Metabolomics
Associate Professor Peter Meikle
Head, Metabolomics
peter.meikle@bakeridi.edu.au
Laboratory Research Overview
Metabolomics is the systematic study of the unique metabolite (small-molecule) fingerprints of biological systems. The Metabolomics Laboratory uses "state of the art" tandem mass spectrometry to obtain metabolic profiles (primarily lipids and fats) from cell and animal models in addition to clinically relevant human samples to better characterise the dyslipidemia associated with obesity, diabetes and cardiovascular disease and its relationship to the pathogenesis of these disease states. These studies are leading to new approaches to early diagnosis, risk assessment and therapeutic monitoring of these most prevalent diseases in our society.
One of the main goals of the Laboratory is to better understand the difference between stable and unstable coronary disease. At present there is no way of knowing which people among a group with what we know as "stable" coronary disease will develop "unstable" disease. This is a critical area of investigation as stable disease can become unstable - leading to sudden heart attack and stroke - at any time. For many people the first sign that their disease is unstable is death, yet others live long lives with stable disease - partial blockages in the coronary arteries that do not undergo significant change.
Recent funding from the National Institutes of Health (NIH) has enabled studies to characterise the changes in blood plasma lipids and fats associated with obesity and diabetes. These studies will not only improve our understanding of the reasons why people develop diabetes but will help to develop new tests to identify those at greatest risk of developing this disease.
In collaboration with other research groups at Baker IDI, we are conducting an investigation into the health effects of dairy products in the diet. Specifically, research will look at the difference to health between fermented dairy products - such as cheese and yoghurt - and non-fermented dairy products, such as cream, milk and butter. It is believed that fermented dairy products in the diet result in a lower blood cholesterol level than non-fermented dairy products. The team will seek to uncover why that is the case and what are the consequences, by analysing blood lipids, and so better understand the role of dairy products in a healthy diet.
Research Focus
- Changes in lipid metabolism associated with coronary artery disease.
- Risk assessment for unstable coronary artery disease: identification of the "vulnerable patient".
- The relationship between lipid metabolism, obesity and diabetes: why do some obese people get diabetes but not others?
- Risk assessment for diabetes.
- The healthy effects of dairy foods.
Research Projects
Prediction of Unstable Coronary Artery Disease
Atherosclerosis (AS) is the single most common cause of cardiovascular disease and is the major contributor to the development of angina, heart attacks, coronary heart disease and stroke. Despite the introduction of statin based therapy to reduce levels of plasma LDL cholesterol, the epidemic of cardiovascular disease claimed over 47,000 Australian lives in 2004 and costs the health system over $5 billion per year.
We have developed: Lipid profiling technology that can quantify over 350 lipid species from 10 uL of plasma using a targeted lipidomic approach (analysis of known lipids).
We have demonstrated that: Individuals with AS have altered lipid metabolism that correlates with different stages of disease (healthy, stable CAD, unstable CAD) and that this is reflected in their plasma lipid profile.
We have used the plasma lipid profiles to create multivariate models that can:
- Stratify healthy from CAD patients,
- Determine plaque stability, and
- Stratify those individuals who have had a cardiovascular event (CVE) from those who have not. Importantly, these models perform better than traditional risk factors (Framingham and Reynolds risk equations) to characterise individuals in our cross sectional studies.
The risk of a CVE is directly related to a) coronary plaque severity (plaque burden) and b) coronary plaque stability. We are working to refine our plasma lipid profiles to better reflect these characteristics, to combine these profiles into a model to predict CVE and finally to validate the new model through a series of prospective studies on clinically defined populations.
Metabolomic studies into the pathogenesis and risk assessment of type 2 diabetes
The Australian population and indeed most of the developed world are facing an obesity epidemic; associated with this is a dramatic increase in the incidence of type 2 diabetes and its precursor, impaired glucose tolerance (IGT). If the current rates of mortality and diabetes incidence continue, the prevalence of diabetes is projected to rise from 7.6% in 2000 to 11.4% by 2025. More than a third of individuals will develop diabetes within their lifetime and there will an additional 1 million cases of diabetes by the year 2025.
- Early detection of diabetes or the identification of those at increased risk provides the opportunity for early treatment to prevent onset or progression of the disease.
- Obesity is an important risk factor for diabetes; however, not all obese individuals will go on to develop diabetes. Improved predictive markers are required.
- Altered lipid metabolism plays a key role in the development and progression of diabetes. However, the metabolic and signalling pathways involved are poorly defined.
This project applies a novel lipidomic approach to characterise the dyslipidemia associated with the different stages of IGT and diabetes. We will determine which aspects of the dyslipidemia precede the onset of disease and develop predictive models for the early identification of those individuals at increased risk of developing diabetes. We will validate this tool using existing plasma samples collected from longitudinal studies of well-characterised populations. We will also use the same lipidomic tools, combined with existing genetic data, to define the molecular mechanisms that perturb lipid homeostasis contributing to disease onset and progression.
Obesity and obesity-related disease: A multi-disciplinary investigation into the impact of dairy consumption
We are studying the effect of dairy containing diets on obesity, diabetes and cardiovascular disease. The program has two parts:
1. The influence of dairy on the risk and progression of metabolic syndrome and cardiovascular disease: An AusDiab prospective study.
We hypothesise that the intake of dairy products is associated with a reduction in the risk of diabetes, cardiovascular disease, metabolic syndrome and obesity, independent of traditional risk factors.
Also, that the influence of dairy products on the risk of diabetes, cardiovascular disease, metabolic syndrome and obesity is mediated, at least in part, by alterations in lipid metabolism: these alterations will be reflected in the type and subspecies (fatty acid content) of lipids present in plasma (the plasma lipid profile).
We are utilising the Australian Diabetes Lifestyle and Obesity Study (AusDiab) cohort to test these hypotheses.
2. The effects of fermented and non-fermented dairy on the level of circulating inflammatory biomarkers.
In this study, we are examining the effect of dairy diets (fermented versus non-fermented) on key disease process associated with the obesity and metabolic syndrome, specifically we are looking at the effect of diet on inflammation and how different dairy products may modulate this process.
Lab Head Profile
A/Prof Meikle completed his PhD in 1986 at James Cook University of North Queensland. Following postdoctoral positions at the National Research Council in Ottawa, Canada, and Latrobe University, Melbourne, he joined the Lysosomal Diseases Research Unit (LDRU) at the Women's and Children's Hospital in Adelaide and established a metabolomics research group focused on the screening diagnosis and pathogenesis of lysosomal storage diseases. In 2000 he was appointed Head of the Metabolic and Therapeutics Program, within the Department of Genetic Medicine while still maintaining his research program within the LDRU.
In 2007 A/Prof Meikle moved to the Baker IDI Heart and Diabetes Institute (BHDI) where he established the Metabolomics Laboratory. In 2008 he was awarded a NHMRC Senior Research Fellowship. The Metabolomics Laboratory at BHDI uses state of the art tandem mass spectrometry techniques to obtain metabolic profiles from cell and animal models in addition to clinically relevant human samples. This approach is combined with cell biology studies to improve our understanding of disease mechanisms and develop new diagnostic, prognostic and monitoring strategies in the areas of obesity, diabetes and cardiovascular disease.
A/Prof Meikle holds affiliate positions at Bio21, Melbourne University and the Department of Medicine, Monash Medical School, Monash University.
Achievements/Awards
NHMRC Senior Research Fellow (2008)
Publication Highlights
- Tan MA, Fuller M, Zabidi-Hussin ZA, Hopwood JJ, Meikle PJ. Biochemical profiling to predict disease severity in metachromatic leukodystrophy. Mol Genet Metab 2010;99(2):142-8.
- Meikle PJ, Duplock S, Blacklock D, Whitfield PD, Macintosh G, Hopwood JJ, Fuller M. Effect of lysosomal storage on bis(monoacylglycero)phosphate. Biochem J 2008;411(1):71-8.
- Meikle PJ, Grasby DJ, Dean CJ, Lang DL, Bockmann M, Whittle AM, Fietz MJ, Simonsen H, Fuller M, Brooks DA, Hopwood JJ. Newborn Screening for Lysosomal Storage Disorders. Mol Genet Metab 2006;88(4):307-314.
- Fuller M, Sharp PC, Rozaklis T, Whitfield PD, Blacklock D, Hopwood JJ, Meikle PJ. Urinary lipid profiling for the identification of Fabry hemizygotes and heterozygotes. Clin Chem 2005;51: 688-694.
- Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999;281:249-254.
Key Staff
| Scientific staff: | Dr Wai Ng |
| Dr John Odontiardis | |
| Jacqui Weir | |
| Students: | Michael Christopher |
| Zahir Alshehry | |
