – come coronopatia, infarto, insufficienza cardiaca, angina pectoris, ictus – che micro-vascolare, con conseguente danno a carico dei reni (nefropatia) e degli occhi (retinopatia). La patologia diabetica ha un’enorme impatto sia in termini di qualità di vita dei pazienti, sia a livello economico, in quanto si stima che più del 10 % dei costi dell’assistenza sanitaria di tutta l’Europa siano imputabili alla cura del diabete. Per questo motivo, nuovi mezzi che permettano di prevenire l’insorgere e il progredire della malattia e delle sue complicanze sono assolutamente necessari. L’obiettivo del seguente lavoro di tesi è quello di proporre nuovi metodi computazionali per lo studio delle complicanze del diabete in un ambito di modellistica multi-livello. Il diabete mellito è una malattia fortemente multifattoriale, nella quale molteplici fattori di rischio di diversa natura (genetica e ambientale) concorrono a provocarne l’insorgenza e lo sviluppo. I meccanismi fisiologici che sottendono allo scatenarsi e al progredire della patologia sono ancora per la maggior parte sconosciuti. Data la natura multifattoriale del diabete, lo studio delle complicanze si presta ad essere affrontato con un approccio multi-livello. Lo schema generale di una malattia multifattoriale, come il diabete, prevede l’azione combinata di 3 elementi chiave sullo stato patologico (l’outcome) del paziente: i) il fenotipo, ovvero l’insieme di tutte le variabili metaboliche, antropometriche e ambientali caratteristiche del paziente, ii) il genotipo, ovvero la sequenza DNA del paziente, iii) il trattamento, ovvero l’insieme di interventi esterni effettuati sul paziente, come terapie ed utilizzo di farmaci. Queste 3 variabili sono interconnesse tramite interazioni e concorrono tutte insieme a determinare l’outcome del paziente. L’approccio multi-livello consente di scomporre il problema completo in sottoproblemi, focalizzando l’attenzione di volta in volta solo su un sottoinsieme di variabili e di interazioni, a seconda del livello di informazione contenuto nei dati a disposizione. Nel seguente lavoro, vengono considerati 3 principali livelli di studio delle complicanze diabetiche, e, per ognuno dei 3 ambiti, vengono proposti nuovi metodi sviluppati durante il periodo di dottorato. I 3 livelli di studio trattati sono: i) modellizzazione dell’effetto del genotipo sull’outcome, ii) modellizzazione dell’effetto combinato di fenotipo e trattamento sulla progressione dell’outcome, iii) modellizzazione dell’azione del trattamento sul fenotipo. Il primo livello di studio si propone di studiare le complicanze diabetiche da un punto di vista statico, ovvero senza considerare l’evolversi e il progredire di tali complicanze nel tempo, ed ha come obiettivo quello di identificare i principali biomarcatori genetici che consentano di predire lo stato di malattia dei pazienti, e di stratificare i pazienti in base al rischio di sviluppare o meno la malattia. I Genome Wide Association Studies (GWAS), sono studi di associazione volti a identificare gli SNPs che, da soli o in combinazioni con altri SNPs, consentono di spiegare le differenze che si osservano in un determinato outcome (a presenza o meno di una patologia) tra casi (soggetti malati) e controlli (soggetti sani) in una popolazione di studio. Diversi metodi di selezione univariata e multivariata sono presenti in letteratura per l’identificazione di marcatori genetici da studi GWAS. In questo ambito, è stato sviluppato un nuovo metodo per la selezione multivariata di biomarcatori genetici e per la classificazione di soggetti a partire da dati di SNPs di studi GWAS, basato sui classificatori di Bayes e arricchito da 3 principali componenti: i) una predizione ottenuta da un insieme di classificatori di Bayes, utilizzando una strategia basata sul bootstrap, ii) un nuovo metodo per ordinare e selezionare gli attributi selezionati da ogni classificatore, iii) una procedura, bastata sulle permutazioni, per selezionare i biomarcatori significativi, sulla base della loro utilità marginale nel processo di classificazione. Il metodo è stato validato sui dati genome-wide del Wellcome Trust Case-Control Consortium, (WTCCC) relativi a diabetici di tipo 1 e le sue performance confrontate con gli algoritmi rappresentanti lo stato dell’arte in letteratura per studi di associazione genetica, in particolare un classificatore di Bayes e un algoritmo di regressione logistica penalizzata (HyperLASSO). Il secondo livello di studio riguarda l’analisi dinamica delle complicanze, nella quale interviene anche la variabile tempo come fattore chiave. In quest’ottica, si vuole modellizzare l’insorgere e la progressione temporale delle principali complicanze legate al diabete utilizzando l’informazione fenotipica e terapeutica, con l’obiettivo di stimare la probabilità che il paziente diabetico possa o meno sviluppare una certa complicanza, ottimizzando quindi i trial clinici ed evitando esami costosi e invasivi. In letteratura, sono presenti diversi modelli delle complicanze di diabete, ma nessuno è in grado di integrare in maniera flessibile le diverse conoscenze –omiche (proteomica, metabolomica, genomica) ad un livello clinico macroscopico. I principali modelli presenti in letteratura sono infatti basati sui modelli di Markov (detti anche modelli si transizione di stato) e utilizzano l’informazione fenotipica senza la possibilità di integrare facilmente informazioni aggiuntive. In questo ambito di studio, viene proposto un nuovo modello in-silico delle complicanze cardiovascolari e renali del diabete, che propone come aspetto innovativo l’utilizzo delle reti dinamiche bayesiane (Dynamic Bayesian Networks, DBNs) per modellizzare le interazioni tra le variabili. Rispetto ai modelli di Markov, che richiedono tanti nodi quante sono le possibili combinazioni degli stati delle variabili, le DBN hanno il vantaggio di rappresentare ogni variabile tramite un singolo nodo e permettono quindi una maggiore facilità nella gestione della struttura e nell’integrazione di eventuale informazione aggiuntiva. Il modello è stato costruito utilizzando i dati del Diabetes Control and Complications Trial (DCCT), un trial clinico randomizzato condotto con lo scopo di confrontare gli effetti della terapia intensiva rispetto a quelli della terapia convenzionale sullo sviluppo delle complicanze vascolari e neurologiche a lungo termine. Il modello sviluppato, è in grado di predire la progressione delle complicanze diabetiche trattate con un’accuratezza superiore al 95% a livello di popolazione. Il modello si presta quindi ad essere utilizzato come tool di supporto nel processo di decisione terapeutica da parte dei clinici e, in quest’ottica, sta portando alla realizzazione di un’interfaccia web. La struttura flessibile del modello inoltre consentirà di integrare facilmente l’informazione genotipica, con l’obiettivo futuro di migliorare le prestazioni a livello di predizione. Il terzo ed ultimo livello di studio considerato è lo studio dell’azione di uno specifico farmaco su un particolare fenotipo, con l’obiettivo finale di sviluppare metodologie che consentano di personalizzare i farmaci, adattandoli alla specifica risposta dell’individuo. Nell’ambito specifico delle complicanze cardiovascolari del diabete, una delle terapie più diffuse è quella del trattamento con aspirina per la prevenzione di eventi avversi nei pazienti ad alto rischio. L’aspirina deve la sua azione preventiva alla capacità di inibire un enzima chiave (la prostaglandina-endoperossido sintase PTGS-1, conosciuta anche come cicloossigenasi COX-1) nella cascata che porta alla formazione di trombossano B2 (TxB2), il principale responsabile dell’aggregazione piastrinica nel sangue e della conseguente formazioni di trombi. È noto, da letteratura, come i pazienti diabetici rispondano in maniera differente alla terapia con aspirina rispetto ai soggetti sani, evidenziando una risposta ridotta al farmaco, tanto da portare in ambito clinico alla coniazione del termine ‘aspirino-resistenza’. Data la mancanza di una trattazione matematica del fenomeno in letteratura, si è deciso di studiare il problema utilizzando un approccio modellistico di farmacodinamica, con un intento. Utilizzando informazioni biologiche ricavate da letteratura, si è sviluppato un modello, in parte compartimentale e in parte distribuito, che descrive: i) la cinetica dell’enzima COX-1 a partire dalla sua produzione all’interno dei megacariociti del midollo osseo fino a giungere nelle piastrine del sangue, ii) la farmacocinetica e la farmacodinamica dell’aspirina, ovvero la distribuzione del farmaco nel corpo e la sua interazione con l’enzima COX-1. Il modello è stato testato su dati sperimentali relativi al recupero di trombossano B2 sierico dopo la sospensione di aspirina in pazienti sani. Sono stati infine discussi meccanismi potenzialmente candidati a spiegare il fenomeno dell’aspirino-resistenza in pazienti diabetici.

Diabetes Mellitus is a chronic disease characterized by uncontrollable chronic high blood glucose (hyperglycemia) and complications, leading to serious damage to different tissues. In clinical studies, diabetic patients are found to have a higher risk of developing neurodegeneration and osteoporosis, and hyperglycemia-induced formation of advanced glycation endproducts (AGEs) may contribute towards the pathogenesis of diabetes-induced neurodegeneration and osteoporosis. Therefore the aim of this project is to investigate the role of hyperglycemia-induced methylglyoxal (MG) on neurodegeneration, neuroinflammation and osteoporosis.;Firstly, the role of MG on neurodegeneration of neuronal astrocytes, a kind of major glia in the brain, was studied. Astrocyte plays roles in the structural and functional support of the brain neurons and maintains normal brain physiology. In the present study, MG disturbed insulin signaling and led to apoptosis in rat primary astrocytes. Furthermore, the protective effects of ginsenosides were studied. From the results, impairment of insulin signaling was found in astrocyte culture under MG treatment. Moreover, cleavage of caspase and Poly ADP ribose polymerase (PARP) was observed together with insulin signaling disruption, showing the neurotoxic effects of MG towards astrocytes. The effects of ginsenosides in MG-treated astrocytes were also investigated. The ginsenosides Rd and R-Rh2 were shown to ameliorate the cell viability of MG-treated astrocytes and improve insulin signaling and inhibit apoptosis, indicating that Rd, R-Rh2, and related compounds may have therapeutic potential in treating diabetes-induced neurodegeneration.;Secondly, the role of MG on neuroinflammation was studied. The effects of MG in astrocytic cultures and hippocampi of experimental animals were compared. The astrocyte DITNC1 and C57BL/6 mice were treated with MG solution and hippocampi were harvested. MG induced astrogliosis in DITNC1 astrocytic cultures and C57BL/6 mice. Also, activation of the proinflammatory JNK signaling pathway was observed. Furthermore, increased gene expression of pro-inflammatory cytokines and astrocytic markers were observed. In addition, inhibition of JNK activities resulted in down-regulation of TNF- in MG-treated astrocytes. Our results suggest that MG may contribute to the progression of diabetes-related neurodegeneration through JNK pathway activation in astrocytes and the subsequent neuroinflammatory responses in the central nervous system.;Thirdly, the role of MG on osteoporosis and osteoclasts were studied. The osteoclasts are bone cells having catabolic action in the bone remodeling cycle. The effects of MG on osteoporosis in both animal and cell models were investigated. SD rats were treated with either MG or streptozotocin and the macrophage RAW264.7 was treated with MG. MG was shown to induce osteoclastogenesis by increased gene expression of osteoclast bone biomarkers CTSK, OSCAR and TRACP5. The results of MG-treated rats were similar to type 1 diabetic model. Furthermore, in MG-treated macrophages activation of the JNK was observed, and inhibition of JNK activities resulted in down-regulation of osteoclast biomarkers. Our results, suggested that MG may contribute to the progression of diabetes-related osteoporosis and the imbalanced bone remodeling through the JNK pathway in osteoclasts.;To conclude, MG causes different diabetic complications in multiple organs. It may be a potential therapeutic target to reduce and delay the development of neurodegeneration, neuroinflammation, and osteoporosis in diabetes.

Factors which may account for the high frequency of macrovascular disease in diabetics are age, sex, cigarette smoking, hypertension, obesity, lack of exercise, diet, hyperglycaemia, hyperinsulinaeroia, hypercholesterolaemia, hypertriglyceridaemia, low HDL-cholesterol concentration, elevated free fatty acid concentration and enhanced platelet aggregation. Twenty seven (13 men and 14 women) non-insulin-dependent diabetics and thirty eight age, height and weight matched healthy subjects (10 men and 28 women) were studied. None of the subjects were smokers, or hypertensive. No subject had any clinical evidence of peripheral arterial disease, coronary heart disease or cerebrovascular disease. All had apparently normal peripheral pulses and normal ankle/arm blood pressure indices. Methods for determining arterial compliance in the segment between the left subclavian artery and each common femoral artery, and proximal resistance at the common femoral artery and posterior tibial artery, have been reviewed and developed. An appropriate food intake methodology for deriving food indices from food records was developed. Biochemical determinants have been made of glucose tolerance, glycosylated haemoglobin, serum total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, plasma free fatty acid and insulin. A significant decrease in the arterial compliance, and a significant increase in the arterial proximal resistance at the common femoral artery and posterior tibial artery in non-insulin-dependent diabetics, compared with their healthy controls, have been found. Significant negative correlation between arterial compliance and proximal resistance and, a significant positive correlation between the arterial proximal resistance of common femoral artery and posterior tibial artery were found. Differences between control (healthy subjects) and non-insulin-dependent diabetic groups indicate that preclinical peripheral arterial disease can be recognised even in mild diabetics by non-invasive measurement of arterial compliance or proximal resistance. There were significant and negative correlations between arterial compliance and each of blood glucose, blood glycosylated haemoglobin (HbAlC), plasma free fatty acid and plasma insulin concentration. There were significant and positive correlations between arterial proximal resistance of common femoral artery and posterior tibial artery and each of blood glucose, glycosylated haemoglobin and plasma free fatty acid concentration. Multivariate analysis to examine each of the biochemical factors Including blood glucose, blood glycosylated haemoglobin (HbAlC), plasma free fatty acid, plasma Insulin and lipids, showed that the factor which most influenced the arterial compliance and the proximal resistance of posterior tibial artery was the glucose level in the fasting state or the glucose response after a glucose load. In addition, the factors which most influenced proximal resistance of the common femoral artery were free fatty acid -level in the fasting state or glucose response after a glucose load. The factors which most influenced arterial compliance were glucose level in men, and the insulin level in the fasting state or the plasma free fatty acid response after a glucose load in women. These findings indicate that blood glucose, plasma free fatty acid and plasma insulin are risk factors for changes in arterial wall characteristic at a stage when no clinical evidence of macrovascular disease is apparent. Arterial compliance was decreased and the proximal resistance of posterior tibial artery was increased in those with a low intake of protective foods compared with those with a high intake whether healthy subjects or non-insulin-dependent diabetics. Arterial compliance was decreased in non-fish eaters compared with the fish eaters whether healthy subjects or non-insulin-dependent diabetics. Proximal resistance of the posterior tibia! artery in non-fish eaters was increased compared with fish eaters in healthy subjects. Overall, food variety, a protective food score consumption and fish consumption emerge as importance determinants of arterial wall characteristics at a stage when no clinical evidence of macrovascular disease is apparent.

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

The increase of blood pressure (BP) is the main risk factor of cardiovascular complications (CVC) for patients with type 2 diabetes mellitus (DM). There are also other markers of these complications such as glycated hemoglobin (HbA1с), dyslipidemia, characterized by atherogenic index (AI). The aim of our study was the determination of connection between markers of cardiovascular complications (CVC) for patients with type 2 DM and AH.

Thesis advisor: Samuel Richardson
HbA1c levels are the most frequently used test for diagnosis and prognosis of diabetes mellitus. Recent studies have shown the biases this test has in particular cohorts, that was not noted when it was originally accepted by the American Diabetes Association in 2008. This study examined how these biases affect HbA1c’s ability as a predictor for complications that arise due to diabetes in specific cohorts, those of ethnicity, age, weight, and other patient attributes, compared to other established diabetes prognosis tests. We discovered that both glucose and HbA1c share similar biases as predictors for particular cohorts (the high glucose, high BMI, Asian, African, and Hispanic descent cohorts), HbA1c works better as a predictor when it is combined with the results of a glucose test and more characteristics of the patient compared to a HbA1c test alone with fewer variables, and glucose and HbA1c are better predictors for different diseases, respectively, that may arise due to diabetes mellitus
Thesis (BA) — Boston College, 2020
Submitted to: Boston College. College of Arts and Sciences
Discipline: Departmental Honors
Discipline: Economics

Thesis (M Med (Family Medicine))--University of Limpopo, 2010.
The number of diabetic patients will continue to rise even in rural settings and the burden of this disease will continue to take its effect on the limited resources of these communities. The effect of such burden will be more pronounced if we are to add the various complications associated with substandard management of diabetes mellitus. The first step in assessing the level of care we give to this category of patients is to measure their level of adherence, in an effort to expose the pitfalls on both the side of the patients and on the side of the health care provider. The aim of the study is to assess the level of adherence to treatment among type2 diabetic patients in Matlala district hospital; Limpopo Province. This cross-sectional study used the convenience method of sampling with the aid of a tested, structured questionnaire, to obtain data from respondents between December 2009 and March 2010, a period of 4 months. The excel computer program was used for data capturing. Percentages and numbers were used for interpretation and cross tabulation was used to determine association. The result of the study indicated that 137 {70%} of the respondents adhere to diabetes treatment. There were two demographical characteristics that are significantly associated with non adherence: age {p=0.028} and employment status {p=0.018}. Of those respondents that keep their appointments, 98% are adherent to treatment. When considering reasons for poor adherence; 29% of respondents stated that the clinic did not have their pills, 16% stated that they forgot to take their medication and 14% stated that they travelled to visit ix and did not take enough pills with them. On the reasons for poor adherence to lifestyle: 29% of the respondents said that they were too old, 22% stated no specific reason, 13% struggled to motivate themselves and 10% simply forgot what to do. Most, 68%, of the respondents that adhere to the recommended use of medication agreed that they take it at meal time, 14% set a reminder, 8% employed the assistance of a treatment supporter and other respondents used other means to remember. The study revealed an above average level of adherence in my setting and it will be logical to assess whether this corresponds to the metabolic control expected of good adherence. More is needed to be done on the reasons why our patients do not adhere to both medication and lifestyle changes and each stake holder needs to address their short comings.

Mild thiamin deficiency is prevalent in diabetes, and high dose thiamin ameliorates some diabetic complications, but there are no definitive studies addressing thiamin intake, diabetes control and thiamin status in diabetes. Subjects were 113 people with diabetes (58 type 1, 55 type 2), 43 with and 70 without thiamin supplementation. Dietary thiamin was estimated by 24-hour recall, diabetes control by HbA1c. Age, BMI, albumin excretion, activity level and smoking status did not correlate with red cell thiamin (RCT) in either group. RCT correlated with serum thiamin (ST) (p < 0.01). In those unsupplemented, adequate dietary thiamin did not ensure normal RCT, with 15.7 % of subjects below the reference range. Supplementation to intake > 4 mg/d, was significantly associated with normal RCT (p = 0.028), with 97.7% of supplemented subjects having normal RCT. Supplementation was also significantly associated with elevated serum thiamin 24 hours post supplementation, contrary to other reports. HbA1c was not significantly associated with RCT. Conclusions: In diabetes, adequate dietary thiamin does not ensure normal red cell thiamin, but supplementation to > 4 mg/day does, raising questions about actual thiamin requirements in diabetes and supporting evidence that thiamin deficiency in diabetes is not primarily due to dietary deficiency. Diabetes control was not significantly related to thiamin status.

Thesis (DPhil (Biomedical Sciences))--Cape Peninsula University of Technology, 2019
Diabetes mellitus is one of the major health challenges facing the world today and it is not restricted by age, gender, education or urbanisation. Increased oxidative stress, inflammation and apoptosis are implicated in the pathogenesis of diabetes mellitus. The progression of diabetes mellitus leads to pathological events and alterations in many tissues of the body, thereby causing damage to these tissues and organs. Anchomanes difformis is has a strong ethnopharmacological relevance and it is known for its diverse traditional uses against hyperglycemia, kidney damage, pain, wounds, inflammation, onchocerciasis and gastrointestinal pathologies amongst others. Scientific investigations have been performed on some of these ethnobotanical claims on Anchomanes difformis using animal models. While some of these claims have been established scientifically, others are yet to be explored. In vivo experimental study on the leaves of Anchomanes difformis revealed its hypoglycemic effect, however, there is no information on the possible effect of Anchomanes difformis on oxidative stress, inflammatory mediators and apoptosis in diabetes mellitus. Therefore, this study investigated the potential benefits of Anchomanes difformis in increased oxidative stress, inflammation and apoptosis in a diabetic model. The study also assessed the ameliorative effect of Anchomanes difformis in diabetes-induced damage in the organs such as the liver, heart, kidney, testis and epididymis. The first phase of the study compared the antioxidant capacity and phytochemical characterisation of three different solvent extracts; aqueous, ethanolic and methanolic from the leaves and rhizome of Anchomanes difformis. All these six extracts (3 extracts each from the leaves and rhizome) exhibited antioxidant properties, however aqueous extract demonstrated the highest antioxidant potential, hence it was selected for further experiment in the study. Furthermore, certain bioactive compounds with antioxidant, antidiabetic and anti-inflammatory properties were identified in Anchomanes difformis. The second phase of the study involved the induction of diabetes, treatment with AD and standard drug and euthanasia followed by biochemical investigations in male Wistar rats. Type 2 diabetes was induced with two-weeks administration of 10% fructose, followed by a single intraperitoneal injection of streptozotocin (40mg/kgBW). Dosages of 200 and 400 mg/kgBW of Anchomanes difformis leaves extract were administered for six weeks to diabetic and normal rats which served as treatment controls. The effect of Anchomanes difformis on glycemic indices, body weights, relative organ weights, organ function markers, antioxidant statuses, inflammatory biomarkers, apoptosis and structural integrity of the liver, kidney, pancreas, testis and the epididymis were conducted. The administration of streptozotocin led to hyperglycemia, hyperlipidemia, body weight loss, increased inflammation, oxidative stress and apoptosis, reduced sperm concentration, viability and distorted sperm morphology. It also induced tissue damage in the liver, kidney, pancreas, testis and epididymis. Treatment with both doses of Anchomanes difformis improved organ functions, markedly reduced and repaired tissue damage in a dose-dependent manner and comparable to the standard drug; glibenclamide. Furthermore, Anchomanes difformis distinctly lowered blood glucose, abnormal lipid levels, enhanced antioxidant status, modulated inflammation, reduced apoptosis and increased sperm functions better than glibenclamide in diabetic rats. In conclusion, the protective and ameliorative properties of Anchomanes difformis projects it as a potential new, reliable therapeutic agent that should be explored and considered in the management of diabetes mellitus and its associated complications.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.
Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Public Health Epidemiology." Discipline: Epidemiology; Department/School: Public Health.

Background and aims: The overall aim of this thesis was to increase knowledge regarding the occurrence of childhood onset T1D and T2D in Sweden and in relation to that describe and elucidate important aspects on two grave complications to diabetes; end-stage renal disease (ESRD) and mortality. The two first studies included in this thesis aimed to describe and analyze the cumulative incidence of childhood onset T1D in Sweden and to assess the occurrence of undetected T2D in Swedish children. The aim with the third study was to describe the cumulative incidence of ESRD, and to analyze how ESRD risk differs with age at-onset and sex. The aim of the fourth study was to show how parental socioeconomic status (SES) affects all cause mortality in Swedish patients with childhood onset T1D. Study populations: The foundation for the studies on T1D was data from the Swedish Childhood Diabetes Registry (SCDR). When studying ESRD we also included adult onset T1D cases from the Diabetes Incidence Study in Sweden (DISS). The study on T2D was a population-based screening study where BMI was measured in 5528 school-children and hemoglobin A1c was measured in children with overweight according to international age and sex specific BMI cut-offs. To study ESRD and mortality, we linked the SCDR to various nationwide registers containing individual information on SES, mortality and ESRD. Results: The incidence rates of childhood onset T1D has continued to increase in Sweden 1977–2007. Age- and sex-specific incidence rates varied from 21.6 (95% CI 19.4–23.9) during 1978–1980 to 43.9 (95% CI 40.7– 47.3) during 2005–2007. Cumulative incidence by birth-cohorts has shifted to a younger age at-onset over the first 22 years of incidence registration. From the year 2000 there was a significant reverse in this trend (p<0.01). In contrast to the increase of T1D, we found no evidence of undetected T2D among Swedish school children. Despite a relatively high incidence in T1D in Sweden there is low cumulative incidence of ESRD, 3.3% at maximum 30 years of duration. We found difference between the sexes regarding long-term risk of developing ESRD that was dependent on the age at onset of T1D. When analyzing how socioeconomic status affects mortality in different age at death groups, we found that having parents that received income support increased mortality up to three times in those who died after 18 years of age. Conclusion: The incidence of childhood onset T1D continued to increase in Sweden 1978-2007. Between the years 1978-1999 there was a shift to a younger age at-onset, but from the year 2000 there is a change in this shift indicating a possible trend break. The prevalence of T2D among Swedish children up to 12 years of age is probably very low. There is still a low cumulative incidence of T1D associated ESRD in Sweden. The risk of developing ESRD depends on age at-onset of T1D, and there is a clear difference in risk between men and woman. Excess mortality among subjects with childhood onset T1D still exists, and low parental socioeconomic status additionally increased mortality in this group.

Studies concerning social consequences, gastrointestinal and urinary tract symptoms were conducted in a population-based cohort comprising patients with long-standing type 1 diabetes and matched control persons. Three different questionnaires were sent by mail to diabetic patients and control persons. After a mean duration of 28.7±2.6 years, compared to the controls the diabetic patients showed an almost 10 times higher mortality, a lower employment rate and greater need for welfare benefits. These differences were mainly due to diabetic late complications. Education, housing conditions, life-style, civil state, alcohol and smoking habits were similar in the two groups. The prevalence of gastrointestinal symptoms was significantly higher in the diabetic patients than in the controls, and this was found to be attributable to the female diabetic patients. Female diabetic patients had been treated with antibiotics for urinary tract infections more often than controls, they experienced more social problems than controls in daily life because of urinary tract problems and used clamps to prevent wetting more often than did controls.

Body composition and bone mineral density were evaluated in parts of the cohort with long-standing type 1 diabetes and control persons in another population-based cohort comprising diabetic females aged 16-19 years with type 1 diabetes since childhood and matched controls. Besides a tendency to reduced abdominal fat mass in diabetic males, no difference was observed in fat mass, muscle mass or bone mineral density between the patients with long-standing type 1 diabetes and controls. Significant correlations were found between insulin dosage and whole body fat mass in diabetic females and between serum cholesterol levels and abdominal fat mass in diabetic males. The female adolescents had a higher body mass index than the controls, and their overweight was shown to consist almost entirely of an increased fat mass. The distribution of fat, expressed as abdominal-to-leg ratio, correlated significantly to HbA1c and daily dosage of insulin. Bone mineral density did not differ between the groups. IGF I was significantly lower both in patients with long-standing type 1 diabetes and in the adolescent diabetic females compared with their matched controls.

Momordica charantia fruit is traditionally used as a vegetable in the Indian subcontinent and is claimed to have hypoglycaemic effects in human and experimental diabetes. The oral administration of M. charantia fruit juice was investigated for its effects in streptozotocin (STZ)-induced diabetes in rats. The results of this study have revealed that the fruit juice administration reduced the blood glucose levels, improved glucose tolerance and increased blood insulin levels and body weights in STZ-induced diabetes in rats. However, the treatment of fruit juice did not completely normalize these parameters as the values were still significantly different from those of age-matched controls. The systolic blood pressure was significantly increased in diabetic animals when compared to untreated diabetic rats. The treatment of Lvi. charantia to diabetic animals completely prevented such an increase as the values were not significantly different from that of age-matched controls. The administration of M charantia to STZ-induced diabetic rats also reduced the absorption of glucose by the brush border of small intestine. A similar reduction in glucose uptake by muscle cells in vitro was also observed. In an immunohistochemical study of the pancreas on number and distribution of endocrine cells, a significant increase in the number of insulin positive cells was observed in Lvi charantia treated-diabetic animals as compared with untreated diabetic rats. However, their number was still significantly less than that obtained for control animals. The effect of M charantia treatment on myelinated fibre abnormalities in the tibial nerve of STZ- induced diabetic and control rats was also investigated. The mean cross-sectional myelinated fibres area (p C 0.03), axonal area (p C 0.02) and myelin area (p < 0.04) including the mean maximum myelinated fibres area (p C 0.03) were significantly reduced in untreated diabetic animals when compared with age-matched controls. In the M. charatia treated diabetic animals, myelinated fibre area and myelin area were significantly greater than untreated diabetics (p C 0.05) and not significantly different from age-matched controls. The mean value for the maximum fibre area was also significantly greater than that of untreated diabetics (p< 0.05) and was not significantly different from that of age-matched controls. In summary, the administration of M. charantia normalised the structural abnormalities of peripheral nerves in experimental diabetes. The changes in STZ-induced diabetes related to oxidative stress and expression of P450 and GST isoenzymes was studied. The results indicated an increase in CYP4Adependent laurie acid hydroxylation in liver, kidney and the brain of STZ-diabetic rats. An increase in CYP2B-dependent aniline hydroxylation and CYP lA-dependent ethoxycoumarin-O-deethylase activities was also observed. A significant increase in aminopyrene-N-demethylase activity was observed only in rat kidney while there was a decrease in the liver and brain of diabetic rats. A significant increase in NADPHdependent lipid peroxidation (LPO) in kidney of diabetic rats was also observed. On the other hand, a decrease in hepatic LPO was seen during chronic diabetes. During diabetes an increased expression of CYP1AI, CYP2E1 and CYP4A2 proteins was also seen by western blot analysis. Mi charantia fruit juice feeding modulated the protein expression and catalytic activities in a tissue and isoenzyme specific manners. A marked decrease in hepatic glutathione (GSH)) content and glutathione Stransferase (GST) activity and an increase in brain OSH and GST activity was observed in diabetic rats. On the other hand, renal GST was markedly reduced while GSH content was moderately higher than that of control rats. Western blot and immunohistochemical analysis using specific antibodies have confirmed the tissue specific alterations in the expression of OST isoenzymes. M. charantia juice feeding, in general, reversed the effect of long tenn STZ-diabetes on the modulation of both P450-dependent monooxygenase activities and GSH-dependent oxidative stress related LPO and GST activities. These effects were found to be tissue specific and related to the modulation of various specific isoenzymes during diabetes. These results have suggested that the modulation of xenobiotic metabolism and oxidative stress in various tissues may be related to altered metabolism of endogenous substrates and hormonal status during diabetes. These findings reported in this thesis may have implications in elucidating the therapeutic use of M charantia in the management of diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is a complex metabolic condition that results in hyperglycemia due to insulin deficiency (Daneman, 2006). Diabetes has a range of effects on almost every system in the body including the kidneys, the eyes, the cardiovascular system, the genito-urinary system, the gastro-intestinal system and the nervous system (Daneman, 2006). The effects of this ondition are widespread and have a significant impact both on life expectancy and the quality of life of individuals suffering from diabetes (Scottish Diabetes Survey Monitoring Group, 2011). The impact of diabetes on oral health has been investigated over many decades, however, the conclusions have been varied and study design has not always been adequate (Mealey et al., 2006; Khader et al., 2006; Chávarray et al., 2009). Research presented in this thesis is largely the result of a cross-sectional clinical study examining the oral cavities of non-smoking T1DM patients, funded by the Chief Scientist Office of the Scottish Government. The clinical part of the study took place between January 2006 and May 2009 in Glasgow Dental Hospital. Chapter one provides an introduction and narrative review on the subject of T1DM, periodontal disease, and the various other reported oral manifestations of diabetes mellitus. The methods for measuring general and oral health related quality of life outcomes are also discussed. Chapter one reveals some of the inadequacies of studies nvestigating the link between T1DM and oral disease to date and ontextualises the studies presented in this thesis. Chapter two presents the main periodontal findings of a large cross-sectional study. 112 non-diabetic subjects and 203 subjects with type 1 diabetes were examined. 203 diabetic patients were divided into well controlled and poorly controlled groups based on their average blood sugar levels over the previous two years. 169 were poorly controlled. (PCD). Those with T1DM, (especially those with poor glycaemic control) had a greater extent and severity of periodontitis than those without diabetes. There was also some evidence that never smoking T1DM patients were more likely to have periodontal disease than non-diabetic subjects. The odds ratio (OR) was 1.43 [0.74 to 2.75] (p = 0.29) for all T1DM patients and 1.58 [0.75 to 3.33] (p = 0.23) for PCD. This difference remained even after the multivariable analysis took into account age, gender and lifestyle including: body mass index of the subject; whether they had smoked in the past; whether they attended a dentist; their level of education and how deprived the area they lived in was. Chapter three presents an analysis of the impact of age, HbA1c, and duration on the expression of periodontal disease in T1DM subjects. Cross-tabulations and multivariable logistic regression analysis was performed on the periodontal data from T1DM subjects and non-diabetic subjects in order to determine the relationship between age, HbA1c and duration, and periodontitis. Diabetic subjects developed periodontitis at a younger age than non-diabetes subjects. This will represent a significant impact on life time dental service provision for subjects affected at a young age. The relationship between HbA1c and severe periodontitis is not a simple one. It is possible that unknown factors confound the relationship between glycaemic control and periodontitis. There was no relationship between duration of diabetes and periodontitis when age was controlled for. Chapter four presents the results of a small study investigating biomarkers of bone turnover in patients with and without T1DM and in patients with and without periodontitis. Patients with T1DM had higher levels of osteoprotegerin an osteoprotective molecule that normally leads to a reduced propensity for bone loss. T1DM patients were also shown to have reduced levels of biomarkers of bone formation (osteocalcin). It is possible that a reduced capacity for bone repair and regeneration may account for the increase levels of periodontitis seen in T1DM. Further prospective studies would be required to confirm this hypothesis. Chapter five investigated the level of caries and oral mucosal abnormalities in T1DM. There was little difference in caries indicators or in oral mucosal lesions between the groups. There was no difference in the bacterial microflora and in the level of resistance to antibiotics found in this cohort. T1DM patients, however, did have an increase in the symptoms of dry mouth, an increased density of candida colonisation and reduced salivary flow rates.Chapter six reports the data derived from the oral health questionnaire, including the Oral Health Impact Profile -14 (OHIP-14) and the Audit of Diabetes Dependent Quality of Life (ADDQOL©). Patients with T1DM, despite having increased levels of periodontal disease, reduced salivary flow rates and increased symptoms of xerostomia did not have higher OHIP scores by any measure. The reasons for this apparently negligible impact of oral disease or oral health related quality of life are discussed. The OHIP-14 was shown to have construct validity in this population although the correlations were relatively weak and the differences were small. It is possible that patients with T1DM do not consider the impact of their oral health to be a significant problem in light of their other on-going medical issues. This finding requires further in-depth investigation of the psychology behind this apparent reduced impact. This is the first study of its kind to examine the oral and dental health of non-smoking type 1 diabetic patients. The conclusions from the clinical data support the view that patients with T1DM should be targeted with oral and dental health advice. Encouragingly the prevalence of periodontitis was lower in well controlled diabetic subjects suggesting that the effect of T1DM on the oral cavity can be ameliorated by good glycaemic control even though logistic regression analysis did not show a linear relationship. It is important that health rofessionals work together in order to prevent and manage the oral complications of T1DM in the same way that there are preventive and screening programmes for other diabetic complications. The pathogenesis behind the increased prevalence and severity of periodontal disease in T1DM requires further study.

Type 2 diabetes is a chronic metabolic disorder and the seventh leading cause of death in the United States. Type 2 diabetes is linked to many chronic diseases, including cardiovascular disease, stroke, and chronic kidney failure. African American adults have a high prevalence of Type 2 diabetes with early onset of diabetes complications. Poor dietary behavior is the primary cause of Type 2 diabetes and its complications, changing dietary behaviors can prevent the onset of diabetes complications or impede existing ones. The purpose of this phenomenological study was to explore patients’ perceptions of diet-only therapy in the prevention of diabetes complications. Face-to-face interviews were conducted with six African American adults with Type 2 diabetes between 40 to 64 years using purposeful sampling method. Health belief model formed the conceptual framework of the study. I applied inductive coding process and manually analyze data for themes. Participants expressed fear of diabetes complications, acknowledged effectiveness of dietary therapy, physician communication and strong family support in Type 2 diabetes management. Findings can produce positive social change among African American adults with type 2 diabetes. Patients can be motivated to change their dietary behaviors to prevent disability and death from diabetes complications. Adherence to diet can reduce medical costs associated with Type 2 diabetes and its complications at the individual, family, community, and government levels. Health care providers can apply the findings in their interactions with patients to provide a more patient-centered education that integrates patients’ cultural and dietary preferences to facilitate adoption of dietary interventions and long-term adherence.

Type 2 diabetes is a chronic metabolic disorder and the seventh leading cause of death in the United States. Type 2 diabetes is linked to many chronic diseases, including cardiovascular disease, stroke, and chronic kidney failure. African American adults have a high prevalence of Type 2 diabetes with early onset of diabetes complications. Poor dietary behavior is the primary cause of Type 2 diabetes and its complications, changing dietary behaviors can prevent the onset of diabetes complications or impede existing ones. The purpose of this phenomenological study was to explore patients' perceptions of diet-only therapy in the prevention of diabetes complications. Face-to-face interviews were conducted with six African American adults with Type 2 diabetes between 40 to 64 years using purposeful sampling method. Health belief model formed the conceptual framework of the study. I applied inductive coding process and manually analyze data for themes. Participants expressed fear of diabetes complications, acknowledged effectiveness of dietary therapy, physician communication and strong family support in Type 2 diabetes management. Findings can produce positive social change among African American adults with type 2 diabetes. Patients can be motivated to change their dietary behaviors to prevent disability and death from diabetes complications. Adherence to diet can reduce medical costs associated with Type 2 diabetes and its complications at the individual, family, community, and government levels. Health care providers can apply the findings in their interactions with patients to provide a more patient-centered education that integrates patients' cultural and dietary preferences to facilitate adoption of dietary interventions and long-term adherence.

In patients with diabetes, hyperglycemia leads to functional impairment of endothelial cells (ECs) and microangiopathy. Inflammation and endothelial dysfunction (ED) have been associated with the development of several cardiovascular complications. Concentration of methylglyoxal (MG) - a highly reactive aldehyde is increased in diabetes. In a non-pathological state, MG is detoxified by the enzymes glyoxalase-1 (GLO1) and glyoxalase 2 in presence of glutathione. This thesis examines the role of MG accumulation in ECs and bone marrow cells (BMCs), with the consequences it has for their function. To this end, a transgenic mouse model was used in which the human enzyme GLO1 is overexpressed in the vasculature By using a GLO1 overexpressing mouse model studies described here examined the contribution of MG-induced inflammation in vivo to cardiovascular complications of diabetes, namely diabetic heart failure and peripheral vascular disease. This study confirmed that accumulation of MG leads to inflammation and cell death, and further explained how MG affects the role of ECs in development of the heart failure and BMCs in the revascularization. Overexpression of GLO1 in the vasculature diminished MG-induced inflammation, reduced EC death and delayed and limited the loss of cardiac function in streptozotocin (STZ)-induced diabetic mice (Chapter 2). The in vitro part of this study showed that MG and tumor necrosis factor (TNF- have a synergistic effect on cell death (Chapter 3). Overexpressing the GLO1 in BMCs only, restored neovascularization in ischaemic tissue of mice with STZ-induced diabetes (Chapter 4). Taken together, the results of this thesis suggest that hyperglycemia increased MG leads to endothelial inflammation, EC death and decreased angiogenic potential of BMCs. Furthermore, this MG-induced inflammation and reduced cell function observed, identifies a potential target for therapy of the cardiovascular complications seen in diabetes.

This PhD project aimed to investigate the underlying genetic component of complications secondary to diabetes. This was accomplished by the combination of novel and emerging genetic technologies as well as bioinformatic approaches to probe the genome of multiple populations to determine the role of genetics in diabetic complications, specifically diabetic kidney disease and coronary artery disease. Additionally, I have had a long-standing interest in the functions of telomeres in human biology. I was fortunate to have the opportunity to incorporate this interest into this PhD thesis. Chapter 3 comprises a technical review and comparison of three next generation sequencing techniques for potential future clinical use. It gives an overview of current genome-wide association study methodologies and presents how next-generation sequencing technology is improving upon these established methods. Chapters 4 and 5 explore the role of telomeres in diabetic kidney disease and end-stage renal disease. First, telomere length was established and compared between cases and controls. Secondly, genome and epigenome wide association data were used to explore variations in nuclear genes known to have a role in telomere function between cases and controls. Chapter 6 describes the discovery and replication steps in a large collaborative genome wide association study for genetic variation in coronary artery disease secondary to type 1 diabetes.

Type 2 diabetes is a heterogeneous condition, but evidence gaps exist with respect to risks and outcomes for sub-populations. The tenet of this thesis is that routinely collected clinical data captured within the eHR can be utilised for diabetes research; the eHR can provide new information with specific regard to further characterising diabetes sub-populations, which can meaningfully inform patient care. Clinical data captured in the course of usual patient care for over 20,000 patients held within the longstanding RPAH Diabetes Centre eMR was studied. Data linkage was undertaken with the National Death Index to ascertain the survival status. Studies were undertaken to examine 1) the heterogeneity of survival outcomes for 7 different ethnic groups, 2) the survival of young onset type 2 diabetes compared with type 1 diabetes and usual onset type 2 diabetes, 3) how systematically collected retinopathy data could be used to inform public health decisions and 4) the comprehensiveness and degree of standardisation in the reporting of retinopathy sourced from optometrists and ophthalmologists . Significant differences in diabetes complications and mortality were observed amongst ethnic groups; for Chinese, Indian, Arab and Mediterranean groups survival was better than the Anglo-Celtic reference group. In contrast, Indigenous Australians had the highest adjusted hazard for death. We also found that young onset type 2 diabetes had a 2 fold greater mortality than type 1 diabetes, with deaths occurring at a significantly younger age. Furthermore, in comparison to older onset type 2 diabetes, we found the greatest mortality impact in younger onset type 2 diabetes. Taken together these results newly highlighted the aggressive nature of early onset type 2 diabetes. We demonstrated the potential utility of cross-sectional retinopathy data 1) in the prediction of the future retinopathy burden for different sub-groups and 2) to provide an index of past glycaemic exposure for subgroups to identify those most at risk. Finally, we identified a lack of standardisation in the reporting of retinopathy amongst providers. Overall, this body of work demonstrated the wide-ranging utility of the routinely collected eHR, to further characterise heterogeneity in type 2 diabetes and to meaningfully inform future diabetes research and care.