Diabetic nephropathy: early detection and therapeutic strategies

The increasing global prevalence of diabetes poses a huge challenge to health services. The diagnosis is accompanied by a reduction in life expectancy, primarily due to cardiovascular disease which is inextricably linked to microvascular complications such as diabetic nephropathy (DN). Microalbuminuria (MA) is generally accepted as the primary clinical hallmark of DN, but despite widespread prescribing of agents blocking the renin angiotensin aldosterone system (RAAS) in these patients many continue to progress towards end-stage renal disease (ESRD). Clinical trials evaluating early initiation of RAAS blocking agents in untargeted, nonalbuminuric diabetic patients have shown potential for delaying disease progression but these effects are generally counterbalanced by side effects and adverse events associated with these therapies. Discovery of novel biomarkers to identify individuals at highest risk of DN who would stand to benefit most from targeted preclinical intervention would be a significant step towards implementation of personalised medicine in this population. One technique which shows promise is proteomics, based on the concept of separation and quantification of peptides in a biological sample to produce a disease-specific pattern. A panel of 273 urinary peptides (CKD273) has been shown to have potential for identification of nonalbuminuric diabetic patients who are at risk of progression to overt DN. However, many such novel biomarkers are described in the literature and to date none have successfully made the transition from research studies to routine clinical practice. In order to be considered for clinical implementation novel biomarkers are required to be subject to a rigorous evaluation process. In brief there are several key steps beginning with proof-of-concept studies; progressing through validation in independent populations to demonstration of incremental value beyond the current guideline-endorsed tests; thereafter proof of clinical applicability in determining treatment strategies and cost-effectiveness are required. The work contained within this thesis is designed to address each of these aspects with regard to use of the CKD273 proteomic panel as a biomarker for early detection of DN

Vascular function in hyperglycaemic pregnancy: studies into potential mechanisms for adverse obstetric outcomes in diabetes

To be adde

Determinants of myocardial and vascular function in young subjects with Type 1 diabetes mellitus

Cardiovascular disease including myocardial dysfunction and vascular disease is a major cause of morbidity and mortality among patients with type 1 diabetes mellitus. Early detection of myocardial dysfunction and identification of its determinants may be helpful in preventing diabetic heart muscle disease. In this thesis, I studied myocardial and vascular function in 53 subjects – 19 with type 1 diabetes mellitus (aged 21 ± 4 years, HbA1c 8.8 ± 1.6 %) and 34 controls (aged 25 ± 3). I measured myocardial functional reserve using myocardial velocity imaging during dobutamine in 18 patients and 21 controls. The main findings of this thesis were: 1. Longitudinal shortening of the left ventricle was reduced in type 1 diabetes mellitus. (medial mitral annular excursion 1.2±0.2 vs. 1.4±0.2 cm, p =0.01). 2. During dobutamine, long-axis peak systolic velocity was lower in type 1 diabetes by 20% at 10 and 13% at 20 μg/kg/minute (both p =0.05; ANOVA, p=0.003) but systolic velocities at peak dobutamine were similar and thus myocardial functional response was. 3. Longitudinal displacement was reduced in subjects with type 1 diabetes mellitus both at rest and during dobutamine stress. (by 15%, p =0.001). 4. Early diastolic relaxation was lower in type 1 diabetes, measured globally as the mitral E/A ratio (1.5±0.4 cm/s vs. 1.8±0.4 cm/s, p=0.02) or regionally as the early diastolic velocity of the medial mitral annulus (e’ -13.0±2.7 cm/s vs. -14.8±2.0 cm/s, p=0.02). 5. Features of adiposity and adverse lipid profiles, more than glycaemia, are major determinants also for myocardial and vascular dysfunction in young subjects with type 1 diabetes mellitus. In conclusion, there is evidence of myocardial dysfunction in young subjects with type 1 diabetes mellitus, and early changes may be related to metabolic rather than structural changes. Control of other risk factors such as dyslipidaemia, and maintenance of normal body weight, may be important measures in preventing progression of subclinical myocardial dysfunction into overt clinical disease

INTRODUCTION OF A NOVEL HOME-BASED HIGH-INTENSITY INTERVAL TRAINING PROGRAMME TO IMPROVE CARDIO-METABOLIC HEALTH IN AT-RISK INDIVIDUALS

New strategies are urgently needed to increase physical activity participation in the increasingly sedentary population to combat the rising rates of obesity and metabolic disease. The aim of this thesis was to provide evidence that practical high-intensity interval training (HIT) strategies can remove many of the major exercise barriers for obese individuals and people with type 1 diabetes that could potentially increase physical activity participation. Secondly, this thesis aimed to provide mechanistic evidence to explain the physiological effectiveness of HIT as a means to reduce the risk of cardio-metabolic disease. In Chapters 4 and 5, 32 obese adults with at least 3 additional cardiovascular disease (CVD) risk factors completed one of three 12-week training programmes 3x/week: Home-HIT (n=9); Laboratory-based supervised HIT (Lab-HIT; n=10) or home-based moderate intensity continuous training (Home-MICT; n=13). Changes in V ̇O2peak, insulin sensitivity, body composition, flow-mediated dilation (FMD) and aortic pulse wave velocity (PWV) were assessed. Muscle biopsies were taken to assess changes in capillarisation, mitochondrial density, intramuscular triglyceride (IMTG) content and eNOS and GLUT4 protein expression using quantitative immunofluorescence microscopy. Adherence and compliance (Home-HIT 96±3% & 99±1%; Home-MICT 88±4% & 100±0%; Lab-HIT 97±1% & 100±0%, respectively) to training did not differ between groups. Training increased V ̇O2peak and Matsuda insulin sensitivity index (P<0.05). BMI, body fat percentage and visceral fat decreased (P<0.05). FMD increased and aortic PWV decreased in each group (P<0.05). Immunofluorescence microscopy revealed increased capillarisation, mitochondrial density, IMTG content and eNOS and GLUT4 protein expression (P<0.05). In Chapter 6, 14 people with type 1 diabetes completed a randomised counterbalanced crossover design whereby continuous glucose monitoring was used to assess glycaemic control and risk of hypoglycaemia following a single bout of HIT and moderate-intensity continuous training (MICT) on separate days, compared to a non-exercise control day (CON). In Chapter 7, 14 people with type 1 diabetes (n=7 per group) completed six weeks of HIT or MICT 3x/week and the effect on glucose control and markers of cardio-metabolic health were measured. Chapter 6 showed no difference in the time, incidence or severity of hypoglycaemia over the 24-hour or nocturnal period between the CON, HIT and MICT days. In Chapter 7, six weeks of HIT or MICT improved V ̇O2max by 14% and 15%, respectively and aortic PWV by 12%, with no difference between groups. Therefore, Chapters 6 and 7 demonstrate that HIT is an effective exercise strategy for people with type 1 diabetes that reduces the two major barriers of lack of time and fear of hypoglycaemia. Finally, in Chapter 8, eleven previously sedentary individuals with type 1 diabetes completed 6 weeks of Home-HIT. Blood glucose was monitored before, immediately and 1h after all of the exercise sessions. Perceptions of the program along with attitudes towards exercise, barriers to exercise and previous experiences of exercise were evaluated using an online survey. Training session adherence was 93±2%, with participants achieving their target HR in 99±1% of sessions. Blood glucose was not different from baseline immediately or 1h post HIT exercise. Training increased V ̇O2peak by 8% (P=0.015), but blood pressure was unchanged (P=0.445). The qualitative data showed that the Home-HIT programme was positively received with many benefits. In conclusion, this thesis provides strong evidence that HIT can reduce major barriers to exercise and potentially increase exercise participation in these at-risk populations. Furthermore, Home-HIT was shown to be an effective strategy to improve a wide range of physiological markers indicative of improved cardio-metabolic health. Importantly, Home-HIT not only reduced traditional barriers to exercise, but also the key barrier in people with type 1 diabetes, fear of hypoglycaemia. As such, Home-HIT may represent an effective strategy to improve health in obese individuals with elevated CVD and people with type 1 diabetes by increasing exercise participation. Future research should investigate the effects of Home-HIT on a larger scale using larger cohorts and longer training periods using large-scale randomised controlled trials