Biochemistry of Diabetic Complications

Professor Merlin Thomas
Head, Biochemistry of Diabetic Complications
Laboratory
NHMRC Senior Research Fellow
merlin.thomas@bakeridi.edu.au
Phone: +61 3 8532 1277
understandingdiabetes.com.au

Research Overview

The Biochemistry of Diabetes 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. Our work 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.

Research Focus

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
Increased expression of the type 1 angiotensin receptor in rats exposed to increased levels of AGEs

Research Projects

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.

AGEs forming in a test tube

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 appetizing. 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).

Immunostaining for the organic cation transporter (OCT2) in the kidney of a rat

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.

A glomerulus from a kidney in a patient with type 1 diabetes showing a Kimmelstiel-Wilson nodule

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.

Lab Head Profile

Professor Merlin Thomas
MBChB (Otago), PhD (University of Melbourne), FRACP

Professor Thomas is a physician scientist based at the Baker IDI Heart and Diabetes Institute where he heads the Biochemistry of Diabetic Complications laboratory. He is also an honorary Professor at the Department of Epidemiology and Preventive Medicine at Monash University, Melbourne.

Dr Thomas has had career success from an early stage, establishing an outstanding track record for research productivity. He trained in medicine at the University of Otago, New Zealand, and qualified with distinction in 1992. In 1996, he was awarded the Peter Greenberg Award by the Internal Medicine Society of Australia and New Zealand (IMSANZ) and in 1998 his continuing postgraduate research in New Zealand was rewarded when he was named Royal Australasian College of Physicians 'Young Investigator of the Year'. In 2001, he was awarded a Dora Lush Biomedical research scholarship to study for a PhD at the University of Melbourne with Professor Mark Cooper. His PhD involved studies to investigate the role of tubular dysfunction in diabetic nephropathy, with a focus of the pathogenetic role of advanced glycation end-products (AGEs) and the renin angiotensin system (RAS). During his PhD, he received a number of grants and awards including the Rod Andrew Prize and the Paul Korner medal for Outstanding Achievement and the Victorian Premiers Award for Medical Research.

At the completion of his PhD in 2004, he took up the RACP/Don and Lorraine Jacquot Fellowship, to continue his research into advanced glycation end-products in South Carolina, USA, the world-leading centre for the study of the Maillard reaction (the biochemical process leading to the formation of AGEs). In 2005, he took up the RACP/Diabetes Australia Research Trust fellowship to continue his work on diabetic complications, re-joining Professor Cooper as a senior investigator on a JDRF international Program Grant. The following year, he was awarded the inaugural Partnership Award: Diabetes Australia/NHMRC Career Development Award as well as an NHMRC Project Grant to continue the work initiated in South Carolina into the role of AGEs in the development and progression of diabetic complications.
In 2007, he took over running of the JDRF-funded biochemistry core of the JDRF Centre for Diabetes Complications, moving this work from South Carolina to the Baker Institute. In 2009, he was awarded the National Heart Foundation Ross Hohnen award for the best research proposal for that year. This work focusing on new player in the renin angiotensin system has now been published in Circulation Research. In 2010, he became an NHMRC Senior Research Fellow (Level A). In 2011 he was awarded the 20th Servier Lecturer/15th Augusto Litonjua Lectureship by Diabetes Philippines.
Dr Thomas has established an exceptional track record of productivity (over 220 articles, books and chapter at greater than 20 per year) at the highest international level in the field of diabetes and its complications, including Diabetes, Circulation Research, FASEB and JASN, encompassing basic, preclinical and clinical research. He has also been successful in obtaining competitive funding from the NIH, JDRF International, NHMRC, NHF, DART and Kidney Health Australia.

His work has allowed him to establish an international profile with a number of invited presentations at major international meetings, including the World Congress of Nephrology, European Association for the Study of Diabetes (EASD), International Diabetes Federation (IDF) World Congresses, the American Society of Nephrology (ASN) and the International Atherosclerosis Society (IAS). In 2012, he was invited to present the findings to the Institute of Medicine (IOM) as part of their Committee on the Consequences of Sodium Reduction in Populations mandated by the US Congress.
His high profile has allowed him to establish a number of local and international collaborative research projects with the leaders in his field. Dr Thomas is also recognised as key opinion leader involved in the development of a number of guidelines and consensus statements for the management of chronic kidney disease and diabetes, including the Australian CARI Guidelines, NHMRC Diabetes Guidelines and the European DIAMAP Project. He is involved in GP education and presents widely at local meetings promoting opportunities for better diabetes management in general practice. He has written several modules of General Practice Queensland's (GPQ) diabetes education programs.

He is also the author of many book chapters and books on diabetes management, including Understanding Type 2 Diabetes (Exisle 2013), Diabetes: Health and Wellbeing (Penguin Press 2011) and Fast Living, Slow Ageing (Mileage Media 2009) which deals with the practical application of up-to-date research on healthy living for the general public. He also regularly writes and comments on health issues for the academic website The Conversation on health and wellbeing issues.

Significant Prizes / Awards

  • RACP Young Investigator of the Year, 1998
  • RACP/Don and Lorraine Jacquot Travelling Fellowship, 2004
  • Victorian Premier's Award for Medical Research, 2005
  • Kidney Health Australia Bootle Award, 2006
  • NHF Ross Hohnen Award recognising Research Excellence, 2009
  • 20th Servier Lecturer/15th Augusto Litonjua Lecturer, Diabetes Phillipines, 2011

Publication Highlights

Tikellis C, Pickering RJ, Tsorotes D, Huet O, Chin-Dusting J, Cooper ME, Thomas MC. Activation of the renin-angiotensin system mediates the effects of dietary salt intake on atherogenesis in the apolipoprotein E knockout mouse. Hypertension 2012;60(1):98-105. 

Okabe J, Orlowski C, Balcerczyk A, Tikellis C, Thomas MC, Cooper ME, El-Osta A. Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells. Circ Res 2012;110(8):1067-76. 

Thomas MC, Moran J, Forsblom C, Harjutsalo V, Thorn L, Ahola A, Waden J, Tolonen N, Saraheimo M, Gordin D, Groop PH. The association between dietary sodium intake, esrd, and all-cause mortality in patients with type 1 diabetes. Diabetes Care 2011;34:861-6.

Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, Toffoli B, Nguyen-Huu TP, Head GA, Fu Y, Chin-Dusting J, Cooper ME, Tikellis C. Genetic ACE2 deficiency accentuates vascular inflammation and atherosclerosis in the apoe knockout mouse. Circ Res 2010;107:888-97.

Groop PH, Thomas MC, Moran JL, Waden J, Thorn LM, Makinen VP, Rosengard-Barlund M, Saraheimo M, Hietala K, Heikkila O, Forsblom C. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 2009;58:1651-8.

Staff

Dr Chris Tikellis BSc(Hons), PhD, JDRF Senior Research Fellow, Deputy Head
Dr Raelene Pickering BSc(Hons), PhD
Despina Tsorotes BSc(Hons)