Well, good afternoon.
It's almost afternoon now, almost lunch time.
I hope in the next 15 to 20 minutes to summarize to you what
I've been doing in my research and why I think it matters and
I hope that you will appreciate the importance as well.
So first I'm gonna start by talking about diabetes in older
adults and why it's such a growing, not only medical, but
public health concern as well.
One-third of our older adults have diabetes.
And of this, about half is undiagnosed.
An additional one-third have what we call pre-diabetes.
So they haven't quite developed diabetes, but
are on the way there.
And so, in some two-thirds of our older adults have some sort
of glucose abnormality.
And the prevalence of diabetes in older adults will only
increases as our population ages.
So this is clearly a large public health and economic
burden that our society will be facing in the near future.
We know that peripheral glucose disposal occurs in
different sites of the body at different times of the day.
In the fasting state, so before eating the first meal of
the day, it occurs primarily in sites of the body that don’t
depend on insulin such as the brain.
After eating, it occurs primarily in sites of the body
that are insulin-dependent, such in skeletal muscle.
And that's where I'll be talking mostly about today.
We know that as people age, insulin resistance tends to
increase with older age and this is due to a variety of factors.
Lean body mass declines,
there's decreased mitochondrial function.
I won't really go into much of that today, but there's also
likely some impaired eyelet insulin secretion as well.
And again, I won't talk too much about that, but needless to say,
our older adults are already at a disadvantage as they age
in terms of how their islets are functioning and
their insulin resistance.
However, impaired glucose metabolism is not an unavoidable
companion of aging.
Not everyone who gets older, develops diabetes.
And we see this here.
This is a graph.
On the side here is HOMA IR,
a surrogate of insulin marker of insulin resistance.
And you don't need to
understand the details of what that calculation is,
except to see that it rises as people get older.
And in those that live to the age of 100,
it's actually much lower.
And so whether this is a marker or merely an association
is an interesting finding, that those who live beyond the age of
100 actually have relatively well-preserved insulin status,
insulin glucose status.
So, what I'd like to talk about today is that population that
does have insulin resistance with aging, and
talk about why older adults with impaired glucose metabolism
may represent a vulnerable subset
of people in our population at high risk of adverse outcomes.
The outcomes I'll talk about are probably
not the ones that you're used to hearing about, heart disease,
kidney disease, nerve disease.
These are all very important, but in our older population,
functional status is also very important.
And that's what I'll be focusing on today, particularly,
physical disability, functional limitations,
such as walking, and accelerated muscle loss.
All of which contribute to quality of life in our older
adult with diabetes.
So first, I'm going to talk a little bit about the importance
of physical functioning and walking.
So in a previous life, I used to work with nonhuman primates
on a small island off the coast of Puerto Rico, and
as anyone who has ever worked with nonhuman primates knows,
there's a lot of similarities, but also a lot of differences.
And I'm not going to go into the evolutionary biology here, but
needless to say,
locomotion has changed as we look across the species.
And one of the things that makes us as humans unique over here
on the right hand side, is that we walk on two feet, bipedalism.
And why is this so important?
Well, it's actually an energy advantage.
Walking upright takes less energy than walking on all fours
or even moving with your thumbs.
In fact, it takes 25% less energy than required for
moving on all four legs.
And so it might no be surprising that there's been many
observational studies, and I've referenced one here if you're
interested in JAMA, which is a phenomenal study,
that shows that higher gate speed in both men and women
is associated with increased survival and this is remarkable.
But perhaps not surprising when you think about it as an energy
advantage.
So why would gate speed predict survival.
So, it requires a lot of energy like I talked about,
it places demands on multiple organ systems,
such as the heart and the lungs.
Slowing gait may reflect damaged systems, discoordination of
multiple systems, resulting in an energy imbalance.
Some have proposed that walking speed may be a simple indicator
of the health of the older person.
In fact, there are geriatricians who swear that they can tell
the health of an older person just by watching them walk.
And so there are some who think that walking speed should be
the next vital sign.
And so this merely underscores the importance of physical
function and walking in our older population for health.
So now I'll talk a little bit about sarcopenia.
So sarcopenia is the loss of muscle mass that occurs with
aging, age related muscle loss.
It's derived from the Greek words meaning loss of flesh.
And this is important because again, as people age, their
total muscle mass decreases from about 50% of total body weight
in young adults to about a quarter by the age of 80.
And this is just something that happens as people age.
We don't really understand why.
It may affect up to half of the older population.
We don't have a clear definition, so
prevalence estimates are difficult and it's costly.
A 10% reduction in age related muscle loss would save
the United States a billion dollars or more each year.
And so understanding why this happens and how we can treat it,
is important.
It's a strong risk factor for hospitalization.
I already mentioned disability and death in older people.
It can improve quality of life and
save money if we can understand how to treat it.
But there is currently no cure for sarcopenia.
We have no idea how to treat age-related muscle loss.
And so identification of novel, potentially modifiable,
targets for this condition are important.
So how does this relate to diabetes?
So the research that I have done to date has looked
at accelerated muscle loss in older adults with diabetes and
here is the research question.
So, to what degree do high glucose levels represent
a risk factor for accelerated muscle loss in diabetes?
So why is this important?
Not only for an older adult with diabetes,
but I already shared with you that all people as they age,
to a certain degree, develop insulin resistance.
So, could this give us some insight into a target,
something that can be changed with therapies we currently have
available that can improve muscle function for
people as they age?
And so for this research, we applied the disablement process,
again, often used in geriatric literature, to understand how
diabetes affects various parts in the pathway to disability.
Starting on the left side, low muscle mass, which can lead to
low muscle strength, functional limitations, disability, and
then ultimately to mortality.
So I'm gonna walk you through,
starting distally, then moving more proximally
into how diabetes can affect various steps of this pathway.
So we know that people with diabetes have
increased mortality.
In fact, this was a very large study that was published
in the New England Journal of Medicine,
that reported that Type 2 diabetes is associated with
a reduced lifespan of six years for the average 50-year-old
person with diabetes, compared to a counterpart without.
And surprisingly,
40% of this difference was not due to vascular deaths.
We think of heart disease, stroke, very important,
clearly in people with diabetes, but there is a big black box.
Cancer is also a big one, but 40% of the deaths
were not due to cancer or cardiovascular disease.
So what were these, the authors mentioned liver disease,
kidney disease, infections and musculoskeletal disease.
So I'll talk about how could disability in diabetes relate to
the increase risk of death in people with this condition.
So what do we know about disability?
So with the disability, it can be someone in a wheel chair that
you see on the side of the street, but we actually have
ways to formally define this in our research.
There's many different tasks that people can have difficulty
with, I've listed some of these here.
You might be familiar with activities of daily living,
ADLs, such as walking or dressing, or instrumental
activities of daily living such as managing your money,
which requires some more complex skills.
There's also lower extremity mobility,
which is very important and general physical activities, and
leisure, and social activities as well.
And what we found, you can just focus on the sentence
at the bottom, but the data is there is that in this nationally
represented population of U.S. adults, older adults had two to
three times increased odds of disability if they had diabetes
compared to without across all these domains.
And this was self reported, so
people filled out a questionnaire and
told us if they had difficulty in these different tasks.
We also know that people with diabetes walk slower,
not everyone with diabetes clearly,
but when we look at groups of people.
And this seems to be related to the degree of glucose elevation.
So in this study that we had done,
this was done in the women's health and
aging study of women who were 70 and older in the Baltimore area.
We found that those women who had a hemoglobin A1c of 8% or
greater, compared to those with an A1c of less than 5.5% were
three to fourfold more likely to report walking difficulty.
And, actually when we measure their walking speed,
I'm not showing that data here,
they also had lower walking speed as well.
So how does this relate to muscle function?
Well, in another study that we did,
we looked at whether high blood glucose levels were associated
with lower muscle strength in people as they age.
And, again, this gets back to the question can we identify
a target that we can intervene on in people with diabetes
to preserve muscle function.
And what we found is that those who are in the highest category
of A1c actually had lower muscle strength that stayed low up
to ten years later in this study.
Suggesting that high glucose does some how relate
to the low muscle function we see in people with diabetes.
And this is a slide that shows that, the dotted line at
the bottom is those that are in the highest quartile of A1c and
you can see it's not even that high here.
It's 6.1% or greater and
so even people in pre-diabetes range were showing
lower muscle strength that stayed low as they aged.
And, as you might expect, again in another
study that we subsequently did, you can see that those in
the highest categories of A1c had the lowest muscle mass.
So what does this tell us about the pathway to disability in
diabetes?
Well, we've now done research that shows that
not just diabetes,
but high blood glucose levels themselves are associated with
each step of the disablement process in people with diabetes.
And could this be a target that we could intervene on
to preserve muscle function in this population?
In the last few minutes,
I want to now talk about the inverse association.
So I talked a little bit about how diabetes can lead to
accelerated loss of muscle function and
decreased physical function.
But now, what about the opposite?
Can changes in body composition, as people age, relate to
the increased burden of diabetes that we see in this population?
Well, we know that body mass index is a predictor of
diabetes.
Obesity is well established as a major risk factor for
developing type-2 diabetes.
That's why we're here.
That's what we're talking about.
We know that modest weight loss is associated with reduced
diabetes risk.
So if you intervene, it actually improves, however, weight loss
includes not only fat mass, but muscle mass as well.
And this may not be desirable in our older adults, for
the reasons that I just talked about.
People who are older are already at a disadvantage with
lower muscle mass.
So BMI is, in fact, not always a good measure of excess fat mass.
And when you account for age,
it's associated with fat mass only less than 60% of the time.
So it's a good surrogate for most people,
but not necessarily people as they age.
We know that BMI is weight over height squared.
BMI for obesity were, in fact,
based on an increased risk of mortality at a BMI of 30 or
greater in the general population.
However, the obesity paradox has been described, and this is
the idea that those with a BMI of 27 to 30, might actually have
a protective effect, might have decreased mortality.
There's been conflicting studies that have come out, but
it underscores that BMI is not necessarily perfect predictor
of mortality or associated with increased adverse outcomes.
And the BMI cutoffs that we ordinarily use are shown
here for obesity and overweight.
So we know that BMI does not account for body composition.
So you can see a weightbuilder,
bodybuilder here compared to a man who's obese.
Same weight, same height, same BMI, different body composition.
So this shows why BMI is not always the best measure of
excess adiposity because it doesn't necessarily account for
the composition.
It also doesn't account for body weight distribution.
All these women here have the same BMI,
but they have a different distribution of central to
peripheral adiposity, and so again, BMI as a measure of
where weight is distributed is also very limited.
So how does this relate to our older adult?
Well, you can see here that these are two people who
look the same, but one is the younger person, on the left.
And you can see that they have more muscle and less fat, but
the one who's older has more fat and less muscle.
But they look the same from the outside.
In fact they might have the same total body weight.
And so just using BMI is clearly a difficult surrogate for
adipose in our older generation.
So why does this matter?
It matters because a loss of muscle mass that occurs with
aging is typically offset by gains in fat mass, so
we don't really know what's going on underneath,
if we just measure weight.
And, in fact, weight can look stable, or can increase just
slightly as people age, although there are important metabolic
changes that are going that can impact diabetes risk.
And it's unclear, while we know that excess adiposity is related
to increased risk of diabetes, what about the parallel decline
in muscle mass that's occurring in adults as they age?
It's unclear how that relates to the increased risk of diabetes
in older adults.
And this is a summary of the clinical guidelines we have for
a older adult with diabetes to demonstrate that we have a range
of A1c targets that we aim for.
We individualize them based on functional status,
expected life expectancy, comorbidities.
But we don't know the risks of letting the A1c target go up.
What are the risks of
uncontrolled hyperglycemia in this population?
Again, I just shared with you that high blood glucose levels
are associated with accelerated loss and muscle mass and
physical function.
So where do we go from here?
We have a changing paradigm.
So keep calm, there's a paradigm shift going on.
What are the risks of uncontrolled high blood glucose
levels and accelerated muscle loss?
We don't know and we need to know because our older
adults are gonna grow in number.
We need to know how to manage them, and we really don't know
how to optimally treat them with the blood glucose targets.
And it's important to understand because,
can glucose lowering therapies improve physical functioning in
our older adults with diabetes.
Right now, we have clinical guidelines that I shared
where we actually shy away from treating
our people who are older with these therapies, because
we're not sure if there's any benefit to glucose lowering.
But what are the risks
of letting the glucose ride too high?
And how does the loss of muscle mass with aging
relate to the development of diabetes?
We know that fat mass is important, but
we clearly need to know how to better prevent diabetes, and
there's a whole session related to that in the afternoon.
But can future therapies that increase muscle mass
be beneficial to reduce the global burden of diabetes.
And that's the future direction of our research, to try and
understand how muscle function relates to this increased risk.
So I'd like to thank those who have contributed to this work
that I described today.
And this is our goal for all our older adults with diabetes that
they can jump for joy and not worry about their functional
status and we have a ways to go but we're working towards it.
Thanks for your attention.
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