Our research is focused on the molecular pathways by which glucose-induced changes can contribute to diabetic complications, with a particular emphasis on the role of mitochondrial dysfunction in this process. Understanding of the pathways via which raised blood glucose contributes to organ damage, especially in the kidney, the eye and the brain could help to design novel biomarkers and identify therapeutic targets. We use various in-vitro and in-vivo model systems, as well as a large cohort of clinical samples in our research, in combination with molecular and cellular experimental approaches.
Mitochondria and Diabetic COMPLICATIONS
Diabetes can, over time, lead to various complications including kidney damage, eye damage, cardiovascular problems and peripheral nerve damage, and there is an immense health cost with more than 10% of the UK NHS budget being used for treatment of diabetes and its complications. The research conducted in the Malik lab on the molecular mechanisms involved in the development of diabetic complications in the last 20 years has shown, amongst other things, that diabetes can cause damage to mitochondria, cellular organelles which are the site of energy production. Specifically, we have found that diabetes induced damage to mitochondrial DNA (MtDNA) could be involved in the processes that lead to diabetic complications. We have developed methods to detect alterations in mitochondrial function in human blood, urine samples, and tissues and cells. We are interested in unravelling these pathways to understand how to prevent and treat cell and organ damage in diabetes that leads to diabetic complications.
Biomarkers of diabetic nephropathy
Diabetic nephropathy (DN) is a major cause of end-stage renal failure and affects between 30% and 50% of all diabetics, developing within 10–30 years of the onset of diabetes. There is an urgent need to develop new therapeutic strategies to intervene with the pathways involved in the development of DN, as diabetes currently affects >400 million people worldwide and both diabetes and associated complications are predicted to rise to epidemic proportions in the near future. In an attempt to find novel therapeutic targets for DN, the Malik lab has identified a large number of genes expressed in the kidney that are regulated by glucose.
Diabetes, mitochondria and alzheimer's disease
Alzheimer’s disease (AD) is the most common form of dementia, affecting an estimated 46.8 million people worldwide and predicted to rise to 131.5 million by 2050. Despite the amyloid hypothesis, progress in AD remains slow. Diabetes leads to increased risk of AD, suggesting similar pathogenic mechanisms may be involved. We have found that changes in mitochondria are detectable both in the brain and peripheral blood of subjects with AD as well as in experimental models of diabetes, suggesting that mitochondrial dysfunction could play an important role in the pathophysiology of AD. We are evaluating whether diabetes induced changes in MtDNA in the brain play a role in the increased risk of AD in subjects with diabetes and whether damage to MtDNA is associated with the mechanisms that lead to AD.
mitochondrial dysfunction and liver disease
Chronic liver disease (Non-Alcoholic Fatty Liver Disease (NAFLD), affects 6-37% of the population worldwide, and is described as a ‘silent killer’ since clinical symptoms only surface at late stages of the disease, when it is no longer treatable: untreated, NAFLD can lead to cirrhosis and hepatocellular carcinoma, culminating in liver failure. We are part of an EU consortium mtFOIE GRAS (Foie Gras being French for "fat liver") which proposes to develop non-invasive, accurate, detection of NAFLD where we plan to develop mitochondrial DNA, RNA and protein biomarkers in a combination of model systems, and patient samples from our European collaborators.
Co-ordinated from Boston, USA, and comprising of scientists from over 15 countries worldwide, this initiative aims to discover genetic associations among adipose and glycemic traits and variants of MtDNA and nuclear encoded genes implicated in mitochondria. Our lab was invited to join in May 2015 to design functional studies for any loci discovered. Click here to view our latest publication.