Novel approaches in diabetic nephropathy

Dit proefschrift laat zien dat het carnosinase-1 gen (CNDP1) voorspellend is voor het risico op eindstadium nierfalen bij patiënten met type 1 diabetes. In tegenstelling tot de bevindingen van cross-sectionele studies bij patiënten met type 2 diabetes, blijkt de homozygote variant voor het laagste aantal leucines (5L-5L) in het CNDP1 gen niet te beschermen tegen achteruitgang van nierfunctie bij patiënten met type 2 diabetes. Vrouwen met 5L-5L lijken een verhoogd risico op cardiovasculaire mortaliteit te hebben vergeleken met vrouwen met andere varianten. Deze bevinding kan van invloed zijn geweest op de resultaten van cross-sectionele studies. Prospectief onderzoek is noodzakelijk om een beter inzicht te krijgen in de rol van het CNDP1 gen bij diabetische nefropathie. De rol van ACE I/D SNP als genetische risicofactor voor het ontwikkelen van albuminurie bij patiënten met type 2 diabetes kunnen aantonen. Een recent beschreven SNP in het CCR2 (CCR2 V64I) is echter niet voorspellend gebleken voor het risico op het ontstaan van albuminurie. Analyse van eiwitten en collageenfragmenten in de urine (urine-proteomics) is een bruikbare diagnostische methode voor diabetische nefropathie in vroeg stadium. Hierdoor is het in de toekomst wellicht mogelijk om patiënten met diabetes en een verhoogd risico op nefropathie tijdig te behandelen. De laatste conclusie van dit proefschrift luidt dat er geen bewijs is voor het gebruik van benfotiamine (een vitamine B1 derivaat) bij patiënten met type 2 diabetes, omdat het niet leidt tot vermindering van albuminurie of andere markers van nierschade

Antihypertensive Drug-Gene Interactiosn and Cardiovascular Outcomes

Hypertension is a major public health hazard, because of its high prevalence and strong positive association with cardiovascular diseases. Suboptimal blood pressure control is the number one attributable risk for death in the Western world, despite the possibilities to treat hypertension. Higher pre-treatment blood pressure levels are associated with a greater antihypertensive drug response, but this relation is not specific to a particular antihypertensive drug or drug class nor can it be predicted from patients characteristics. Therefo

Hypoglycaemia in type 1 diabetes: risk factors, symptoms and recovery

Hypoglycaemia is the commonest side-effect of insulin treatment for diabetes mellitus. Appreciation of the risk factors for hypoglycaemia and early recognition of its symptoms can help the affected individual with prompt self-treatment of hypoglycaemia, preventing progression to severe hypoglycaemia. The proposed MD project will consist of three major studies to investigate the risks for, symptoms of, and rate of recovery from, hypoglycaemia.STUDY ONE: This study will examine the alleged association between severe hypoglycaemia and serum angiotensin converting enzyme (ACE) levels. While many patients rarely experience severe hypoglycaemia, a small subgroup experiences recurrent episodes. These are very disruptive to daily life and may be dangerous, for example if they occur when the individual is driving. It is therefore of clinical importance to identify risk factors for severe hypoglycaemia.Scandinavian studies have reported an association between elevated serum ACE activity and an increased risk of severe hypoglycaemia in type 1 diabetes. A hypothetical explanation for these findings is that lower ACE activity confers increased ability for cerebral function to be maintained despite metabolic substrate deprivation. It is possible that in diabetes, this could manifest as greater impairment of mental ability during hypoglycaemia in people with high ACE activity. This would explain their increased risk of severe hypoglycaemia for a given level of blood glucose as they would be more incapacitated, and therefore less able to self-treat. However these studies have methodological limitations and these findings have not yet been reproduced outside Scandinavia.In this study, it is proposed to examine the relationship between serum ACE levels and the incidence of severe hypoglycaemia. Blood will be sampled for serum ACE activity and the self-estimated frequency of severe hypoglycaemia will be recorded in 300 people with type 1 diabetes attending diabetes clinics at the Royal Infirmary of Edinburgh.STUDY TWO: This study will examine the variability of hypoglycaemia symptom reporting. It is known that the symptoms of hypoglycaemia are idiosyncratic and age-specific. However, no studies have assessed the extent of any intra-individual variability in symptom reporting.A cohort of 350 people with type 1 and type 2 diabetes, with different disease durations and varying treatment modalities, will be recruited and the symptoms associated with each hypoglycaemic episode will be recorded prospectively over a 12 month period. The reported symptom clusters will be analysed to assess the consistency of symptom reporting for each individual. Regression analysis will be used to assess whether an individual's consistency coefficient is related to any other factors such as disease duration or treatment modality. The ability to predict which individuals will report a consistent group of symptoms and which individuals will experience an erratic pattern of symptoms would assist patient education and allow clinicians to inform patients about how to anticipate and recognise hypoglycaemia.STUDY THREE: This study will examine the time taken for full cognitive recovery from hypoglycaemia and the possible effect of the clinical syndrome of impaired awareness of hypoglycaemia on this process. The effects of acute insulin-induced hypoglycaemia on cognitive function have been investigated extensively but the recovery period after hypoglycaemia has not been rigorously assessed. Previous studies examining recovery have had multiple limitations.The objective of this third study is to measure the recovery time for various domains of cognitive function in a large group of patients with type 1 diabetes who have either normal (n=20) or impaired (n=l 6) awareness of hypoglycaemia. A hyperinsulinaemic glucose clamp technique will be used to induce controlled hypoglycaemia and a battery of cognitive tests will be applied at baseline, at the beginning and end of a one hour period of hypoglycaemia, then at ten minute intervals during a 90 minute recovery period. Each subject will act as their own control by undergoing a euglycaemic clamp on a separate occasion. Test scores will be compared using general linear modelling with awareness of hypoglycaemia as a betweensubjects factor. The findings of this study will have important clinical implications and help to advise patients how long to wait after restoration of euglycaemia before resuming activities such as driving

Integrative physiology of human aerobic fitness and the influence of the ACE I/Dp genotype

The search for genes that influence human performance and health constitutes a popular topic of current research. One such genetic constituent that has caused much interest over the last 20 years is the angiotensin converting enzyme insertion/deletion polymorphism (ACE I/Dp). There is much controversy in the literature regarding the role (if any) of this polymorphism as effects and effect size vary between populations of different origin and training status. The aim of this thesis was to analyse at the whole organism level whether skeletal muscle plasticity explains the association of the ACE I/D polymorphism with metabolic fitness. Regular endurance exercise reduces the risk of a plethora of diseases, but the exact molecular mechanisms are not fully understood – the ability of muscle to adapt to exercise stimulus is key. Trained individuals demonstrated clear physiological differences of aerobic processes such as increased oxygen usage, greater power output and reduced body fat that would be expected (T-Test: p<0.001). By contrast, when examining metabolite changes, at rest, in the local muscle there were few (n=6) nonpolar (lipid species) metabolite (assessed by mass spectrometry) differences between the trained and untrained. However, after an acute exercise bout working muscle in trained individuals displayed a significant up-regulation of (n=76) non-polar metabolites (Repeated ANOVA: p=0.0004), illustrating that training produces significant adaptations in substrate metabolism at the local level. Would there be a genetic component contributing towards these physiological and local muscle differences? Individuals with the ACE I-allele (insertion sequence) had increased capillary density, and there were significant differences in transcripts, together with both polar and non-polar metabolites in the untrained population at rest and following an acute exercise bout. These differences were lost in the trained population. In a different population (Swiss) capillary density was increased following a training programme in the absence of the I-allele – in contrast to the other population (British). However, gene expression response of important factors, to exercise was preserved. In conclusion, a trained population demonstrated enhanced non-polar metabolism in the working muscle after an exercise bout, and the dominant stimulus of regular exercise over-rides the influence of the ACE I/Dp. Nurture over-rides nature