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Aim To examine the risk factor of coronary artery calcium (CAC) in individuals with diabetes and those without diabetes in Central Appalachia. Methods Study population included 2479 asymptomatic participants who underwent CAC screening between August 2012 and November 2016. CAC score was classified into four categories [0 (no plaque), 1–99 (mild plaque), 100–399 (moderate plaque), and ≥400 (severe plaque)]. Multinomial logistic regression analyses were conducted to test the association between CAC and cardiovascular disease (CVD) risk factors among participants with diabetes, age and gender matched controls, and randomly selected controls. Results 13.6% of total participants had diabetes. Around 69%, 59.8%, and 57.7% of the participants with diabetes, matched controls, and randomly selected controls had CAC score ≥1, respectively. Participants with diabetes had higher prevalence of all CVD risk factors than controls. Among participants with diabetes, hypertension and physical inactivity increased the odds of CAC = 100–399, while among those without diabetes, hypertension and hypercholesteremia increased the odds of having CAC = 1–99 and CAC ≥ 400. Conclusion Half of study participants had subclinical atherosclerosis (i.e., CAC), and individuals with diabetes had higher CAC scores. This study suggests that individuals with diabetes in Central Appalachia might benefit from screening for CAC.

[Truncated abstract. Please see the pdf format for the complete text.] The discovery of the C282Y mutation and its role in the development of hereditary haemochromatosis has allowed a greater understanding into the effects of iron overload and its involvement in other conditions such as diabetes and heart disease. It has also allowed the better classification of heterozygotes, who were previously only diagnosed through the use of family studies. There are however, areas of conflict between phenotyping and genotyping methods. My research involved examining the relationship between Haemochromatosis and certain diseases such as diabetes and heart disease; genotyping versus phenotyping discrepancies and the possible interaction of secondary mutations. In Chapter 3 a population study was undertaken with the aim of comparing genotyping versus phenotyping methods as well as increasing general practitioner awareness regarding hereditary haemochromatosis and its diagnosis. It was determined that a minimum of 5000 subjects would be required to give the study sufficient power. Individuals were to be between the ages of 20—40 years, and thus presumably presymptomatic. Participation was entirely voluntary and a consent form was to be signed. Recruitment of subjects proved to be difficult and there was a selective bias towards individuals already displaying symptoms of haemochromatosis. In total less than a 100 subjects were recruited for the study. There were several issues encountered in the implementation of this study. Firstly the number of GPs participating was probably insufficient to recruit the subjects required. A more extensive campaign was probably required to enroll more GPs. Secondly it is very difficult for a busy GP to find the time necessary to explain the study to each of his patients and to get them to sign the consent form. Finally a bias developed in some of the requests. The subjects participating in this study were supposed to be random but in many cases the GPs had enrolled them in the study because they had symptoms of iron overload. In effect the biggest obstacle this study faced was the recruitment of subjects. Due to the small number of subjects little statistical data could be obtained from this study. It was noted, however, that genotyping methods detected two individuals who were homozygous for the C282Y mutation. Both also had increased transferrin saturation levels. Phenotyping detected 5 individuals with increased transferrin saturation. The three others detected via phenotyping were C282Y heterozygotes. Haemochromatosis has long been though to be related to the development of diabetes due to the effect of iron overload on the pancreas. If this is so it would be logical to assume that the prevalence of haemochromatosis would be higher in a diabetic population. Chapter 4 examined the possibility that diabetics have a higher frequency of the C282Y mutation. A population group consisting of 1355 diabetics was genotyped for the C282Y mutation and iron studies were performed on all heterozygotes and C282Y homozygotes. Initial findings indicated that there was a significant difference between the diabetic and control population. However, this finding was the opposite of what was expected, there seemed to be a decreased frequency of the Y allele in the diabetic population rather than an increased one. The control and diabetic populations were not matched in terms of ethnicity. The removal of the ethnic bias in the diabetic population altered the statistics so there was no longer a significant difference between the two groups. This study highlighted the importance of using appropriate control populations as comparison groups. The final results of the study indicated that there was no significant difference between the diabetic population and the control population. This would seem to indicate that there is not an increased occurrence of the C282Y mutation in the diabetic population when compared to the control group. Chapter 5 considered the possible association between C282Y heterozygosity and cardiovascular disease as well as the potential for early mortality. Several recent studies have indicated that C282Y heterozygosity may be a risk factor for the development of atherosclerosis, possibly on the basis of increased iron loading. Using a control population and a population of individuals with known coronary events the incidence of the C282Y mutation was compared against other risk factors. C282Y heterozygosity did not appear to be a risk factor for atherosclerosis. There was however, a statistically significant link between increased ferritin in women and carotid plaques. A population of elderly women was genotyped in order to examine the effects of C282Y heterozygosity on longevity. The first hypothesis addressed in chapter 5 was that C282Y heterozygosity was a risk factor for the development of coronary heart disease.

Background. With increasing personal affluence and changes in lifestyle, there is rising prevalence of type 2 diabetes mellitus in Hong Kong. Approximately 60% of diabetic subjects in Hong Kong are asymptomatic and previously undiagnosed. Since diabetes carries significant mortality and morbidity risk, it is important to diagnose these subjects early for intervention. There are many known factors associated with development of type 2 diabetes. Some are remediable such as obesity, dyslipidaemia, hypertension, while some are non-remediable such as age and past history of gestational diabetes. Identifying high-risk subjects will increase the yield and cost-effectiveness of screening program for diabetes and related risk factors and provide useful epidemiological information on the natural history of these diseases. / Methods. I used data from several cross-sectional and prospective studies of which I was the principal investigator or one of the co-investigators to test these hypotheses. The studies include mainly the following: (1) A public utility company workforce survey on cardiovascular risk factors in 1990 (n=1513). (2) Chinese subjects with risk factors for diabetes who underwent 75 gram oral glucose tolerance test (OGTT) screening at the Prince of Wales Hospital (PWH) between 1988 and 1995 (n=3718). (3) The 'United Christian Nethersole Community Health Service' (UCNCHS) primary health screening program database in 1997 (n=17764). / Objectives & hypothesis. I aimed to study the various factors associated with the development of type 2 diabetes in Hong Kong Chinese. With this information, I can design a screening method to early identify those subjects who are at high-risk for diabetes. I hypothesize the following: (1) Many risk factors for diabetes in Caucasians are also applicable to Hong Kong Chinese. (2) The presence of multiple factors increases the risk of diabetes in a linear fashion. (3) Chinese subjects are at risk of developing diabetes at a lower threshold of obesity, which is one of the most important risk factors for type 2 diabetes. / Results. Based on a cohort of 1513 asymptomatic subjects from a workforce survey, those in the top quartile of body mass index (BMI), as compared to those in the lowest quartile, had a 4 to 10-fold increased risk of diabetes and a 2.5 to 5-fold increased risk of impaired glucose tolerance (IGT) for men and women. (Abstract shortened by UMI.) / Ko Tin Choi. / "May 2005." / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0173. / Thesis (M.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 264-283). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Exercise has a wide range of benefits for patients with type 1 diabetes, including improvements in body composition, cardiovascular risk profile and glycaemic control. Unfortunately, exercise also increases the risk of hypoglycaemia in children with type 1 diabetes, both at the time of exercise and for many hours afterwards. The availability of clear, evidence-based guidelines regarding appropriate adjustments in carbohydrate intake or insulin doses may help to prevent this exercise associated hypoglycaemia. However, current guidelines regarding exercise in children with type 1 diabetes rely heavily on adult literature or the consensus of experts. Therefore, further studies are needed in young people with diabetes to document the metabolic responses during and following exercise. In particular, the mechanisms underlying hypoglycaemia occurring many hours after exercise require further exploration. In addition, as children often exercise in the afternoon, studies performed at this time of the day are more likely to be transferrable to a real life situation. For this reason, we studied adolescents with type 1 diabetes to investigate physiological responses to exercise, focusing on afternoon activity and employing a novel variation of the euglycaemic insulin clamp technique. The core experiments involved studying diabetic adolescents on two occasions in a counterbalanced, paired design during and after afternoon exercise. Insulin was infused at a constant rate based on the subjects' usual daily insulin dose and glucose was infused to maintain euglycaemia. At 1600 hrs subjects either exercised at a moderate intensity (95% of their lactate threshold) for 45 minutes on a cycle ergometer (exercise study), or sat on the ergometer without exercising (rest study). Using this experimental design, it was found that glucose infusion rates (GIR) to maintain euglycaemia were elevated during and shortly following exercise and again from 7-11 hours after exercise compared with the rest study. Counterregulatory hormone levels were similar between the exercise and rest studies except for peaks in noradrenaline, cortisol and growth hormone levels at the end of exercise. Glucagon and adrenaline levels did not increase with exercise. The observed biphasic increase in glucose requirements paralleled the observed clinical risk of hypoglycaemia immediately during exercise and the delayed risk of hypoglycaemia which often occurs overnight.

Fok, Tsz Nam = 香港二型糖尿病併發症風險評估模型 / 霍梓楠. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (p. 71-72). / Abstracts in English and Chinese. / Fok, Tsz Nam = Xianggang er xing tang niao bing bing fa zheng feng xian ping gu mo xing / Huo Zinan. / Abstract --- p.i / 概要 --- p.iii / Acknowledgements --- p.iv / Chapter 1 --- Introduction --- p.1 / Chapter 2 --- Dataset Information --- p.3 / Chapter 3 --- Background and Literature Review --- p.9 / Chapter 3.1 --- The Idea of Risk Model --- p.9 / Chapter 3.2 --- Discrimination Problem --- p.10 / Chapter 3.3 --- Receiver Operating Characteristic (ROC) Curve --- p.11 / Chapter 3.4 --- Summary Indices of the ROC Curve --- p.13 / Chapter 3.4.1 --- Area Under ROC Curve (AROC) --- p.14 / Chapter 3.4.2 --- Maximum Vertical Distance --- p.16 / Chapter 3.5 --- Discrimination Performance in Prognostic Model --- p.18 / Chapter 3.5.1 --- Survival Data --- p.18 / Chapter 3.5.2 --- Survival Function --- p.20 / Chapter 3.5.3 --- Time-dependent ROC Curve for Censored Data --- p.21 / Chapter 3.6 --- Earlier Work on Diabetic Complications Risk Models --- p.22 / Chapter 3.6.1 --- Maximization of the AROC --- p.28 / Chapter 4 --- Model Development --- p.29 / Chapter 4.1 --- Overview --- p.29 / Chapter 4.2 --- Estimating the ROC curve and the AROC --- p.29 / Chapter 4.3 --- Choosing Suitable Risk Factors --- p.30 / Chapter 4.4 --- Mixing Risk Factors and Optimizing Coefficients --- p.31 / Chapter 4.5 --- Validation of Risk Equations Using Test Set --- p.33 / Chapter 5 --- Results and Validation --- p.34 / Chapter 5.1 --- Performance of the Risk Factor Candidates --- p.34 / Chapter 5.2 --- Estimation of the Coefficients --- p.37 / Chapter 5.3 --- Checking the Uniqueness of the Solution --- p.41 / Chapter 5.4 --- Validation Using Test Set --- p.46 / Chapter 5.5 --- Comparison of AROC-optimized and MVD-optimized Risk Equations --- p.56 / Chapter 6 --- Comparison of our Results with Earlier Work --- p.58 / Chapter 7 --- "Discussion, Outstanding Issues and Future Works" --- p.66 / Chapter 7.1 --- Comparison Between the AROC and the MVD --- p.66 / Chapter 7.2 --- Applications of Risk Models --- p.68 / Chapter 7.3 --- Limitations of the study --- p.69 / Chapter 7.4 --- Outstanding Issues and Future Works --- p.69 / Chapter 7.4.1 --- The Estimation of Error Due to Sampling Variance --- p.69 / Chapter 7.4.2 --- Time-dependent Coefficients --- p.69 / Chapter 7.4.3 --- Extending the Idea to other Datasets --- p.70 / Chapter 7.5 --- Conclusion --- p.70 / Bibliography --- p.71

Indiana University-Purdue University Indianapolis (IUPUI) / Obesity increases cardiovascular disease risk and is associated with factors of the “metabolic syndrome” (MetS), a disorder including hypertension, hypercholesterolemia and/or impaired glucose tolerance. Expanding adipose and subsequent inflammation is implicated in vascular dysfunction in MetS. Perivascular adipose tissue (PVAT) surrounds virtually every artery and is capable of releasing factors that influence vascular reactivity, but the effects of PVAT in the coronary circulation are unknown. Accordingly, the goal of this investigation was to delineate mechanisms by which lean vs. MetS coronary PVAT influences vasomotor tone and the coronary PVAT proteome. We tested the hypothesis that MetS alters the functional expression and vascular contractile effects of coronary PVAT in an Ossabaw swine model of the MetS. Utilizing isometric tension measurements of coronary arteries in the absence and presence of PVAT, we revealed the vascular effects of PVAT vary according to anatomical location as coronary and mesenteric, but not subcutaneous adipose tissue augmented coronary artery contractions to KCl. Factors released from coronary PVAT increase baseline tension and potentiate constriction of isolated coronary arteries relative to the amount of adipose tissue present. The effects of coronary PVAT are elevated in the setting of MetS and occur independent of endothelial function. MetS is also associated with substantial alterations in the coronary PVAT proteome and underlying increases in vascular smooth muscle Ca2+ handling via CaV1.2 channels, H2O2-sensitive K+ channels and/or upstream mediators of these ion channels. Rho-kinase signaling participates in the increase in coronary artery contractions to PVAT in lean, but not MetS swine. These data provide novel evidence that the vascular effects of PVAT vary according to anatomic location and are influenced by the MetS phenotype.