Holy Grail: insulin resistance and brain vascular function



Can you describe the aim of your research in 10 words?

To understand how blood vessels contribute to brain function.

Tell us more:

My interest lies in understanding how capillaries respond to hormones such as insulin in normal health and how this response changes with disease.

Based on what we know so far, insulin is likely to have several effects in the brain but whether it acts on blood vessels to increase blood flow in specific areas has never been investigated.

We are also interested in understanding whether insulin may act on larger vessels to control overall perfusion or whether the effects are more subtle and involve pericyte-mediated capillary diameter regulation.

To understand this, we are currently using real-time contrast enhanced ultrasound to measure brain blood flow changes in vivo in the fully intact rodent head (no craniotomy needed) in response to insulin in healthy or obese rodents.

We are coupling this in vivo imaging with a technique that lets us generate a fluorescent vascular cast at the end of the experiment that we can then use to interrogate region-specific vascular changes using microscopy.

Image of vascular cast

The left image shows a fluorescent vascular cast of the cortex where blood vessels are visualised in green. The right image shows a high magnification of the green (vascular) signal where on arteriole branches off into several smaller capillaries. Blue indicates cell nuclei. Unpublished data.

We’re also investigating how common anti-diabetic drugs such as metformin and exenatide improve stroke outcomes and whether this is linked with normalisation of brain vascular responses post-stroke. We have previously shown that metformin improves microvascular function in peripheral organs in obesity/type 2 diabetes (T2D) but whether this also occurs in the brain is not known.

Our work focuses on understanding these microvascular changes in the brain because cerebral microvascular dysfunction has been linked with obesity, T2D, stroke and Alzheimer’s Disease.

What have you discovered in this area so far?

My lab has developed a non-invasive ultrasound technique that allows for dynamic and high-frequency blood flow imaging in intact brain vasculature.

This is crucial because we can now see real-time brain blood flow changes in response to stimuli such as insulin as well as how these responses change with disease. We are currently using this technique to understand brain blood flow changes in health, obesity, and disease states such as T2D and stroke.

In the context of ischaemic stroke, we are paradoxically finding that blood flow is increased at the time of recanalisation where we expected to see reduced blood flow. Interestingly, in the presence of comorbidities like T2D, this blood flow response post-stroke is further increased and appears to predict the extent of brain damage. We are working on understanding why this is and the significance of this vascular response to increased brain damage.

How could your work affect patient care?

The primary application of our ultrasound technology so far has been in the context of ischaemic stroke. We are beginning to understand more about blood flow changes in the seconds/minutes after a clot is removed and blood flow to the brain is restored.

We are finding that the extent of blood flow in the brain after a stroke predicts how much brain damage there will be. We are now working on developing ways to normalise blood flow after stroke to hopefully reduce brain damage. Given there is no treatment for stroke beyond removing the clot, this is an exciting area to be involved in that may have real applications in the near future.

How long before your work affects patient care?

This is a difficult question to answer. I’m hopeful that the work we are doing in the area of ischaemic stroke will have tangible outcomes in near future. One of our current projects aims to understand whether metformin, the number one drug given to people with T2D, can reduce brain damage in the context of stroke. If we find some promising effects of metformin, there’s no reason why this clinically-approved drug cannot be put into trials for stroke treatment.

What aspect of your research excites you the most?

I get really excited about discovering something no one else has been able to show before. At the moment, I’m most excited about using the ultrasound technology we have in my lab to understand blood flow and its regulation in the brain in health and disease. The other exciting aspect of my work is being able to train honours and PhD students and pass on the skills and information that I have to get them excited and engaged in research.

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

With research funding being so hard to come by these days, it would be great to obtain sufficient funding from large funding bodies (e.g. NHMRC) to fully support my staff and students in the work that we do in my lab.

From a scientific point of view, it would be fantastic if my team could contribute to the development of a new treatment for stroke in the next 10 years.

What is your biggest research hurdle?

As I am sure all other researchers would say, the biggest research hurdles are time and money. Research takes a long time to perform well and there are many challenges along the way that have to be solved before we can make sense of the data we collect — sometimes this means that what we think is a simple and quick project ends up being highly complex and taking years to finish. The other main issue we have is chronic underfunding of research in Australia. When success rates for research grants are ~10%, it is very disheartening for early career researchers.

Who has inspired you in work or life? 

I have been lucky enough to have some excellent mentors in my work over the past 10 years. Each of them has helped me at different times and I have grown a lot as a person thanks to the discussions and advice I have received.

In my life, I think the two people that inspire me the most are my parents — they came to Australia as refugees from eastern Europe in 1994 with nothing to their names. They worked extremely hard to provide me with the opportunity to go to university and pursue a career in research — I think this is where my work ethic comes from.

What new hobby have you picked up during COVID?

I don’t think I’ve picked up any new hobbies that I am fully engaged with — the closest one might be the daily Wordle competition I have with my wife and a larger group of people.

Other than that, I was lucky enough to maintain most of my hobbies through COVID and there’s not much time in the day with three young kids to chase after.

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