Metabolism and Obesity

Professor Bronwyn Kingwell
Head, Metabolic & Vascular Physiology 
bronwyn.kingwell@bakeridi.edu.au

Laboratory Research Overview 

Research in this lab is focused on two main areas: coronary plaque stability (in collaboration with Dr Stephen Duffy and Professor Anthony Dart) and diabetes. Work is largely driven by the goals of better management of existing disease and the development of better predictive tools against it.

The formation of plaques, known as atherosclerosis, inside the heart’s blood vessels is a major contributor to heart attack. Plaques, essentially small fatty deposits, are characterised by a thick, fibrous layer, like a scab, containing a soft, semi-liquid core.

It is understood that most people have plaques in these arteries by a certain age, but in roughly half of that group the plaques don’t cause any problems – they are stable. For the other half though, those with unstable disease, plaques rupture, exposing the soft substance within it to the blood flowing through the artery. Once there, this substance forms a clot, also known as a thrombus. That clot can block off the whole blood vessel, causing a heart attack by stopping blood supply to some of the heart muscle. Some plaques, however, grow outside of the blood vessel. While this type of plaque doesn’t obstruct blood flow it is prone to rupture causing a sudden heart attack.

The difficulty with this type of plaque growth is that standard diagnostic techniques – the use of an angiogram, where dye is released into the middle of an artery to identify problems – are not effective because the artery looks clear. The introduction of intravascular ultrasound has made diagnosis of this type of plaque possible by examining the blood vessel wall and it’s a technique used in the research conducted in this lab.

Predicting the stability of coronary plaques is a major research interest of Bronwyn’s team. Understanding why some people have unstable plaques and others do not will go a long way towards preventing heart attacks. Looking at what the plaque releases into the blood might hold clues as to why some plaques rupture.

Using intravascular ultrasound techniques, researchers have identified plaques in patients and collected blood samples from either side of the deposit. A recently completed three-year study, collecting blood samples from about 200 patients, has shown that people with a particular genetic version of an enzyme in the blood seem to be more susceptible to plaque rupture. In a recently submitted paper, Bronwyn and her research team argue this enzyme is associated with positive remodelling – where the plaque grows outside the blood vessel wall – and increases the patient’s susceptibility to unstable disease, or sudden heart attack. This finding will significantly contribute to heart attack risk prediction.

Another significant research study has focused on patients with peripheral vascular disease (PVD). This group suffers from the formation of these plaques– atherosclerosis – in the top of their legs. A symptom of this disease is great pain on walking, essentially angina of the leg. Drug treatments, such as anti-platelet therapy to stop the blood clotting, are available but not very effective. One of the best treatments is exercise but getting this group to exercise is difficult because of the pain associated with physical activity.

This lab tested the effects of an Angiotensin-Converting Enzyme (ACE) inhibitor drug on patients with PVD. This group of drugs is commonly used to treat other forms of heart disease, but has never before been examined in relation to symptoms of this leg disease. Results in this relatively small but groundbreaking study have been startling: 20 patients in the study taking the ACE inhibitor increased their walking distance by as much as 200 percent over 24 weeks: this group doubled their treadmill walking time, from 300 to 600 seconds. The 20 patients in the other half of the study took the placebo drug and no change was evident in the distance they could walk without pain. This study has major implications for the treatment of patients with PVD and by providing them with a treatment that makes it easier for them to exercise, their own ability to manage their disease is dramatically improved. This work was recently published in the high impact medical journal, Annals of Internal Medicine.

Research Focus

The Metabolic and Vascular Physiology Laboratory takes a multidisciplinary approach to discovery and translation of novel molecular mechanisms to clinical application with a focus in the following areas:

• Vascular function including mechanical and endothelium properties and their relationship to cardiovascular risk
• Identification of novel predictors of unstable coronary heart disease
• The role of HDL cholesterol in modulation of glucose and fat metabolism
• Exercise mimetics
• Mechanisms for increasing energy expenditure in obese humans

Research Projects

Metabolic Actions of HDL

Recent studies in our laboratory have identified novel actions of HDL cholesterol in relation to glucose and fat metabolism which provide new opportunities for therapies to prevent and treat type 2 diabetes.
In a combination of in vitro molecular investigations and a clinical trial of reconstituted HDL (rHDL) infusion, we have recently shown that HDL lowers blood glucose through both stimulation of insulin release from pancreatic cells and activation of the key metabolic regulatory enzyme, AMP-activated protein kinase in skeletal muscle. Our current studies also support a third mechanism involving enhanced insulin sensitivity via anti-inflammatory actions in both metabolic tissues and macrophages. These findings provide a rationale for therapeutic approaches to raise levels of circulating HDL to manage the metabolic syndrome and type 2 diabetes.

 
Schematic diagram of the mechanisms by which HDL is postulated to modulate plasma glucose

Large Artery Stiffness

Large artery stiffness is a key determinant of central blood pressure and an important risk factor and therapeutic target in cardiovascular disease. We have developed and validated methodologies to non-invasively assess large artery stiffness in humans. This project has enabled improved assessment in major clinical trials including the second Australian National Blood Pressure (ANBP2) trial.

Other outcomes include:

• Identification of intrinsic and lifestyle (including exercise) influences on coronary and large artery stiffness. 
• Experimental evidence indicating the mechanisms by which large artery stiffening increases cardiovascular risk in human coronary disease
• Discovery of major genetic contributors to large artery stiffening in humans

Pharmacological interventions which improve arterial stiffness in humans:

• Atorvastatin reduces large artery stiffness and systolic blood pressure in patients with isolated systolic hypertension
• Ramipril reduces large artery stiffness and markedly improves walking ability in patients with peripheral arterial disease
• Perindopril reduces large artery stiffness and aortic diameter in Marfan syndrome
   

Markers of acute coronary syndromes

Worldwide, more than 19 million people experience a sudden cardiac event annually, however, accurate identification of patients at risk for unstable coronary syndromes is still not possible. Better predictors of individual vulnerability (or risk) are required and this is driving the search for new biomarkers of susceptibility to coronary plaque rupture or surface erosion, the most frequent precipitating events. Our research has demonstrated that unstable patients have a greater differential in coronary artery stiffness between the stenotic and adjacent regions using intravascular ultrasound. While this observation may help to explain susceptibility to plaque rupture, coronary biomechanical properties are obviously not a useful clinical marker of plaque stability. Matrix metalloproteinases (MMPs) are plausible candidates for prediction of unstable coronary syndromes due to their role in extracellular matrix degradation. We have recently shown that a genetic variant of MMP-3 (6A allele) promotes positive coronary remodelling, greater plaque burden, and increased susceptibility to unstable coronary syndromes in humans. Current studies using electrospray ionisation mass spectrometry have identified novel lipids which contribute to a profile of lipid biomarkers which classify stable and unstable coronary disease patients more accurately than traditional risk factors.

Lab Head Profile

Achievements / Awards 

• Total of 130 scientific publications (103 original data)
• Identification of new predictive markers for acute coronary syndromes
• Pioneering studies in exercise research influencing public health guidelines and identifying new therapeutic targets

Publication Highlights

Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, Thomas WG, Mukhamedova N, de Courten B, Forbes JM, Yap FY, Kaye DM, van Hall G, Febbraio MA, Kemp BE, Sviridov D, Steinberg GR, Kingwell BA. HDL modulates glucose metabolism in patients with type 2 diabetes. Circulation 119(15):2103-11, 2009. (IF=14.6, Citations=11)
This work represents a paradigm shift from low HDL being a bystander to active player in the glucose intolerance of the metabolic syndrome, and is highly relevant to the rising epidemic of diabetes and its dramatic impact on cardiovascular disease. HDL reduced blood glucose in patients with type 2 diabetes through novel metabolic actions in part mediated through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase (AMPK) and via elevation in plasma insulin. These findings provide a rationale for application of HDL raising therapies to not only combat cardiovascular disease, but also type 2 diabetes mellitus.

Ahimastos AA, Aggarwal A, D'Orsa KM, Formosa MF, White AJ, Savarirayan R, Dart AM, Kingwell BA. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA 298(13):1539-1547, 2007. (IF=31.7, Citations=26)
This manuscript demonstrates that in patients with Marfan syndrome, therapy with the ACE inhibitor perindopril for 24 weeks reduced aortic stiffness by up to 60% and aortic diameter by between 3 and 7 mm. These are substantial changes over a relatively short intervention period and are highly clinically significant. It is likely that ACE inhibitor therapy would delay the need for surgery and reduce the incidence of aortic rupture

Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA. Ramipril markedly improves walking ability in patients with peripheral arterial disease. Annals Int Med 144: 660-664, 2006. (Impact factor=17.5, Citations=19)
This manuscript demonstrates that the ACE inhibitor, ramipril has efficacy in controlling peripheral vascular disease symptoms. Specifically, in patients with peripheral arterial disease, ramipril therapy increased walking distance by a significantly greater magnitude than current therapies. Our study demonstrates that ramipril has benefits beyond reduction in vascular events in this high-risk population, and provides substantial improvement in clinical symptoms and quality of life

Drew BG, Fidge NH, Gallon-Beaumier G, Kemp BE, Kingwell BA. High-density lipoprotein and apolipoprotein AI increase eNOS activity via direct protein association and multisite phosphorylation. P Natl Acad Sci USA 101(18): 6999-7004, 2004. (Impact factor=9.4, Citations=46)
This work demonstrates the mechanism by which HDL cholesterol activates nitric oxide synthase. Furthermore, this occurred via activation of a critical enzyme in glucose and fat metabolism (AMPK). My more recent work published in Circulation in 2009 has extended these findings to demonstrate that HDL elevation in humans reduces blood glucose and may therefore have efficacy with respect to metabolic control in type 2 diabetes and obesity

Ferrier KE, Muhlmann MH, Baguet J-P, Cameron JD, Jennings GL, Dart AM, Kingwell BA. Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol 39: 1020-1025, 2002. (Impact factor=11.1, Citations=145)
The clinical relevance of this paper is exemplified by the relatively high citation rate. It demonstrates that intensive cholesterol reduction may be beneficial in the treatment of patients with isolated systolic hypertension and normal lipid levels, through a reduction in large artery stiffness.

Key Staff

Contact

Direct: +61 3 8532 1518
Email: bronwyn.kingwell@bakeridi.edu.au

Related Links

Bronwyn Kingwell speech @ the Lifeblood Medical Education conference