Background: The Kingdom of Saudi Arabia faces one of the highest prevalence rates of type 2 diabetes mellitus (T2DM) in the world. However, there are no credible local data on the trends and future projections of the disease, and the relevant international studies underestimated the true prevalence rates. This thesis used epidemiological modelling to study the trends in T2DM prevalence in Saudi Arabia, predicted its future levels, and quantified the impact of reducing some risk factors on the disease prevalence trends. Methods: This thesis developed and validated the “Saudi IMPACT Diabetes Forecast Model”, which integrates data on the population, obesity and smoking prevalence trends in Saudis aged ≥25 years to estimate the trends in T2DM prevalence (1992-2022) using a Markov modelling approach. The model considers different reasonable scenarios of future trends in obesity prevalence, and incorporates a number of parameters to model the disease epidemiology. These parameters include the estimated diabetes incidence, case-fatality, total mortality, relative risk of diabetes if obese, and relative risk of diabetes if a smoker. The model data inputs and parameters were obtained from different sources, including local departments, medical literature and assumptions. The model results were validated against local data from the STEPwise survey in 2005, and against the model of the Global Burden of Disease study, where the model produced reasonably close results to both of these studies. Results: The prevalence of T2DM among the Saudi population aged ≥25 years was estimated to rise substantially during the 30-year period of 1992-2022 from 8.5% to 39.5%, assuming some levelling off of obesity trends (capping), or to 44.1%, assuming uncapped increasing obesity trends. In men, T2DM prevalence was estimated to increase from 8.7% to 39.2% with capped obesity trends, or to 41.3% with continuing linear increase in obesity trends. In women, T2DM prevalence was estimated to increase from 8.2% to 39.8% with capping of obesity trends, or to 47.7% without such a capping. The model showed that if the trends in obesity start to decline by 10% in 12 years (2010-2022), a relative reduction of 13% in diabetes prevalence could be achieved. If the prevalence of obesity was halted at the 2010 levels, a 10% relative reduction in diabetes prevalence could be attained by 2022. ii Conclusion: T2DM is currently a major public health challenge in Saudi Arabia, and this thesis predicted that its burden will increase substantially in the next decade. Intensive and aggressive preventive measures directed to reduce the levels of risk factors, particularly obesity and smoking, can result in reasonable reduction of the disease prevalence, and therefore should be an urgent action.

Background: Diabetes prevalence is increasing worldwide. Increased burden of diabetes and recent developments in treatment and prevention of diabetes and cardiovascular complications present opportunities for screening of people at risk of diabetes in order to implement disease-modifying intervention and prevent long-term complications. Aim: The aim of this study was to develop a simple inexpensive score for identifying individuals with undiagnosed diabetes in the African context. Methods: A population based sample of 5193 individuals aged 15 years and above from diabetes surveys in Tanzania, Senegal and Guinea was used to develop the score, the derived score was then validated in populations from South Africa, Guinea and Tanzania. New cases of diabetes were defined using fasting glucose measurements. Binary logistic regression model coefficients were used to assign individual scores for the predictor variables in the model. Results: Age, hypertension and waist circumference were the variables included in the final model. The model has an area under the ROC curve (AUC) of 0.83 (95% CI 0.82 to 0.84). A meta-analysis of applying the score at individual country data yielded a summary ROC curve with an AUC of 0.8 (95% CI 0.74-0.85) and an inconsistency score (I²) of 0%. The performance of the newly derived risk score in the validation samples was comparable to the performance in derivation study population with Area under the ROC curve ranging from 0.7 to 0.82. Conclusion: Presented in this thesis is the first ever diabetes risk score derived from Africa. It is a simple inexpensive tool for identifying individuals with undiagnosed diabetes in African settings. Further work is needed to externally validate the score in other populations.

Introduction People with Type 2 diabetes mellitus are at an increased risk of developing depressive symptoms compared with those without the condition. Diabetes-related distress is commonly experienced and associated with the perceived burdens of self-management and fear of future complications. Psychological difficulties in Type 2 diabetes often go unrecognised by both patients and practitioners. This project used a mixed methods approach to explore the psychological needs of adults with Type 2 diabetes and involved them in the design and feasibility testing of a support web site to promote psychological wellbeing. Methods Phases 1 and 2 of the project consisted of ten patient interviews using an Interpretative Phenomenological Analysis (IPA) approach, three focus groups and a Design Workshop. Patient collaboration using Participatory Design methods was integral to the development of the intervention website. Phase 3 was a randomised controlled feasibility study assessing study procedures, process measures and the appropriateness of outcome measures. Results A complex relationship emerged between participants' objective physical body and how they subjectively experienced it. Mood regulation was often unconsciously prioritised over diabetes management or diabetes-management over mood regulation. Peer-to-peer communication and the anonymity of an Internet platform were felt to be important, particularly by men in the sample. Consent to participate was low in the feasibility study. Half of the intervention arm attempted registration for the website. Registration was found to be too long. All who registered used the website at least once. The main reason given for not registering was that psychological effects of diabetes were not being experienced. Follow-up data was provided by 76% of participants. Conclusion There were substantial barriers to use of an Internet-based intervention for psychological health in the sample. Amendments are required to aspects of the intervention and study design before it can translate to a larger trial.

MicroRNAs (miRs) are small, noncoding RNAs which negatively regulate the expression of targeted mRNA transcripts. Some miRs are known to modulate angiogenesis. The p75 neurotroph in receptor (p75NTR) is upregulated in endothelial cells in models of diabetes, and contributes towards an impaired post-ischaemic reparative neovascularisation in diabetes. Forced overexpression of p75NTR in human umbilical vein endothelial cells (HUVECs) was associated with an upregulation of the microRNA miR-30c-2*. The aim of this project was to clarify the potential role of miR-30c-2* in diabetes and limb ischaemia. This was done using expressional analyses in HUVECs and in murine models of diabetes and limb ischaemia in vivo, as well as functional studies in HUVECs. The effect of miR-30c-2* inhibition in diabetes and limb ischaemia in vivo was determined. In HUVECs, miR-30c-2* was upregulated under conditions of high glucose (HG, which reflects diabetes) and low growth factors (LGF, a model of in vitro ischaemia). Overexpression of miR-30c-2* in HUVECs was associated with reduced proliferation, reduced migration, impaired capacity for network formation, and increased apoptosis. Inhibition of miR-30c-2* in HUVECs rescued functional capacity under LGF conditions. In murine models, miR-30c-2* was predominantly upregulated in the limb muscles by type 2 diabetes. In limb ischaemia, miR-30c-2* inhibition increased capillary and small arteriole density without improving blood flow. In a model of type 2 diabetes, miR-30c-2* inhibition increased limb muscle capillary density. In silico analyses suggested the miR-30c-2* may target genes involved in angiogenesis. These results suggest that the p75NTR-mediated microRNA miR-30c-2* has an overall anti-angiogenic role in endothelial cells. Furthermore, the inhibition of miR-30c-2* may be of some therapeutic benefit in post-ischaemic neovascularisation and diabetic microangiopathy.

Diabetes has now been recognised as an epidemic globally. The burden of the disease and its complications are outstripping health care systems all over the world. The rising prevalence coupled with the increasing life expectancy makes it impossible for specialist centres to cope with the demands of diabetes care, which was the case until 20-30 years ago, thus necessitating a “left shift” to primary care. The aim of this research is to critically appraise the evidence on the effectiveness of interventions targeting primary care professionals on improvement of cardio-metabolic risk factors including glycated Haemoglobin (HbA1c), blood pressure and total or LDL-cholesterol. A further aim is to quantify the effect of intensive glucose lowering either alone or as part of a multifactorial intervention on non-fatal myocardial infarction (MI), non-fatal stroke, cardiovascular disease (CV) mortality and all-cause mortality in patients with type 2 diabetes. Finally, the impact of any interventions effective in controlling the cardio-metabolic risk factors will be considered in a real world restructured diabetes service on non-elective bed days, outpatient attendances and hospitalisation for diabetes and its complications will be assessed. This thesis used 2 methodologies. In the first instance, a systematic review of interventions targeting primary care professionals on improvement of cardio-metabolic risk factors, and another systematic review and meta-analysis of studies on intensive glucose lowering and multifactorial interventions on cardiovascular and mortality outcomes were conducted. Secondly, a before- and-after study of general practices on non-elective bed days, outpatient attendances and hospitalisation for diabetes and its complications was also conducted. Main findings: 1. A systematic review of interventions targeting primary careprofessionals on improvement of cardio-metabolic risk factorsshowed that multifaceted professional interventions were moreeffective than single interventions targeting single primary orcommunity care professionals in improving glycaemic control. 2. A meta-analysis of studies on intensive glucose lowering andmultifactorial interventions on cardiovascular and mortalityoutcomes showed that apart from non-fatal myocardial infarctions,there was no evidence that intensive treatment reduced the risk ofcardiovascular and mortality outcomes. Compared to standardcare, intensive glucose lowering and multi-factorial interventionreduced the risk of non-fatal MI (RR 0.89, 95% CI 0.83 to 0.96) butnot non-fatal stroke (RR 0.96, 95% CI 0.86 to 1.07), CV mortality(RR 1.01, 95% CI 0.91 to 1.13) or all-cause mortality (RR 1.01, 95%CI 0.94 to 1.08). The predictions indicated that, intensive glucoselowering is more likely to be beneficial in populations where thebaseline incidence of CVD mortality is greater than 6.3 deaths per1000 person-years. 3. A before-and-after analysis of a structured diabetes shared careservice redesign, involving enhanced diabetes-skilled primary carephysicians, nurses and health care assistants in primary caresettings was conducted. Compared to an integrated specialist–community care core diabetes service, the new enhanced servicedid not show an increase hospitalisation (the difference betweenthe non-elective bed days in core practices and that in enhancedpractices was not significant, mean = 2.20 per 100 patients, p =0.14)), first outpatients’ attendances (the difference between the mean first outpatient attendance in the core practices and that in enhanced practices was 0.02 per 100 patients p=0.92) and admissions for diabetes related complications (the difference was 0.30 per 100 patients, p=0.55). Conclusion: The rising demand of diabetes care requires a primary care well organised to deliver a diabetes services without compromising quality. A well-organised multidisciplinary diabetes-skilled primary care team, using multi-faceted interventions, can deliver a diabetes service without increasing diabetes related complications, out-patient attendances and hospitalisations. Cardio-metabolic risk factor control is an essential part of diabetes management. Intensive glucose lowering and multifactorial interventions can reduce non-fatal myocardial infarctions.

Diabetes prevalence is increasing above and beyond what can be attributed to population growth as reduced physical activity and increased sugar in people's diets is leading to an epidemic that is pushing healthcare systems to breaking point. While therapeutic treatments remain limited for diabetes patients, measurement and management of their glycemic status can prove beneficial. Glucose and HbA1C are currently utilised to manage diabetes in the short and long term respectively. However, problems with the accuracy of the HbA1c in certain diabetes patients, particularly those with renal problems and/or anaemia make it not ideal in all situations. Additionally its half life of 2-3 months make it slow to respond to glycemic changes. Measurement of human serum albumin may be beneficial in both filling the gap between glucose and HbA1c and being less susceptible to interferents. HSA has a half life of between 2-3 weeks and like haemoglobin is readily glycated. Any changes in glycated HSA will demonstrate changes in a patient's glycemic status over the preceding weeks instead of months like HbA1c. Additionally it has been demonstrated to be a better representation of glucose levels in certain patient groups. The relative lack of GHSA testing in the clinic comes down to the cost, complexity and lack of specificity of current techniques. A simple test is needed which can determine the GHSA/HSA ratio of a patient more accurately then current techniques while at a cost that is viable for restrained healthcare budgets. Within this thesis the selection and subsequent testing of aptamers to HSA and early stage glycated HSA (GHSA) is demonstrated.

The 3D-study sought to explore depression and/or diabetes-specific distress (DSD) in people with Type 2 diabetes (T2DM), or ‘the 3-Ds’, to gain novel data and inform the design of a potential care pathway for this poorly identified and inadequately managed population. Firstly, a review of existing literature was performed to determine current understanding. Two systematic reviews with meta-analyses were performed: firstly, to determine the prevalence of DSD in people with T2DM; and secondly, to identify existing interventions that are successful in reducing DSD and physiological measures. A qualitative interview study was then conducted, with both patient and healthcare professional (HCP) participants, supplemented by field notes from development work, to elicit and explore the understanding, perceptions and experiences of the ‘3Ds’. The findings were then mapped against existing programmes of care, identifying areas lacking within current provision and informing the design of a proposed model of care. The 3D-model identified a lack of HCP understanding of ‘the 3-Ds’ and their interplay, and poor representation of holistic and patient-centred care, highlighting a fundamental need for training and education prior to any patient-level intervention. The model also identified a need for a change in how psychological concerns are identified, with a need for screening within meaningful discussion and adequate exploration of an individual’s wider-life circumstances. The model recognised a need for patient-choice, offering a stepped model of education and psychological support, utilising established programmes and building upon these with a specific ‘3Ds’ education programme. The model recommended a collaborative care design, with a sole care-coordinator to allow continuity of care, accessibility, and encourage shared-decision making and empowerment. The 3D-study formed the development phases of the Medical Research Council’s Framework for the development and evaluation of complex interventions, providing novel data to the field and laying the foundations for future work.

The number of Chinese patients with type-2 diabetes in China and Wales has been increasing dramatically, which has been one of the most prominent health challenges in the two countries. Self-management provides an effective strategy to encourage patients with type-2 diabetes and their family carers to be involved in activities such as lifestyle modification, self-testing of blood glucose, and adherence to daily medication treatment to control their condition in daily lives. However, there is limited research that has explored the perspectives and practices of self-management among Chinese patients in China and Wales. The aim of this study was to investigate self-management of type-2 diabetes from the perspectives and practices of Chinese patients with type-2 diabetes and their family carers living in China and Wales. Data were generated through the use of ethnography that entailed semi-structured interviews with a purposive sample of Chinese patients with type-2 diabetes in China (n=13) and their family carers (n=7) and Chinese patients with type-2 diabetes in Wales (n=13) and their family carers (n=7). Data generation also included a review of participants’ own records of self-management, and observation of public diabetes education sessions in China and in Wales. After thematically analysing the data five key themes emerged: symptom perception and emotional responses to being diagnosed with type-2 diabetes, diabetes-related knowledge and information sources, the positive and negative consequences of type-2 diabetes, the practices of self-management, and barriers and facilitators of self-management of type-2 diabetes among Chinese patients and their family carers in China and Wales. The findings indicated that there was limited awareness and knowledge regarding type- 2 diabetes and self-management among Chinese patients and their family carers in both China and Wales. This was mainly attributed to lack of financial support and access to reliable information sources in China and language barriers in Wales. Another important barrier to self-management among Chinese patients in Wales was lack of family support. In addition, this study has also identified the positive and negative influences of Chinese tradition cultural norms on self-management. This study makes a significant contribution to the limited research on the perspectives and practices of self-management among Chinese patients and their family carers in China and Wales. In particular the findings provide an in depth understanding of the Chinese cultural influences on self-management of type-2 diabetes in two different contexts. Recommendations are provided for health care providers, diabetes educators, health policy makers, and research community.

Background: One of the major health, social and economic problems in the Kingdom of Saudi Arabia is the rising prevalence of overweight and obesity amongst young people and the implications this has for the future burden of chronic diseases, such as type 2 diabetes. Nearly 10% of the Saudi population are now diagnosed with diabetes at a cost to the nation in 2010 estimated at $0.9 billion. Aim: To investigate factors influencing choice of healthy food items by students in a university cafeteria in Saudi Arabia. Theoretical framework: Psychological theories of how individual factors affect behaviours and concepts from the emerging field of behavioural economics underpinned the studies. Methods: Three empirical studies involving students at the University of Ha’il, central Saudi Arabia: 1. Questionnaire gathering background information about students’ health-related behaviours and knowledge of behavioural risk factors for type 2 diabetes, 2. Investigation of student purchasing patterns and intentions through a) a questionnaire probing willingness-to-buy fruit (a healthier option) if available in the campus cafeteria, b) a controlled experiment manipulating menu choices, 3. Analysis of actual purchasing decisions when fruit was introduced to the campus cafeteria. Impacts of price variation and health messages were explored in Studies II and III. Results: 1. Students report poor health-related behaviours (dietary and physical activity); knowledge of the link between lifestyle and type 2 diabetes is patchy. 2a. Over 50% of cafeteria users said they would buy fruit if available. 2b. Choice of healthy items was responsive to price manipulation. 3. When fruit was available, it was purchased by less than 10%. Health messages had no effect on healthy item choices. Conclusions: Pricing strategies may be effective to stimulate healthier choices. Additional health education targeting individual psychological determinants of behaviour change may also be required.

There is very limited evidence available on the impact of changes in diabetes care at the interface between general practice and hospital based services. It seems pertinent to ask whether hospital resources could be saved through earlier identification of problems and better management producing reductions in hospital admissions. An alternative, and equally credible, scenario is that improving identification and surveillance of individuals with diabetes will increase the number of referrals to hospitals for investigation and treatment of identified problems. It is therefore important to critically examine the current predictors of admission. This will help to predict future patterns of demand and the impact of further changes in the organisation of care. There is currently another reason for interest in factors which predict admission rates. Admission rates for acute long-term diabetic complications represent a useful, routinely available outcome reflecting overall quality of diabetes services and could be used to assess services. The major purpose of this thesis therefore is to address the issue of whether a process of routine regular review may influence the risk of hospital admission or attendance at the accident and emergency department for an individual with diabetes. The new chapter sets out the aims and objectives in more detail. The available evidence for suggesting that changes in organisation of diabetes care may influence admission rates and the extensive literature on determinants of hospital admission have been examined (Chapter 3). Initially, a pilot study was conducted which resulted in some significant changes to the study methodology (Chapter 4). For the main study, data from 1120 individuals with diabetes from seven different practices were collected and analysed (Chapters 5 to 10). A comparative study of accident and emergency department use by individuals with diabetes was also conducted (Chapter 11). The final chapter (Chapter 12) brings together some conclusions from these studies and proposes some potentially fertile areas for further research.