Ladies and gentlemen, we are pleased to be
here this very significant meeting. So straight to disclosures, none of which
will affect any of the opinions I have to express. In response to Fiona’s challenge, I like food
and enough of it, because without it my bicycle won’t go. So there is a story in there. Let’s start off at the New Castle key site. This is New Castle upon Tyne. Here we have the River Tyne and our famous,
famous bridges, routes. Let’s just go back to that. And the Millennium Bridge, prominent in the
foreground, a magnificent structure that you can use to walk or cycle from one shore to
the other. So, here we are looking at the Tyne and its
reflections, really perhaps a good place to reflect on the nature of Type II diabetes
because unless we know the nature of the enemy we don’t really know what to do about it. Now over a career that I’ve spent largely
doing acute general medicine and diabetes and endocrinology and increasingly pure diabetes,
there’s been a driving question of what causes Type II diabetes. In the late 1990s, the early 2000s, we were
looking at liver insulin sensitivity and the role of liver fat, and then quite suddenly
in 2002, in 2006, everything dropped into place and it was possible to write down on
a sheet of paper what possibly was causing it. Not a mysterious disease that was complex
and had different causes affecting the beta cell, amyloid, beta cell death, apoptosis, oxygen stress, but a single cause, and it went like this. People only development Type II diabetes if
they’ve been in positive calorie balance for some substantial years, and that will have
the major effect of driving the accumulation of liver fat. Now our work and that of many groups worldwide
has shown the higher the liver fat, the more insulin resistant was the liver, purely the
liver. So that will have the consequence of driving
liver insulin resistance, and the liver insulin resistance will inevitably lead to basal insulin
secretion creeping up because of homeostasis. The body wants to keep down the big function
of the liver which is producing glucose. Hepatic glucose production goes on all the
time, just kept under control by insulin. If it’s creeping up because of insulin resistance,
then that will increase, but here’s a funny thing. Insulin itself stimulates the process whereby
glucose is turned into fat. So if there is insulin resistance, high insulin,
that will tend to stimulate the liver fat, and this vicious cycle will begin to run so
that there’d be a tendency and indeed a real, small increase in plasma glucose which will
increase the insulin production, increase the liver fat, and this will spin on until
such a time as we get to a point where the liver fat starts spilling over. Now not only is the main job of the liver
to supply the glucose that the brain requires, as mentioned earlier, but also supplies fat
to the rest of the body in the form of very low density lipoprotein triglyceride. Quite a mouthful, but the LDL triglyceride. If there’s too much of that, it silts up in
your coronary arteries and elsewhere. But we know there one tissue that takes it
up quite avidly because of in vitro studies, and also because of the in vitro studies,
it was possible to say that decreases the beta cell ability to respond to a meal or
an increase in glucose. But in that case, it will cause plasma glucose
to stay up for much longer. There’ll be insulin around for hours. That is going to drive on your
lipogenesis, maximize whatever conversion of sugar to fat is going on, and we have a
vicious cycle that will miserably grind on over the years until a point when the system
breaks down suddenly, and Type II diabetes appears. Now some years after that hypothesis, published
in 2008, the Whitehall II data showed exactly this. 0.6 minimal per liter rise
in plasma glucose over a decade, followed by a rapid rise over about 18 months. But this is a hypothesis, if you like a fairy
story, built up of observations, and the only point for a scientist to produce a hypothesis
is to try and destroy it. So that’s what we have to set about. How should we best destroy this? How about cutting off its head? If we remove the positive calorie balance
and make it negative, if we’re right, these cycles should go into reverse and we should
be able to normalize plasma glucose. Does that happen? Well we can test it, but how are we going
to understand the mechanisms? Well in order to understand the mechanisms,
we need to measure four main parameters, the liver fat and the pancreas fat … and we
did this using magnetic resolute methodology, developing the necessary methodology … We
need to measure this, which is quite easy, and also measuring directly the acute insulin
response. So this was a counterpoint study, and we calculated
how many people with Type II diabetes we needed to study to cause this hypothesis to be destructed,
and we utterly failed to destroy the hypothesis. We can see that taking this group of people
with Type II diabetes, all agents were stopped after the baseline studies. Plasma glucose normalized within seven days
and it remained normal thereafter. And further, we were able to show that that
normalization in the first week was due to a rapid fall in liver fat, 30% fall in seven
days. And that can completely normalized the hepatic
insulin sensitivity. I’d add muscle insulin sensitivity
did not change. It’s a different parameter. These two things are often confused. What happened in the pancreas followed an
interestingly different time course. There was a gradual fall in pancreas fat and
a gradual rise in first phase insulin response. Let me just put some flesh on the bones by
perhaps taking the flesh away and looking inside with an MR scan because here we have
an MR scan looking across the abdomen. If we look at the subcutaneous tissue here,
every pixel is color coded for the amount of fat at that tiny point in space. The key is here. So there it is 100% fat, but just look at
the liver, this big organ here, as a nasty bluish green and you can see that indeed it’s
36% liver fat. One of the surprises of this study was the
extent of liver fat accumulation in people with ordinary Type II diabetes. The average was about 13%. But what happened after the weight loss? Well, rather shockingly, this happened. It went back 30% in the first week, but by
eight weeks, it was down to 2%. So that’s the liver side of the story. In the pancreas, we were seeing a slow steady
fall in pancreas fat, and a slow steady recovery towards normal of first phase insulin response. Now this is heresy. We’ve known in diabetes for years that Type
II diabetes is characterized by an absent first phase response and there’s nothing you
can do that will bring it back. Well, sulfuranes will make a small
increase if you change the plasma glucose itself, you get a small increase. But normalization, this has never been seen
before. So in putting this set of data forward, you
could imagine that I ran into controversy. We weren’t arguing about the data. It was conflicting with a belief system. But some real questions were asked, one of
which was but the relationship of the pancreas fat to this change of insulin secretion, surely
this people are just losing weight, and so of course the fat in the pancreas would go
down. Well, we thought we’d deal with this by examining
people with diabetes and without diabetes, matched for weight, bring about equal weight
loss, and compare the fat content in the pancreas to find out whether in fact that was true. Here we see the data before weight loss in
the red, Type II diabetes, significantly higher than those people with non-glucose tolerance,
and after weight loss, about 13% weight loss, the diabetes people significantly decreases
their pancreas fat to normal sort of level. Normals did not change. There is a small pool of fat in the pancreas,
which is specific to diabetes. Two other questions were asked. Hang on, you’ve only done these studies in
people with short duration Type II diabetes, up to four years in the first study. How about longer duration? What happens? And also, come on, this first phase insulin
secretion is going to disappear as soon as you go back to eating normal foods, because
don’t forget, we devised the very low calorie diet we used in the first study as a tool
to test the hypothesis. It wasn’t meant to be a therapeutic effort. It wasn’t testing diets for an effect. It was a metabolic tool to perturb the system
and find out how wrong we were. So does this first phase remain long term? Well dealing with the first question, these
are the results of the second major study that we carried out, the counterbalance study,
and you can see that with increasing duration of diabetes, there was less and less likelihood
of achieving a non-diabetic plasma glucose level. Indeed some people with short duration diabetes
might not even return to normal. So we’re clearly dealing with a range of responses,
but affecting potently by duration of diabetes. What about the long term? Well, in the same follow up study, we looked
at the effect of six months of normal eating. The types of foods were not specified. It was asked that people remain the same weight,
and indeed they did. So having achieved the 15 kilogram weight
loss, they kept it off over six months of normal eating. The liver fat remained at that normal level
of around two and a half percent. Interesting on this slide, here we have the,
in general, longer duration people, and you can see that they too normalize that liver
fat content and kept it down. But just look at the baseline. Fasting insulin had already fallen significantly
in this group as the years go by and the beta cell really is bearing out. Because of that removal of de novo lipogenesis
stimulation perhaps, we were seeing a fall in the level of liver fat. So trying to get rid of the liver fat at that
stage was bolting the stable door after the horse has gone. Back to Newcastle. Here we’ve got Newcastle. It’s always nice to have a break from the
data slides, and this is our new castle. It was built in 1086, but people don’t change
their habits of calling things certainly things very easily. What can we say more generally. Well what we can say is what was in the paper
that Nita prudently put together from the list of co-authors there on nutritional approaches
for the prevention and the management of Type II diabetes. What can we say about this? Well in the first page, there’s just one little
sentence that might be overlooked, and that is the idea of being on a diet for life is
enough to put many people off. So we need to actually see the human side
of this, that the relationship between humans and food is not quite what it’s talked about
in nutritional meetings. Food is something that happens in a social
setting, and if we overlook that social environment, then we’ll rather miss the point of effectiveness
in what we’re doing. There are two other basic points in that first
page, and the first is doctors are highly trained in using drugs, and hardly at all
with nutrition. And secondly, eating patterns vary in different
populations. There’s no one size that fits all, and we
really do need to grasp that. There’s a tendency for us to talk about nutrition
as though it was something that only related to people living in westernized countries,
whereas of course, the truth is otherwise. Specifically, we were asked to deal with areas
of consensus and areas of controversy. The consensus, weight management was mentioned
in all the guidelines. There’s no doubt about that, although the
extent of it wasn’t much emphasized and the effect of it wasn’t much emphasized. You just do it. Now in practice, it’s often skipped, but the
consensus is there. Patterns of food intake … well, most of
the guidelines, all of the guidelines in fact, reflected the need for higher vegetable intake,
all the usual things, fruit, legumes, reduced saturated fat, consensus. Foods to avoid, again consensus. Calorie dense foods. But how about the areas of controversy? So as we’ve already heard, at this meeting,
the optimal macro-nutrient composition is an area of controversy. But what’s going on here? Well, I just point out that the guidelines
are varied between the European and Canadian guidelines saying 45 to 65% carbohydrate,
India, 50 to 60% carbohydrates, and less than 30% as fat. The ADA recently has said there is no ideal
mix. It’s an individual thing. How about defining a low-carbohydrate diet? The phrase is often bandied around, but when
we look hard, some authorities are saying that it’s less than 4%. Others are saying less than 40%. Clearly we’ve got a problem with words here
and we need to be quite precise about what we’re talking about. Dairy products, really the confusion here
is over type and how much, always struggling with this existential angst about fats and
especially saturated fats very reasonably. Oils, now the hydrogenated oils are recognized
as being bad if they’re mentioned in guidelines, but there is still variation between the guidelines
and lack of consensus. Trying to pull things together, how about
this prevention business compared with the management of Type II diabetes. The two are often seen as being different
with regard to dietary advice. But we’d like to emphasis that in fact, we’re
talking about the same kind of approach to eating foods in those social groups. So we have to see our individuals managing
Type II diabetes as having come from this population, but living within the general
population. So in all populations, we would want to manage
weight. That really is essential. And the quantity of food clearly matters,
as Mike defined obesity with having accumulated more fat than was healthy, that carbon’s got
to come from somewhere, and it can only come from food. The quality is highly relevant, as Darius
elegantly pointed out. Focus has to be on food, not isolated nutrients,
and overall patterns of eating, a lot happens in society. But turning to Type II diabetes, we now have
reversal of the processes underlying Type II diabetes. How about going through a mission, or you
not want to do that? Well we can manage that. We’ve got very good guidelines. Low carbohydrate, low calorie, any sudden
change like that for a person with diabetes requires monitoring and careful observation,
especially in view of change required in medications. And we shouldn’t miss out the non-dietary
factors. Physical activity clearly is important, especially
in keeping weight steady after having achieved the step change of weight loss needed to reverse
Type II diabetes. But how about these populations? They differ. India in the last had … few decades … sharp
increases of fat intake on the background of high carbohydrate intake. How about China? Well, an increase in animal protein and fat
with decrease in cereal consumption. South Asia, shift to refined carbohydrate,
and increase in the sugar sweetened beverage. The increase in our lifetime is staggering
if we just take this data from China. So I think we can put all those factors together,
heading back to the Newcastle Quayside and reflecting upon this whole business, and as
you stay with me into the inky waters of the Tyne, hopefully you see something similar
to me in the conclusions we might draw. Here we have a potentially reversible state
of excess fat within liver and pancreas. Population and individual factors are critical
in moving from where we are to where we want to go. And a move to consensus is going to really
require some further, very robust studies. Thank you.