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Paradigm shift: Rethinking type 2 diabetes as a heterogeneous disease
May 2012
SHARING OPTIONS:
By now, you're probably familiar with the alarming
statistics about diabetes. Twenty-six million people in the United States have
diabetes
today, with type 2 diabetes (T2D) accounting for 95 percent of all
diabetes cases. Seventy-nine million people in this country have pre-diabetes,
and
an estimated one in three people will have diabetes by 2050. Despite the
intense focus on diabetes, and the availability of myriad therapies and other
tools for diabetes management, we largely aren't effective in treating this
disease. In fact, an estimated 60 percent of T2D patients don't achieve
adequate glycemic control —resulting in poor patient outcomes and skyrocketing
healthcare costs. Where are we falling short?
I believe the primary reason we aren't effectively treating
diabetes today is because our current understanding of
this disease is quite
rudimentary. Our lack of awareness and appreciation about the inherent
complexity and heterogeneity of diabetes has confined us
to a one-size-fits-all
paradigm for managing this disease. For millions of patients, this approach is
simply not working.
Our current methodology of trial-and-error drug development
and prescribing is neither prudent nor sustainable—and its days
are numbered.
The whole model of medicine is shifting to one that is centered on patient
subpopulations—defining, identifying and grouping patients by
disease
subclassifications, and then prescribing treatment regimens tailored to those
subclassifications. Thanks to the increasing sophistication and
use of
innovative technology platforms such as genetics and epigenetics, genomics,
proteomics and metabolomics, personalized medicine has been gaining
momentum—with the most notable early success being in the oncology field.
With the influx of and
access to massive amounts of
information at the genetic and molecular levels, we are faced with the arduous
task of sifting through and understanding
the data, determining what is
relevant and potentially clinically applicable and then figuring out how to
ultimately translate all of this information
to real-world patient care. It's
not an easy task, and we'll have many trials and errors along the way. But the
key is that we are most definitely
"along the way." Consider that 30 percent of
all treatments in late-stage clinical development and 60 percent of all
treatments in preclinical
development today rely on biomarker data.
We are at the point where we should be applying these
same
tools and technologies to revolutionize and deepen our understanding of
diabetes. I believe the only way we will see true, long-term success in
treating diabetes is by fundamentally rethinking this disease and shifting our
focus to pursue a targeted, personalized approach to prevention,
diagnosis and
treatment.
What's so complex
about T2D?
Typically, we think of diabetes as falling under two main
classifications: type 1 diabetes (T1D)
and T2D. I often hear the argument: T2D
is caused by poor diet and lifestyle choices; what's so complex about it? People
just need to eat less and
exercise more. The fact of the matter is that many
people do, in fact, eat a healthy diet, exercise regularly and make good
lifestyle choices, yet
still have pre-diabetes or develop diabetes. So, why is
it that some people are predisposed to develop diabetes? Why are some people
more apt to gain
weight—a known risk factor for T2D—and others have difficulty
losing weight and maintaining weight loss? What we are learning is that T2D
diabetes
patients actually can be classified into many further subpopulations.
Hopefully, in the future, knowledge about these subpopulations will help inform
a
patient's susceptibility to develop the disease and certain related risk
factors, and also predict response to specific treatments.
To date, there are already 25 disorders that have been
identified in which the alteration of a single gene results
in abnormal glucose
levels with clinical features that overlap with typical T2D. Most of these
metabolic disorders are rare, accounting for no more
than 5 percent of all
diabetes cases. However, when you consider that hundreds of millions of people
have this disease globally, 5 percent is a
significant number. Like other rare
diseases, these disorders often go undiagnosed or misdiagnosed due to a lack of
appropriate diagnostic guidelines
and tools—and a general lack of awareness
about the existence of these disorders. In other words, many patients are being
treated (unsuccessfully) for
T2D when in fact they actually have a different disease.
Beyond these examples, what about the
millions of people
with diabetes whose disease is, in fact, caused by excess weight, poor diet and
lack of physical activity? Where does "personalized
medicine" come into play
here? While we need to stress prevention and healthy lifestyle at every turn,
we can't ignore the fact that hundreds of
millions of people around the world
are very sick today as a result of this disease. We also need to consider the
fact that emerging research shows
that many patients are resistant to the beneficial
effects of exercise. In addition, weight loss from dieting is more difficult
for patients with
diabetes. We don't fully understand why these variances
occur, but they point to the diabetes' heterogeneous nature. A therapeutic
approach focused
merely on reduction in plasma glucose concentration ignores
the varied pathophysiological disturbances at play from individual to
individual.
By shedding light on the complex pathophysiology of
diabetes, we can move beyond the current standard of
treatment and arrive at
more personalized—and more effective—therapies and treatment approaches, and
hopefully, someday, cures for certain patients.
What's more, by better
understanding the molecular pathways at play in T2D, we may be able to identify
and detect subpopulations who are at higher
risk for developing complications
and co-morbidities that often accompany the disease, such as hypertension,
hypertriglyceridemia, hypercholesterolemia
and inflammation (what we've
previously referred to as metabolic syndrome). Ultimately, the goal would be to
develop therapies that address the
underlying cause that leads to both T2D and
associated co-morbidities, or to preempt the onset of co-morbidities through
early intervention.
To move us in this direction, we need to embrace—and act
on—a more modern, more logical view that
there is a broad list of tissues known
to play an important role in T2D pathophysiology, including adipocytes (fat
cells), the GI tract and
enteroendocrine cells in the gut, pancreatic
alpha-cells, the kidneys and the brain. The relative impact of each of these
organs on the underlying
disease process in an individual is unknown.
For instance, exciting new data suggests that
bariatric
surgery is highly effective in controlling—and in some patients, completing
eliminating—T2D symptoms. Why is this? We now know that bariatric
surgery triggers
massive changes in metabolism, specifically related to the gut and hormones,
which leads to a decrease in appetite and improved
diabetes. Preclinical and
some early clinical efforts to replicate these hormonal changes without surgery
are quite promising. While surgery is
certainly an important option right now
for overweight patients with diabetes, our long-term focus should be on
accelerating research efforts in this
area. If we can produce the same hormonal
changes without surgery and elicit the same improvement in diabetes, imagine
the far-reaching impact that
would have on treating this disease.
From concept to
reality: What will
it take?
As our understanding of the complex genetic and molecular
causes of diabetes matures,
so will our need for companion diagnostics. The
only diagnostic criterion clinicians utilize today for diabetes is measuring
blood glucose levels, and
glucose is the target of the clinical management of
diabetes. As our knowledge base of diabetes expands, we will have to expand, in
parallel, the
methods and algorithms with which we diagnose the subtypes of
diabetes to help identify patients who are most likely to respond to a
treatment and/or
patients' risk levels for diabetes complications.
From a more universal standpoint, advancing the
concept of
personalized medicine in diabetes will require a general acceptance and a
greater understanding of the heterogeneity of T2D. It will also
require focused
resources and commitment at both the government and industry levels to help
drive progress forward. We have a great deal of work ahead
of us. But, given
the broad and significant ramifications of diabetes from a medical, economic
and societal standpoint, this is a wise investment in
our future—one we can't
afford to overlook.
Dr. Steven R. Smith is the scientific director
of the
Translational Research Institute for Metabolism and
Diabetes (TRI), an
innovative partnership between Florida
Hospital and Sanford-Burnham Medical
Research Institute. The TRI is focused on the advancement of a new paradigm of
personalized approaches to researching and treating diabetes and
obesity.
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