DIABETES & ENDOCRINOLOGY • CONTINUED FROM PREVIOUS PAGE
A metabolic elasticity
As an adult gastroenterological surgeon in the late
1990s, Dr. Inge performed bariatric surgeries on
adults long before almost anyone would perform
one on a teen. Dr. Inge’s first, during his first year
of pediatric practice, was an extreme case: an
adolescent weighing 400 lbs. with obstructive
sleep apnea so severe his otolaryngologist and
pulmonologist were considering a tracheostomy.
But because of the thickness of the patient’s neck,
they feared that, too, could threaten his life.
Knowing Dr. Inge had experience with bariatric
surgeries, they asked if he’d consider their patient.
At the time, and even today, it was seen as a risky
and potentially controversial proposition. Just a
handful of publications described it. Longitudinal
research was non-existent. Dr. Inge saw an
opportunity.
response for diabetes and hypertension, and these
advantages occur with little additional risk.”
Compared side by side, teens enrolled in Teen-
LABS did better than TODAY-enrolled teens in
almost every conceivable measure. In fact, at
baseline, teens in the surgery group started off
heavier and with worse glycemic control — but
by two years out, the surgery group had better
hemoglobin A1c, lower blood pressure and less
dyslipedimia, plus weight loss of nearly 30 percent.
Most TODAY participants saw none of those
improvements. In fact, they were nearly uniformly
worse off. That comparison study appeared in
JAMA Pediatrics last year.
“My guess is if we followed the TODAY group out
another ten years we’d perhaps find more heart
attacks, amputations, infertility, blindness and
renal failure,” says Dr. Inge. “We’ve only scratched
the surface in telling the story of these individuals.
It’s a pretty convincing argument for bariatric surgery being,
at least for now, the most effective treatment we’ve got.”
P H I L I P Z E I T L E R , M D, P h D
Chief, Pediatric Endocrinology
Most than a decade after first enrollment,
Dr. Inge and his group are still following more than
200 participants — at a better than 85 percent
retention rate. They achieved it, Dr. Inge says, by
making it easier for participants to stay in touch,
through supports like travel assistance and even
home visits.
They’ve amassed more information on adolescent
bariatric than any other group in the world. And
what they’ve found, in new and forthcoming
research, is nothing short of revolutionary.
“Teens appear to have a metabolic elasticity that
allows them to reverse certain obesity-related
health conditions to a greater extent than adults,”
says Dr. Inge. “Both age groups experience the
same relative weight loss, but teens have a better
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When you look at the surgery group, my suspicion
is we’re going to find a higher quality of life.”
“It’s a pretty convincing argument for bariatric
surgery as being, at least for now, the most
effective treatment we’ve got,” says Dr. Zeitler. “A
lot of people have come around from seeing it as
a last resort to something we should be talking
about with these kids from the beginning. The
next step is to figure out a way to get the benefit of
surgery without the invasiveness. Could you put
that in a pill, for example.”
Harnessing a new hope
Currently, Dr. Zeitler and his team are studying
just that, using data from TODAY to better
understand the underlying mechanisms of
Teen-LABS vs. TODAY:
BY THE NUMBERS
Mean HbA1c concentrations
Teen-LA BS Stud y
FROM 6.8
TO 5.5
TO DAY Stud y
FROM 6.4
TO 7.8
Mean body mass index
Teen-LA BS Stud y
29%
TO DAY Stud y
3.7%
Prevalence of high blood pressure
Teen-LA BS Stud y
FROM 45%
TO 20%
TO DAY Stud y
FROM 22%
TO 41%
The RISE of type 2 diabetes
Before TODAY, there was no consistent course of treatment
for kids with type 2 diabetes. Pediatric providers sporadically
treated with metformin, although nobody knew what that
would look like long-term, and rosiglitazone had just hit the
market. TODAY tested both. Neither performed as expected
based on the adult literature. Metformin had a failure rate of 13
percent in adults. In kids it was more like 50 percent.
“And failure meant we couldn’t manage them with oral
medicines. They had to go on insulin, and then you have shots,
checking blood sugar multiple times a day. It’s more expensive.
There’s more risk,” says Dr. Nadeau. “So the thought was, well,
maybe TODAY intervened too late. Maybe you can’t even wait
until diabetes sets in. We recruited kids with less than 6 months
of diabetes, and another half with prediabetes.”
complication in diabetes, particularly long-term
effects on cognition. Meanwhile, Dr. Inge and
pediatric endocrinologist Kristen Nadeau, MD,
MS, are working on a funding proposal to study
the biological mechanisms of bariatric surgery,
including pancreatic and gut hormone function, as
well as measures of cardiovascular and liver health. That work became the RISE study, for which Dr. Nadeau
has served as national primary investigator. She and her
multicenter peers knew teens were more resistant to insulin
because of the hormonal environment of puberty. What they
didn’t know was exactly to what extent: One of RISE’s most
troubling findings came from measuring teens’ insulin output
against that of adults in a hyperglycemic clamp.
Partnering with pediatric cardiologist Uyen
Truong, MD, and bioengineer Michal Schafer, PhD,
experts in a novel technology called 4D flow MRI
(see “In Living Color,” p. 14), Dr. Nadeau has already
shown metformin can improve arterial stiffness
in adolescents with type 1 diabetes, even though
it hasn’t been shown to improve blood sugar —
potentially altering the course of type 1 treatment. Teens made twice as much insulin in response.
That study recently appeared in Circulation.
Dr. Nadeau is now partnering with Dr. Inge to
examine before-and-after cardiovascular health in
the bariatric population using the same technology.
And work remains to be done in the bariatric
population. Kids who have the surgery may
see complications down the road, such as iron
deficiency and problems with bone health.
If you could give those overtaxed beta cells a rest early, they
hypothesized, maybe you could improve their function. RISE
tried one group on 12 months of metformin and another on 3
months of insulin, followed by 9 of metformin.
“These kids’ maximal beta cell response actually got worse
on treatment,” says Dr. Nadeau. “Some of the kids, their
blood sugar got so high they couldn’t even come in for the last
measurement.”
For some kids, beta cell response will get better when they
grow out of puberty and their insulin resistance ends. But for
about half of the kids in TODAY, that beta cell function never
came back.
NEW CONSTELLATIONS
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