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The overall purpose of this thesis was to identify determinants of quality of life in adults with diabetes mellitus. This thesis consists of two studies. The first study tested a comprehensive model which comprised of personal, medical and lifestyle factors to explain quality of life in adults with type 2 diabetes. The model was tested with two concepts of quality of life: health-related quality of life and life satisfaction. The second study (1) tested the comprehensive model in adults with type 1 diabetes; and, (2) examined the interaction effects of diabetes type (i.e., type 1 diabetes /type 2 diabetes) on significant determinants of quality of life in the combined type 1 and type 2 diabetes group. The findings of this study identified subgroups that may be at risk for impaired quality of life and topics that require further investigation.

Background: To investigate the link between depressive symptoms and physical activity (PA) by examining their association across genders, age, and race/ethnicity. Methods: Data of the cross-sectional study were from the 2011 and 2015 Behavioral Risk Factor Surveillance System. The Patient Health Questionnaire-8, a well-validated instrument to measure depressive symptoms was used. PA was categorized as active, moderately active, and inactive. A generalized linear model specified with a Poisson distribution and log link was performed to investigate the association between depressive symptoms and PA across population characteristics. Results: No significant association between PA and depressive symptoms between genders and across racial/ethnic groups was found. Persons aged 65 years or older showed a significantly lower risk of depressive symptoms than those below 45 years when physically active (Adjusted Prevalence Ratio (APR) 0.36, 95% CI = 0.16–0.82) and moderately active (APR 0.39, 95% CI = 0.16–0.98). Limitations: The study included only leisure-time PA. Well-designed surveys that reflect a wider scope of PA are needed to strengthen the analysis. Conclusions: Compared to younger adults, older adults may gain further health benefits in reducing the risk of depressive symptoms by being physically active. Similar health benefits may be gained from PA between genders and between racial/ethnic groups. The different association between PA and depressive symptoms provides practical implications for the effective management of depressive symptoms in persons with diabetes.

Background: Fifty percent of medications are not taken as prescribed. This is a major public health issue yet there is very limited evidence on the factors associated with medicines adherence in people with mild to moderate Intellectually Disabilities and diabetes (IDD). This study evaluated the frequency of, and factors associated with, medicines non-adherence in this group compared to people without ID but with diabetes (non-IDD).Methods: A systematic review of the literature informed the theoretical model tested. A two-stage, sequential mixed methods study with 111 people with type 1 and 2 diabetes, (IDD = 33, non-IDD = 78) was then carried out. Stage one (quantitative) compared frequency of medication adherence in the group overall, IDD and non-IDD. Univariate and multiple regression analysis evaluated associations between factors (ID, depression, side effects, self-efficacy and perceived level of social support) and medicines non-adherence. Stage two (qualitative) explored findings of stage one with 12 stage one participants' carers using semi-structured interviews. Results: Data were collected between July 2014 and May 2016. The frequency of medicines adherence was similar in the IDD and non-IDD population (70% vs 62%, p = 0.41). The theoretical model did not predict medicines non-adherence. After controlling for support with medicines and complexity of regime (number of medications and use of insulin), depression was an independent predictor in the non-IDD and group overall (p < 0.001). In the IDD group, perceived side effects was an important, but non-significant, predictor of non-adherence (p = 0.06). Carers' perceptions of adherence and depression were consistent with stage one findings. Conclusions: Optimising adherence to diabetes medicines is equally challenging in IDD and non-IDD populations. Associations between independent factors and adherence differed between the two groups: in the non-IDD population, depressive symptoms were associated with non-adherence whereas in the IDD population perceived level of side effects appeared most dominant. Due to small sample sizes findings were inconclusive therefore, a sufficiently powered study further investigating the relationship between adherence and side effects in people with ID and diabetes is recommended.

Diabetic vasculopathy (DV) is the most important consequence of chronic hyperglycemia in patients with diabetes mellitus (DM). This thesis explores the interaction of blood, bone and kidney in the pathogenesis of DV by i) reviewing the current understanding of pathogenesis of macrovascular and microvascular diseases in DM to identify gaps in literature and generate hypotheses relating to various facets of DV ii) undertaking a series of prospective studies to examine these hypotheses iii) analysing the findings and integrating any new information obtained from the clinical studies into the current knowledge base and iv) generating hypotheses upon which future work might be based. The literature search was carried out with the aim of understanding current concepts of pathogenesis of DV and its potential modulators. The original reviews resulting from this process are presented in chapters 2 to 4. A series of pilot studies reported in chapters 7 to 11, were then carried out to interrogate hypotheses originating from this process. The first study was carried out in healthy individuals to define the biological variation of potential modulators of DV, namely erythropoietin (EPO), parathyroid hormone, 25 hydroxyvitamin D and 1, 25-dihydroxyvitamin D to facilitate the design and interpretation of subsequent studies. It revealed a wide biological variation of these modulators in the healthy population thus,emphasizing the need to have a control group in the subsequent study population. To examine whether tubulointerstitial dysfunction occurs before the onset of microalbuminuria, a measurement of the above mentioned parameters was carried out along with markers of tubulointerstitial injury in patients with type 1 and type 2 DM without microalbuminuria and in non-diabetic controls. It was found that tubulointerstitial dysfunction with low levels of EPO and 1, 25-dihydroxyvitamin D and higher excretion of tubular injury markers, occurs before the onset of microalbuminuria. Subsequently, diabetic and nondiabetic chronic kidney disease (CKD) patients with EPO deficiency anaemia were examined to study the effects of EPO therapy on the excretion of tubular injury markers. However, in these patient groups, we were unable to demonstrate an effect of EPO therapy on the markers of tubular injury in spite of a beneficial haematological response. To examine whether vascular calcification (VC) and bone mineral density (BMD) were linked in patients with diabetes mellitus and to explore their relationship to modulators of DV, an assessment of VC and BMD was undertaken in patients with type 2 DM with different degrees of proteinuria and normoalbuminuria. VC was assessed by CT scan and BMD by a DEXA scan. Modulators of DV were measured including serum Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-b-ligand (RANKL). The findings were i) a high prevalence of VC and osteopenia in normoalbuminuric type 2 DM patients with normal serum creatinine ii) a weak inverse relationship between VC and osteopenia iii) proteinuric patients had worse VC but not osteopenia iv) weak relationships between OPG levels and both VC and osteopenia, masked by age in multivariate analysis. The final study examined the relationship between modulators of DV, including OPG and RANKL, and the degree of CKD. It was found that abnormalities of OPG and RANKL occur before the onset of microalbuminuria and progress with deterioration of renal function. Compared to nondiabetics, DM patients have higher OPG levels in the predialysis phase and lower levels in haemodialysis phase, a phenomenon that might indicate endothelial exhaustion in dialysis patients with DM. The derangements associated with DV seem to occur earlier than previously thought. Further work is required to untangle these complexities and to define the contribution of factors such as the adverse blood milieu, the vasculature, abnormal bone and mineral metabolism, and early tubulointerstitial damage. The findings from the studies reported here may help in the formulation of new hypotheses, which might contribute to future work in this area.