Laboratory head: Professor Merlin Thomas
The Biochemistry of Diabetic Complications Laboratory addresses important clinical questions across the spectrum of diabetic complications. This work is directed towards novel preventive, diagnostic and therapeutic strategies through multidisciplinary approaches combining basic bench-top research with human physiology and clinical studies. The work of this group directly impacts on patient care and has been published in highly regarded journals including Circulation, Circulation Research, Diabetes, Diabetes Care and Diabetologia.
The laboratory is well known for its work on advanced glycation end-products (AGEs), particularly in relation to diabetic complications and ageing. It has also conducted seminal studies into the role and regulation of the renin angiotensin aldosterone system (RAAS) in diabetic complication affecting the eyes, kidneys and major blood vessels.
Significant recent findings include:
- Demonstration of the pro-atherosclerotic effects of sodium restriction.
- Characterisation of the role of ACE2 in atherosclerosis and diabetic complications.
- Establish an animal model of glucose memory.
- Document the importance of kidney disease as a predictor and mediator of adverse outcomes in patients with type 1 diabetes.
Atherosclerosis and the renin angiotensin system
Atherogenesis is a complex process in which a combination of pathogenic factors (dyslipdemia, hyperglycemia, oxidative stress, shear stress, inflammation, etc) activate common pathways that lead to the development of plaques that progressively narrow and harden our major arteries. One of the most important of these is the renin angiotensin system (RAS). We have shown that activating the RAS is able to make atherosclerosis much worse, while inhibiting the RAAS is able to prevent diabetic complications without necessarily lowering the blood pressure. We have been the first to show the importance of the Angiotensin Converting Enzyme 2 (ACE2), the major enzyme that metabolizes Ang II to generate the anti-inflammatory and vasodilator peptide, Ang 1-7 (Tikellis et al. Circulation Research 2011). We are actively working on new ways to use this data to prevent diabetes-associated complications. We are also exploring the potential impact of salt intake in the diet in the development and progression of diabetic complications.
Advanced glycation end-products (AGEs): the sticky persistence of metabolic memories
Despite the clear and present danger of diabetes, how exactly hyperglycemia causes blindness, heart disease and kidney failure is incompletely understood. One important pathway involves the formation of Advanced Glycation End-products (AGEs), formed when sugars bind to protein. In foods like chocolate, caramel and beer, this reaction is appetising. But in diabetes, prolonged hyperglycaemia, dyslipidaemia and oxidative stress also result in AGE accumulation (AGEs) and end-organ damage. AGEs are thought to act through receptor independent and dependent mechanisms to promote vascular damage, fibrosis and inflammation. Their long-lasting actions have also been implicated in the persistence of metabolic memory and the better utility of optimal glycaemic control early in the course of diabetes. There a now a number of different tests for AGEs, which have been shown to correlate with adverse clinical outcomes both in those with diabetes and in the other populations. A number of therapeutic agents to reduce the accumulation of AGEs in diabetes have recently gained interest as potential approaches to prevent diabetic complications. The fact that each of these agents is effective in experimental models, despite their disparate mechanisms of action, supports the keystone role of AGEs in diabetic complications. We are currently working with a number of these agents (reviewed by Thomas MC Contributions to Nephrology 2011) and looking at ways to block the receptor for AGEs (RAGE). Already, we have published that removing RAGE is able to effectively prevent complications of diabetes without needing to fix glucose or cholesterol levels (Soro-Pavonen et al. Diabetes 2011).
Metabolic memory: the bitter legacy of high glucose levels
Metabolic memory is the name given to the phenomenon whereby previous exposure to metabolic perturbations has long-lasting physiological effects, long after the event has dissipated. For example, a period of suboptimal glycaemic control in patients with diabetes, continues to be a risk factor for adverse outcomes, when compared to those who were initially intensively treated, despite the fact that glucose control has been subsequently identical in the two cohorts for over a decade. In addition, we have shown in animal models of diabetes, that restoration of healthy glucose control does not reduce atherosclerosis and the pro-inflammatory impact of hyperglycaemia when compared to that seen in mice with persistent hyperglycaemia. It is said the sweetest things are hardest to forget. However, the scientific question of how periods of poor control can have persistent effects, even decades later, is pivotal to our approach to managing diabetes. It is also apparent that even transient elevations in blood glucose may be sufficient to initiate a range of pathogenic pathways associated with an increased risk of microvascular and macrovascular damage, even while mean glycaemic control may be maintained within normal range.
The physiological mechanism(s) responsible for metabolic memory are still poorly defined. But we are working on it. It is now clear that hyperglycaemia is able to induce a range of persistent changes, including epigenetic modifications, cellular adaptations, compositional changes and resetting of equilibria that contribute to the development and progression of vascular complications. In particular, the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states, appears to be a pivotal regulator of the complex interaction between the cellular environment and our genes that leads to metabolic memory. The importance of such changes are illustrated by our experimental findings that demonstrate when such pathways are blocked, complications may be attenuated, even without restoration of euglycaemia. Defining the events that contribute to metabolic memory will likely lead to new strategies and specific targets to develop therapies to prevent, retard or reverse the long term deleterious end-organ effects of chronic, intermittent and prior elevations in blood glucose levels.
Kidney disease and diabetes
Type 1 diabetes continues to cast a long shadow over the lives of many people. Despite access to insulin, statins, blockers of the renin angiotensin system and self-monitoring technologies, individuals with type 1 diabetes have a risk of dying that is three to four times higher than the age-gender matched general population. The factors that determine adverse outcomes in type 1 diabetes are many and various, including genetic and environmental predispositions, facets of metabolic control, diet and lifestyle, and their complex and dynamic interactions. We have recently explored the causes of this excess risk in Finnish Diabetic Nephropathy (FinnDiane) Study. This study has now recruited over 5000 individuals with type 1 diabetes, equivalent to nearly 20% of all adults with type 1 in Finland. These studies have clearly linked the presence and severity of renal damage, as both a key prognostic marker as well as potential mediator of adverse outcomes. Importantly, mortality in the two thirds of FinnDiane participants without kidney disease was not significantly different to that observed in the general population (adjusted SMR 0.8). This is consistent with the clinical observation that the majority of individuals with type 1 diabetes remain healthy and free of complications, sometimes despite decades of chronically elevated glucose levels. The reason why some people are protected is one of the key focuses of our research. We would want everyone to be protected.
Dr Chris Tikellis BSc(Hons), PhD, JDRF Senior Research Fellow, Deputy Head
Dr Raelene Pickering BSc(Hons), PhD
Despina Tsorotes BSc(Hons)