Prevention of diabetic eye disease: the commonest cause of blindness in individuals younger than 65 years

There has been a considerable advancement in the treatment of diabetes and understanding of the biochemical mechanisms underlying diabetic complications in the last 20 years. However, this advancement has not translated into a consistent reduction in diabetic retinopathy, one of the most frightening complications of diabetes mellitus. It is probable that greater attention to preventive intervention will help reduce the damage load in the next future, and that several drugs for the treatment of more advanced stages of diabetic retinopathy will become available. Competent strategies targeting prevention based on screening programs should be proposed to reduce the burden and to improve the clinical outcome of this devastating diabetes complication

The Genotype-Phenotype Correlation of the key features of Non-Proliferative Diabetic Retinopathy

Diabetic Retinopathy (DR) is a leading cause of visual impairment but its pathophysiology is not well understood. Moderate/severe non-proliferative DR (NPDR) is characterised by the presence of three features: deep haemorrhages (DH), venous beading (VB) and intraretinal microvascular abnormalities (IRMA). They are grouped together as risk factors for progression to sight threatening DR. It remains unclear whether these individual features have similar pathophysiologies, and whether they respond equally to anti-VEGF, a new therapy for NPDR. Optomap images of 504 NPDR eyes were examined to evaluate the distribution and prevalence of these three features. DNA samples from 199 patients with NPDR and 397 diabetic patients with no DR were collected. The genotype of specific candidate genes were evaluated in patients with DR, VB or IRMA vs no DR. Optical coherence tomography angiography (OCTA) images of 30 patients were examined for focal ischemia adjacent to VB and IRMA. The responses of these three features to anti-VEGF treatment were also re-examined in the images from the CLARITY trial. DH were present in most cases of NPDR. VB and IRMA did not always co-exist in the same eye and when they do, were often in different locations. VEGF, TGFb-1 and ARHGAP22 polymorphisms (ischaemia-related genes) were more common in patients with DR and IRMA, but not VB. Areas of focal ischaemia were more frequently adjacent to IRMA than to VB. DH and IRMA responded to anti-VEGF therapy but VB did not. These findings suggest that VB and IRMA do not share the same pathophysiology, and that IRMA are more likely to be ischaemic driven. Nonetheless, some IRMA may not be driven by ischaemia as they have no adjacent ischaemia on OCTA, do not carry the specific genotype, and do not respond to anti-VEGF. Furthermore, patients with VB may not benefit from anti-VEGF therapy

Some studies in the metabolic consequences of diabetes and the management of chronic pain.

This submission details work published between 1979 and 1989 into some of the metabolic consequences of diabetes and the management of chronic pain. The results of these studies are to be found in the 26 published research papers appended. 1. The metabolic consequences of diabetes: studies in this area are various but fall into several distinct sections, a) the use of cortisol creatinine ratio as a marker for nocturnal hypoglycaemic episodes, these studies looked at the possibility that the stress response to hypoglycaemia could be used to identify episodes of nocturnal hypoglycaemia in insulin treated diabetics, b) investigations of the phenomenon of chlorpropamide alcohol flushing. These studies were designed to investigate the possibility that the tendency of some noninsulin dependent diabetic patients to flush when taking alcohol concurrently with chlorpropamide was important as a marker of their susceptibility to the long term complications of the disease, c) other studies involving the metabolic aspects of diabetic complications. The role of magnesium in glucose disposal; urinary albumin as a marker of renal disease; haemoglobin glycosylation and retinopathy; hormones in pregnancy. 2. The management of chronic pain: this work arose as a natural continuation of the work with cortisol as a marker for hypoglycaemic stress and looked at the stress response to other clinical interventions such as surgery and in subjects who experienced chronic pain and sought to discover how this might affect recovery from surgery and general patient well being. As a consequence of these studies a more general assessment was made of pituitary function before and after alcohol destruction of the pituitary as a treatment for the relief of chronic pain. Much of the work required the development of new analytical rests for various analytes e.g. chlorpropamide, free insulin, insulin antibodies, plasma acetate and urinary albumin

The Empirical Evidence for the Telemedicine Intervention in Diabetes Management

Objective: The research presented here assesses the scientific evidence for the telemedicine intervention in the management of diabetes (telediabetes), gestational diabetes, and diabetic retinopathy. The impetus derives from the confluence of high prevalence of these diseases, increasing incidence, and rising costs, while telemedicine promises to ameliorate, if not prevent, type 2 diabetes and its complications. Materials and Methods: A purposeful review of the literature identified relevant publications from January 2005 to December 2013. These were culled to retain only credible research articles for detailed review and analysis. The search yielded approximately 17,000 articles with no date constraints. Of these, 770 appeared to be research articles within our time frame. A review of the abstracts yielded 73 articles that met the criteria for inclusion in the final analysis. Evidence is organized by research findings regarding feasibility/acceptance, intermediate outcomes (e.g., use of service, and screening compliance), and health outcomes (control of glycemic level, lipids, body weight, and physical activity.) Results: Definitions of telediabetes varied from study to study vis-à-vis diabetes subtype, setting, technology, staffing, duration, frequency, and target population. Outcome measures also varied. Despite these vagaries, sufficient evidence was obtained from a wide variety of research studies, consistently pointing to positive effects of telemonitoring and telescreening in terms of glycemic control, reduced body weight, and increased physical exercise. The major contributions point to telemedicine's potential for changing behaviors important to diabetes control and prevention, especially type 2 and gestational diabetes. Similarly, screening and monitoring for retinopathy can detect symptoms early that may be controlled or treated. Conclusions: Overall, there is strong and consistent evidence of improved glycemic control among persons with type 2 and gestational diabetes as well as effective screening and monitoring of diabetic retinopathy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140288/1/tmj.2015.0029.pd

Characterising the Clinical Heterogeneity of Type 1 Diabetes

There is growing evidence that type 1 diabetes is not a single disease with a predictable course, but rather comprises a number of disease phenotypes characterised by distinct immunologic, genetic and metabolic features. Indeed, a recent shift towards onset in patients at lower genetic risk highlights the increasing importance of environmental and metabolic factors in disease pathogenesis. These factors may contribute to the development of microvascular complications and alter mortality risk. This thesis aims to characterise the heterogeneity of type 1 diabetes and its complications by describing four cohorts diagnosed between 1973 and 2014. Findings from this thesis contribute to understanding the heterogeneity of T1D and its disease course, identification of novel risk factors for microvascular complications and early risk factors for increased mortality. These findings may allow appropriate risk stratification and targeted intervention to prevent type 1 diabetes onset, the development of microvascular complications and to reduce mortalit

Outcome of Ischaemic Foot Ulcers in Patients with Diabetes, with or without Revascularization

The aim of the studies presented in this thesis was to study patients with diabetes and severe peripheral arterial disease (PAD) in regard to outcomes of foot ulcers, factors related to outcomes, and occurrences of new ulcerations and amputations following healing of the initial ulcer. Patients with diabetes and a foot ulcer, consecutively presenting at a multidisciplinary foot centre, with a systolic toe pressure <45 mm Hg or an ankle pressure <80 mm Hg, were prospectively included, followed up according to a predefined program, and offered vascular intervention when applicable. All patients had continuous follow-up until healing or death, irrespective of the vascular intervention. In total (n=1,151), 36% of patients healed primarily, 16% healed after minor amputation, 13% healed after a major amputation, and 27% died unhealed. At the end of the study, there was a dropout rate of 5%, and 3% of patients were still in treatment. In patients considered not feasible for revascularization (n=602), 38% healed primarily, 12% healed after minor amputation, 17% healed after major amputation, and 33% died unhealed. Comorbidities, the severity of PAD, and the extent of tissue involvement were strongly related to a low probability for ulcer healing, irrespective of revascularization. Angioplasty or reconstructive vascular surgery increased the probability of healing. The time to revascularization after admittance to a diabetic foot centre was also related to the probability of healing without major amputation. After healing from a previous ischaemic ulcer, 34% of patients developed a new ulceration in the same foot within the observation time. Twenty-two percent of patients who developed new ulcers had an amputation before healing from the new ulcers. Lesser maximal tissue destruction during the previous ulcer and open reconstructive vascular surgery were related to a lower risk of new ulcerations. Patients with diabetes and ischaemic foot ulcers had a median survival time of 33 months. In conclusion, this thesis has shown that a substantial number of patients with diabetes, foot ulcers, and severe PAD can heal without a major amputation. The probability of ulcer healing was strongly related to comorbidity, the extent of tissue involvement, and the severity of PAD. Patients with diabetes and ischaemic foot ulcers not feasible for revascularisation are not excluded from healing without major amputation. Not only revascularization per se, but also the timing of revascularization increased the probability of healing without a major amputation. Following healing, these patients had a high risk of developing new ulcers. The extent of tissue involvement of a previous ulcer and reconstructive vascular surgery affected the risk of developing new ulcers

Diabetes in Canadian Women

Health Issue: Diabetes mellitus (DM) is a chronic health condition affecting 4.8 % of Canadian adults ≥ 20 years of age. The prevalence increases with age. According to the National Diabetes Surveillance System (NDSS) (1998–1999), approximately 12 % of Canadians aged 60–74 years are affected. One-third of cases may remain undiagnosed. The projected increase in DM prevalence largely results from rising rates of obesity and inactivity. Key Findings: DM in Canada appears to be more common among men than women. However, among Aboriginal Canadians, two-thirds of affected individuals are women. Although obesity is more prevalent among men than women (35 % vs. 27%), the DM risk associated with obesity is greater for women. Socio-economic status is inversely related to DM prevalence but the incomerelated disparities are greater among women. Polycystic ovarian syndrome affects 5–7 % of reproductive-aged women and doubles their risk for DM. Women with gestational diabetes frequently develop DM over the next 10 years. Data Gaps and Recommendations: Studies of at risk ethnic/racial groups and women with gestational diabetes are needed. Age and culturally sensitive programs need to be developed an