#221      26 min 30 sec
Pump it up: Exercise, your muscles, and type 2 diabetes

Cell biologist and sports physiologist Prof Mark Febbraio discusses research that uncovers the relationship amongst exercise, muscular activity, obesity and type 2 diabetes. Presented by Dr Shane Huntington.

"The Japanese Sumo wrestler is very, very obese but very metabolically healthy. Unfortunately problems arise when they stop wrestling, but at the point of wrestling they are very insulin sensitive individuals because they train very, very hard." -- Prof Mark Febbraio




Prof Mark Febbraio
Prof Mark Febbraio

Professor Mark Febbraio is a Senior Principal Research Fellow of the NHMRC, is Program Head of Cell Signalling and Metabolism and Head of the Cellular and Molecular Metabolism Laboratory at the Baker IDI Heart & Diabetes Institute. He is also the Chief Scientific Officer and on the Board of Directors of N-Gene Research Laboratories Inc., a USA based Biotechnology company. His research is focussed on understanding cellular and molecular mechanisms associated obesity and type 2 diabetes.  He has authored over 180 peer reviewed papers in leading journals such as Nature, Cell, Nature Medicine, The Journal of Clinical Investigation, PNAS and Diabetes.

Mark has won prizes at international, national and institutional levels including the A K McIntyre Prize for significant contributions to Australian Physiological Science (1999), the Colin I Johnson Lectureship by the High Blood Pressure Research Council of Australia (2006) the ESA/ADS Joint Plenary Lecture (2009) and the Sandford Skinner Oration (2011). He has served on the Editorial Board of Diabetes, The American Journal of Physiology Endocrinology & Metabolism, Exercise Immunology Reviews and Journal of Applied Physiology. He has served on The Council of The Australian Diabetes Society and is a past Honorary Treasurer of this Society (2006-2008). He has served on National Health and Medical Research Grant Review Panels for several years in the areas of Physiology, Cell Biology and Diabetes/Obesity. Professor Febbraio is also dedicated to health and fitness and continues to complete in running races and multi-sport events.

Credits

Host: Dr Shane Huntington
Producers: Eric van Bemmel, Kelvin Param
Associate Producer: Dr Dyani Lewis
Audio Engineer: Gavin Nebauer
Voiceover: Nerissa Hannink
Series Creators: Kelvin Param & Eric van Bemmel

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VOICEOVER 
Welcome to Up Close, the research talk show from The University of Melbourne, Australia. 

SHANE HUNTINGTON 
I’m Dr Shane Huntington.  Thanks for joining us.With modern conveniences, it is now conceivable for a person to live life with little physical activity.  We are surrounded by tempting high-fat high-sugar foods; foods that are crafted to whet an appetite that evolved to save us from starvation when supplies are low by eating well when supplies are abundant.The result, as many Western and increasingly developing nations have found, is obesity, a condition with consequences that are both complex and costly.  Of course we already have a solution to most obesity, healthy eating and exercise, and yet many of us, along with our kids, are not utilising this simple remedy.Obesity is only part of the problem.  There are also an increasing number of people with Type 2 diabetes.  Today on Up Close, we are joined by Professor Mark Febbraio, an exercise physiologist turned cell biologist who is investigating the interplay between exercise and the way our bodies function.Mark Febbraio is Professor of Cell Biology, Head of the Cellular and Molecular Metabolism Laboratory and Director of Basic Science in the Division of Metabolism and Obesity at the Baker IDI Heart and Diabetes Institute.Welcome to Up Close Mark.

MARK FEBBRAIO
Thank you. It’s a pleasure.

SHANE HUNTINGTONWhat exactly is diabetes and what are the different types of this particular disease?

MARK FEBBRAIO
Okay, there are two types of diabetes.  There is Type 1 diabetes which is insulin dependent.  Type 1 diabetes is a disease which is an autoimmune disease.  The onset can be in children, but it can be later in life, and basically it’s an autoimmune disease where the immune system actually attacks the beta cells of the pancreas.  These cells are the cells that produce insulin and therefore when somebody with Type 1 diabetes eats a meal, insulin in the hormone, the signal released from the pancreas to tell other tissues in the body to take the sugar from the bloodstream and deposit it into the tissues such that individuals maintain normal glucose levels.  In the absence of insulin, glucose is elevated and this can cause problems.  This disease of Type 1 diabetes is on the rise, but nothing like Type 2 diabetes.  Type 2 diabetes is non-insulin dependent.  It used to be called mature onset, but now we see children getting the disease, and this disease is caused primarily by a syndrome known as insulin resistance.  Insulin resistance is when the pancreas can secrete insulin okay but then the tissues that take up the sugar don’t have the proper mechanism to deposit the glucose.This is largely thought to be due to excess lipid or fat, and hence this is why Type 2 diabetes is very, very linked to obesity.

SHANE HUNTINGTON 
Now when you described Type 1 diabetes there you referred to an autoimmune disease.  What exactly do you mean by that?

MARK FEBBRAIO
An autoimmune disease is a disease where the immune system becomes disregulated and rather than recognise self from non-self - which the immune system is evolved to do; that’s why when we have a pathogen, a bacteria, it tries to kill the bacteria - it disregulates and starts to kill the self; kill the beta cells in the pancreas.  We are not exactly sure the precise mechanism of that.  I mean that’s not a major area of my research, so my research is mainly on Type 2 diabetes and obesity.

SHANE HUNTINGTON 
Let’s focus on Type 2 diabetes - what sort of symptoms would a person with this condition have?

MARK FEBBRAIO
Well unfortunately the person with overt Type 2 diabetes would start to experience lethargy, frequent urination, thirst, et cetera, and would typically go to their GP and have a blood sample taken and two diagnostic markers are just circulating glucose and glycated hemoglobin.  The hemoglobin becomes glycated, but unfortunately the onset of the disease could occur 10 to 15 years prior to overt diabetes.  This is where glucose levels are actually normal, but insulin levels are elevated.In the pre-diabetes stage - the insulin resistance stage - what typically happens is an individual will have a normal fasting blood glucose but an elevated insulin, and that’s often not picked up. Then the stage is to have impaired glucose tolerance where a person would typically consume 75 grams of sugar in a drink and glucose is monitored over two hours.  The area under the curve gives an indication of how glucose tolerant that individual is.

SHANE HUNTINGTON
Mark, can you describe for us what glycated hemoglobin actually is?

MARK FEBBRAIO
So hemoglobin is the molecule that carries oxygen to the body.  When glucose levels; when sugar levels in the body are high, the sugar levels can attach to the hemoglobin.  Glycated hemoglobin is the diagnostic measure of diabetes. If it is over six or seven or eight then you have degrees of severity of disease.   So glycated hemoglobin is the clinical output measure of Type 2 diabetes.

SHANE HUNTINGTON
In the case of this insulin resistance, do all the cells become resistant at once or is this a progression?  Can it be halted?

MARK FEBBRAIO
That’s a very good question.  There are two answers to that question.The first is that no, not all these cells and tissues become insulin resistant at the same time and most of the work that we have done suggests that the liver is the organ which seems to be disregulated first.  The other interesting thing about insulin resistance is that insulin resistance is selective for glucose metabolism.  If there is excess glucose what happens in the liver is you get de novo lipogenesis which means you start to get a fatty liver, but the origin of the fat is actually sugar.  Now that unfortunately is intact in a person with insulin resistance.  The problem with insulin resistance is that it is selective for glucose metabolism, not fat metabolism.

SHANE HUNTINGTON
Now when you get into the situation where you are either part way down the pathway towards Type 2 diabetes or you have actually been declared as someone having Type 2 diabetes, can it be reversed at that point or are you on that treadmill and it just keeps on running?

MARK FEBBRAIO 
There is a certain degree that you will never be 100 per cent cured, but it certainly can be controlled and it can be controlled several ways.  It is very linked to obesity and a term known as lipotoxicity - which is excess lipid in organs and tissues where lipids shouldn’t be.So paradoxically if you were a person who stored all of your lipid in your fat cells and you were rather obese but didn’t have lipid stored in the liver and skeletal muscle - and there is some evidence in the brain also - then you would be obese but metabolically healthy.The problem is the lipid spills into these other organs.  So you can control the Type 2 diabetes by losing weight and by being more physically active.I guess our area of research, the genesis of my movement from exercise physiology into looking at the pathogenesis of disease was a discovery we made jointly with our collaborators in Copenhagen around the term of the millennium which showed that skeletal muscle, when it contracts - like during exercise - can release proteins that seem to be protective for other tissues.

SHANE HUNTINGTON
Mark how does skeletal muscle differ from the normal muscles in our arms and legs and so forth?

MARK FEBBRAIO
Well skeletal muscle is the normal muscle in our arms and legs.  There are three types of muscles in the body.  There is cardiac muscle - which is your heart.  There is smooth muscle - smooth muscle is like muscles in your gut that work via peristalsis - and then there is skeletal muscle which are the muscles in your arms and legs.  So they’re, we think they are very important because they constitute most of the human body, in terms of mass.

SHANE HUNTINGTON
I’m Shane Huntington and you’re listening to Up Close.  In this episode we are talking about diabetes and exercise with Cell Biologist Professor Mark Febbraio.Now Mark this doesn’t seem to have been a major problem - Type 2 diabetes - say even 30 years ago.  What has changed? I mean it’s not just everyone sitting on the couch.  Something else must have changed.

MARK FEBBRAIO
This is a question that has prompted much debate and discussion amongst the scientific fraternity and the interesting thing is the complexity of the disease involves the gene via an environmental interaction.So if the disease was purely genetic then it would track linearly with an increase in the population.  But it isn’t linear; it’s exponential.  So there is no question that much of the disease is caused by obesity and inactivity.There is proof of that by looking at the regression of Type 2 diabetes in obese people who undergo bariatric surgery.  However there is still a population where they can be incredibly obese but metabolically healthy.  So there seems to be an interaction between genes and environment and what we think is that there is a, what is now known as an epigenetic control of genes that predispose someone for disease. Epigenetic means that the environmental factors can influence the gene of interest.

SHANE HUNTINGTON
Mark, your work specifically looks at the role of muscles in diabetes. What got you into this particular area? It doesn’t sound like the norm that a diabetes researcher would be looking at.

MARK FEBBRAIO
No, it’s very interesting.  You know science is often serendipitous and many, many years ago, whilst I was working as an exercise physiologist - and my interest in exercise physiology stemmed from my interest in physical activity myself - I mean before I did my PhD I was an active sportsperson. But about 15 years ago a student came into my office and said that she wanted to study a particular group of immune molecules known as cytokines.We knew that one particular cytokine - a cytokine known as interlukin-6 - increased in the blood very rapidly during exercise.  It was assumed, although not proven, that the origin of interleukin-6 were in fact the immune cells and that was logical because they’re an immune cytokine.So what this particular student did - her name was Rebecca Starkie, and she’s now a medico - what she did was took blood after physical activity, exercise, and then isolated the particular immune cells that were known to make this cytokine and to our surprise the production within the blood cells actually went down rather than up.  So we were left with this conundrum what is the origin of this particular molecule?  We, by doing several experiments, were able to show that it was in fact the contracting skeletal muscle.

SHANE HUNTINGTON
We have heard before people will give the excuse that their hormones are causing them to be essentially overweight.  What is the role of hormones in, you know, the human physiology and controlling weight?

MARK FEBBRAIO
The definition of a hormone is a protein that is released from one cell to talk to another cell or another organ, and the interesting thing about evolution and hormonal regulation of food intake is that most hormones that are secreted from the gut are telling the brain to stop eating.  There is only one hormone that is released from the gut to tell the brain to eat.So, therefore, we are hardwired to eat and we have got all of these signals telling us to stop eating, and if one of those signals becomes disregulated then that is where you have the concept that oh my hormones are the reason I’m overweight.Now every obese person has hormonal disregulation because there is one central appetite suppressing hormone, known as leptin, and when you are obese you become what is known as leptin resistant.  There is more leptin circulating but it doesn’t act on the brain as it should.

SHANE HUNTINGTON
Does that happen in the reverse where - do you get some people who have an inappropriate production of leptin prior to being obese and it then leads to the obesity?

MARK FEBBRAIO
Yes there are people who are leptin deficient, and in fact leptin was discovered in a mouse that just had an insatiable appetite.  This particular mouse - it’s called an ob/ob or obese/obese mouse - that mouse isn’t subjected to McDonald’s or advertising.  It just continues to eat, whereas other mice regulate their body weight very well.So Jeff Friedman in the early 90s, from Rockefeller University in New York, was able to discover that this mouse had a mutation of the leptin gene, and he cloned the gene; named it leptin.At that point we thought we had cured obesity, because we thought okay, we just give obese people leptin, they stop eating, but then when leptin levels in the blood of obese people were examined, paradoxically they were higher and this is this concept of leptin resistant.  However, in individuals who have a mutation of the gene, leptin cures their obesity.

SHANE HUNTINGTON
Coming back now to the muscle aspect of this topic - how do these molecules that are produced in the muscle area contribute and why is it so unhealthy to be both overweight and inactive at the same time?

MARK FEBBRAIO
Okay, so we coined a term when we made the discovery that muscle secretes interlukin-6, we coined the term myokine - myo being muscle, and kine being as cytokine.  There are now many myokines that have been discovered.Recently Professor Bruce Spiegelman from Harvard University identified a molecule known as irisin which talks to brown fat and white fat -the two different types of fat in the body - but it mainly talks to white fat to increase its energy burning capacity.So to be inactive means that you don’t activate the machinery to produce these molecules that seem to have benefits in other areas of the body.The other side of that is to be inactive means that you then have a positive energy balance whereby your intake exceeds your expenditure.  So there are two reasons as to why obesity is a bad thing.Now if you have obesity in the presence of high activity you seem to be protected, and the classic example of this is Japanese Sumo wrestlers.  The Japanese Sumo wrestler is very, very obese but very metabolically healthy. Unfortunately problems arise when they stop wrestling, but at the point of wrestling they are very insulin sensitive individuals because they train very, very hard.

SHANE HUNTINGTON
What is the converse of this when you look at someone who is very slim but inactive?  Do they have these same problems as an overweight person who is inactive or is it just not a concern?

MARK FEBBRAIO
No, no, it is a concern because quite often you will have an individual who may look - because they are thing - who may look like they don’t carry excess lipid but there could be two concerns there - one is that they have visceral fat, which is fat around the organs, through poor diet and inactivity; and secondly they may have fatty liver disease where the lipid is actually in the liver.  Another point in those individuals is they are probably genetically predisposed to develop disease.So if you have the combination of inactivity, the wrong genes, and a poor diet, you can still be lean and metabolically unhealthy.

SHANE HUNTINGTON
I’m Shane Huntington and my guest today is Cell Biologist Professor Mark Febbraio.  We are talking about diabetes and exercise here on Up Close.Mark, when we think about reducing our risk of developing obesity or Type 2 diabetes, exercise is always, of course, in the mix.  Is this just to make sure that we burn through the calories or is there something more to it than just that sort of input versus output?

MARK FEBBRAIO
I think I alluded to this earlier; I think there is something more to it. I spoke about epigenetics. One of the things that is quite alarming is that genes seem to be programmed now in-utero, and there many scientists we work with - one in particular, Dr Cath Suter from the Victor Chang Institute in Sydney; she’s an epigeneticist - and we are working with her on how genes are programmed in-utero.  If the placenta contains lots of lipid during embryogenesis then this lipid can have an impact on the offspring.  We have even some preliminary evidence suggesting on the offspring’s offspring.  So it’s not only choose your parents; it’s choose your grandparents carefully.So my point in saying that is that if you are physically active as a pregnant woman or as a child, then you have the right environment to make sure that you get the better epigenetic modifications of your genes rather than poor epigenetic modifications of your genes.

SHANE HUNTINGTON
When we do exercise our brain obviously sends electrical signals to inform our muscles they should contract.  What signals are them coming out of the muscles that affect this whole situation?

MARK FEBBRAIO
So there are either neural inputs back to the brain from the muscle - which isn’t an area that has been explored very extensively I might add - but then there are also these myokines that are released from the muscle, and these can talk to the brain, to the adipose tissue, to the liver, and to other muscles to modify the metabolism in those tissues.So it could be either a hormone or a neural regulation.

SHANE HUNTINGTON
When you talk about all these signals, it sounds extremely complex.  How do you actually go about mapping how these work in the body?

MARK FEBBRAIO 
Most of the myokines that have been discovered have been discovered serendipitously. What my lab is doing at the moment is we are using an unbiased proteomic screening approach where we are trying to identify novel myokines using proteomic analysis.

SHANE HUNTINGTON
Are these experiments done directly on people or do you use…

MARK FEBBRAIO
No, no these are done…

SHANE HUNTINGTON
…[unclear]?

MARK FEBBRAIO
…these are usually done either in cell-based experiments or mouse models initially, because what you have to do is you have to label the entire proteome which is all the proteins in a cell or in a muscle and you have to label these.  So it’s impossible to get someone to label a proteome in a human.

SHANE HUNTINGTON
Talk to us a bit about the way in which these experiments are done, because I can imagine, especially in the mouse models, you’re looking at very small quantities of some of these chemicals and there are many chemicals involved.  What sort of equipment do you use to isolate these particular materials, some of which you don’t even know you are looking for?

MARK FEBBRAIO
Right, so the mouse model that we use is quite often the ob/ob mouse, which I spoke to you about before - the obese mouse - or we actually feed the mice high-fat diets.  When you feed a mouse a high-fat diet it does become inactive as well; and these mice become obese.  Then we can take the tissue from the animals and we can use several platforms with the advent of gene sequencing now; we can sequence the mouse genome before and after high-fat feeding; with and without physical activity; with and without physical inactivity; or we can take proteins and run them through a mass spec.One thing that you do is you label the proteome and it gets complicated but it results in a shift in the mass of the protein and we know the shift, we know how much - it is either six or a 10 Dalton shift in the mass of the protein, so we can look for shifts and then we can cut out that particular protein and we can sequence it and work out what it is.

SHANE HUNTINGTON
Many of our listeners are probably thinking a lot of this work leads towards an idea we already know - that more exercise is good for us and so forth.  Are there other applications for these studies?  I mean we are learning a lot about how the body works; does it sort of port over into other areas of health?

MARK FEBBRAIO
You know the frustrating thing from a scientist who works on a disease that is largely we have a cure for, and that is you know lifestyle, and it’s not a cure for people who are morbidly obese because those people have a chemical imbalance.  So we need to work out what the imbalance is.But for those individuals who become creepingly overweight over time, due to an imbalance in their lifestyle, it’s frustrating because as your introduction said; with the advent of technology we need to move less.So the nexus of my work is to find exercise mimetics.  So if we can identify an area or a pathway that is activated by exercise or inactivated by exercise, we can then try and develop a pharmaceutical approach to either blocking the pathway or activating it - so looking for you know exercise mimetic drugs for want of a better term.

SHANE HUNTINGTON
So I am kind of hoping the answer to this is no, but does this mean one day we may be able to take a pill that does the job of exercise for us?

MARK FEBBRAIO
That’ll never happen.  That’ll never ever happen.  Exercise has so many benefits.  You know here is one of the benefits - my daughter who is 14 has started to increase her exercise recently and one of the knock-ons of that is you become more health conscious so therefore you make better food choices. So you’re never going to be able to have a pill to aid the psychological benefit - you know the runner’s high, the endorphins - there will never be a pill and we are not looking for a pill.But in some people, they can’t exercise, or won’t exercise, and in those people maybe this type of approach would be almost a kick starter.  But I think what we need is, in order to really cure this problem we need to think about the problem very differently, because we are not winning the battle at the moment.

SHANE HUNTINGTON
Mark Febbraio, Professor of Cell Biology, Head of the Cellular and Molecular Metabolism Laboratory and Director of Basic Science in the Division of Metabolism and Obesity at the Baker IDI Heart and Diabetes Research Institute; thank you very much for being our guest on Up Close today and talking about diabetes and exercise.

MARK FEBBRAIO
It’s a pleasure.  Thank you.

SHANE HUNTINGTON
Relevant links, a full transcript and more on this episode can be found at our website at upclose.unimelb.edu.au.Up Close is a production of The University of Melbourne, Australia.This episode was recorded on 25 October 2012.Our producer for this episode was Kelvin Param.  Associate producer Dyani Lewis.  Audio engineer Gavin Nebauer.  Up Close is created by Eric van Bemmel and Kelvin Param.I’m Shane Huntington. Until next time, goodbye.

VOICEOVER
You’ve been listening to Up Close.  We are also on Twitter and Facebook.  For more info visit upclose.unimelb.edu.au. Copyright 2012 The University of Melbourne.


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