Metabolomics provide new insights into insulin resistance

Wednesday, 1 May 2019



Can you describe the aim of this project in 10 words?

To understand how adipocytes process glucose.

What have you discovered in this area so far?

After a meal, insulin stimulates adipocytes to take up glucose from the bloodstream. It is typically thought that this glucose is stored as lipid. However, we have found that adipocytes actually secrete a majority of glucose as lactate, which is typically only thought to occur with muscle during intense exercise. We characterised this phenomenon in depth using metabolomics, a technology that allows us to measure hundreds of different metabolites at once. Indeed, processing glucose in this way was required to facilitate the storage of other nutrients as lipid (e.g. amino acids). Thus, glucose is not stored as lipid per se, but nevertheless plays a vital role in the adipocyte’s ‘energy storage’ response to insulin. We predict that when less glucose is taken up by adipocytes during insulin resistance (pre-diabetes), this would impair their ability to store energy. This would result in the accumulation of lipid in other tissues, an impairment to our overall metabolic health.

What’s fascinating about metabolomics and the new insights it might bring?

When nutrients are processed within the cell, they have particular fates – for instance, they can be stored or oxidised as carbon dioxide. Fifty years ago, experiments studying this metabolism could usually only measure one endpoint at a time. Metabolomics technology enables us to measure hundreds of metabolites at once, which not only allows us to infer different fates at once, but the intracellular pathways nutrients take to reach these fates. In addition, we can process numerous samples with ease, which opens up new possibilities, such as testing different models of insulin resistance at once or performing time-courses to study the rapid responses to changes in a cell’s environment.

How long before this work might impact patient care?

There is a lot of interest in preventing the development of type 2 diabetes by targeting the pre-diabetic state. In healthy individuals, glucose is stored in fat and muscle tissue following a meal. This is highly regulated, but becomes defective in pre-diabetes. Most studies focus on the transport of glucose into these tissues, but here we have looked at how glucose is processed after it is taken up (e.g. stored as fat versus burnt for energy). It is hard to predict how long this will take to translate to patient care given we are still at the early stages, but the research is timely given the push for targeting glucose metabolism in other diseases, notably cancer. This will help us to develop targeted strategies to repair these defects in glucose handling, as a means of preventing type 2 diabetes.

What aspect of this research excites you the most?

When each time we ask a question, the experiment yields an answer that we were not expecting. This has happened several times in our research, really changing how we view adipocytes and how we can utilise them to prevent the onset of type 2 diabetes.

What’s your Holy Grail – the one thing you’d like to achieve in your research career?

Classically, we consider metabolism as a biological endpoint – the cell regulates its metabolism in response to hormonal and nutritional cues in the environment. However, there is now a greater appreciation that the reverse is also true, that metabolism itself can influence the cell’s response. Instead of being a mere carrier of carbon atoms and energy, metabolites can act trigger intracellular signaling pathways by acting as ligands for receptors or fueling the chemical modification of proteins. I would love to pursue this further in the future.

What is your biggest research hurdle?

Funding. Although funding concerns are a glass ceiling for every lab, this has also forced me to focus on the most important questions in my research. I am very grateful to funding bodies such as the NHMRC and Diabetes Australia for funding my (and my host labs’) research over the years, providing me with access to new technologies (e.g., metabolomics) and the ability to collaborate with scientists abroad.

Who has inspired you in work or life?

I have been fortunate to be surrounded by many well-balanced, resilient, and intelligent mentors, colleagues, students, and family. It’s hard to think of just one person, as I have learnt different things from each of them! For instance, my students constantly remind me of the joy of learning new things; my work mentors inspire me to focus my research on the important questions in our field; my family grounds and supports me; everyone reminds me why I do what I do.

‘There’s an app for that.’ What’s new on your phone?

One of my most recent apps is a baby tracking app, letting my wife and I log our son’s meals and sleep patterns. It has been fun to watch our son develop over time and the app is even smart enough to predict when he might be going through growth spurts and difficulty sleeping!

Describe your perfect day.

At work, it would have to be when I learn something new, when an experiment yields a cool and unexpected finding. Outside of work, it would have to be just chilling out with my family and binge-watching sci-fi shows.

 

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