Michelle Van Name, MD - Obesity Intertwined with Type 1 Diabetes in Youth: Probing Physiology with Anti-Obesity Medication

March 07, 2024

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00:00All right, everyone. We're going
00:03to go ahead and get started.
00:04And the next section of our workshop today
00:08is going to look at clinical Physiology.
00:11So those are the next two talks.
00:13So I think they're both
00:14going to be really exciting.
00:15And to kick us off with this
00:18section of the workshop,
00:19we have Doctor Michelle Van Name.
00:22So Doctor Van Name graduated from
00:25Boston College and earned her
00:27medical degree from SUNY Downstate.
00:29She completed internship and residency
00:31programs in Pediatrics at Yale University,
00:34where she also did a fellowship
00:37in pediatric endocrinology.
00:38Her research investigates the
00:40intersection of diabetes and obesity
00:42in children and young adults,
00:45as well as treatment strategies
00:46for these diseases.
00:48So welcome to the stage Doctor Van Name
00:51and we're very excited for your talk.
00:59Thank you. And I'm excited to be here today.
01:01I'm going to be telling you just a
01:03little bit about some of the work
01:05done in pediatric obesity at Yale
01:07as well as really focusing the talk
01:09on obesity and type one diabetes.
01:12These are my disclosures and so
01:15pediatric obesity research is
01:16not a new thing for our team.
01:19So many years ago,
01:21doctor Sonia Caprio Mary Savoy identified
01:24that there was a need for interventions
01:26for youth who are developing obesity.
01:28And so they not only developed but then
01:31rigorously tested the Bright Bodies
01:33program which is an intensive behavioral
01:36lifestyle intervention program and
01:38actually one of very few recommended
01:40by the American Academy of Pediatrics.
01:42And so we can see why the effectiveness
01:45of this program here in black,
01:48we can see circles for changes on the
01:51left in body mass index and on the
01:54right on body fat amongst youth who
01:56were randomized to the Bright Bodies
01:59weight management group compared to the
02:01control group who had increases in both
02:04of those measures at both 6 and 12 months.
02:06But just seeing the these
02:08outcomes was not enough.
02:11I'll tell you more about the Physiology
02:13as well as the fact that this
02:14effectiveness has been evaluated as
02:16well by newer members of our team by
02:19Stephanie Samuels and Mona Sharifi
02:21looking at at the real world adaptation.
02:23So we know that these programs
02:25are effective when used clinically
02:26and they're currently studying
02:28virtual adaptations as well.
02:30And now more about the background,
02:31we wanted to know why did they
02:33see these changes and what was
02:35happening in terms of the Physiology.
02:36So they studied these adolescents and
02:40children using oral glucose tolerance
02:42tests and you can see that data here
02:44with minutes along the X axis and we
02:46can see that plasma glucose in the
02:48graph on the left in blue declined
02:50in the bright bodies cohort while
02:52insulin also declined very nicely.
02:55So they were able to understand some
02:57of the changes in in the glycemia
03:00seen in these kids.
03:02The research has not been limited to this.
03:04There's, you know,
03:05our teams have been asking questions
03:07about what is the Physiology that changes
03:09that's promoting obesity in youth.
03:11And so with Sonia Caprio,
03:13Nikola Santoro,
03:14Anya Yasterboth and Alfonso Galderisi,
03:17you know, we have looked at ghrelin,
03:19the hunger hormone,
03:20and see how the response of that
03:22hormone varies,
03:23whether you're drinking glucose or fructose,
03:25whether you have a body type that is
03:27lean or in one of the obesity categories
03:30and whether that end of that child is
03:32insulin resistant or insulin sensitive.
03:34We've seen differences in the
03:35response of the hormone GLP One.
03:37One of the main discussion points
03:40today is GLP one and that that varies
03:43by drink type and your BMI status.
03:46And additionally we've looked at a
03:49high omega-3 isocaloric diet and
03:52seen that that decreases hepatic
03:54fat fraction here over 12 weeks
03:57in kids with metabolic associated
03:59steatotic liver disease.
04:01So that was a very nice change seen
04:03despite them not losing any weight and
04:05there was an common to decrease in their
04:09insulin over their tolerance study.
04:13We've additionally been looking
04:14at type 2 diabetes in youth.
04:16So this is data from the NIDDK Multi
04:19Center Today study of which Sonia Caprio
04:21was one of the founding investigators.
04:24And I was fortunate to serve as
04:27investigator during the extension phases
04:29years 6 through 15 here alongside
04:31Cindy Guanzolini and Paulina Rose
04:33who were also working on this study.
04:36And very importantly,
04:37these kids who were originally
04:40enrolled after,
04:41you know between ages 10 and 17 in
04:44longer term follow up after the trial.
04:46You know here you could see in
04:48yellow that a third to almost half
04:51had a hemoglobin A1C of greater
04:53than 10 indicating chronic severe
04:55hyperglycemia during that time period.
04:58And unfortunately that has led to
05:00many microvascular complications.
05:02So these are numbers of complications
05:04amongst the participants at a
05:06mean age of only 26 years.
05:08So it's a very severe disease and you
05:10know seeing this data and now knowing
05:12that in type one diabetes we are
05:15seeing the medical problem of obesity,
05:17we are seeing higher insulin needs,
05:19but we really don't know anything about
05:22how this adiposity will change the
05:24disease process in type one diabetes.
05:27And so for the purposes of today,
05:28we will focus the rest of the
05:30talk on on obesity,
05:31complicating type one diabetes.
05:37So while I think some of the earlier
05:41slides showed you from I think Doctor
05:44Horvath's talk about insulin that
05:45individuals really used to not be
05:47able to gain weight when they were
05:49diagnosed with type one diabetes.
05:50But now we're seeing a completely
05:52different change to the landscape.
05:54So here we have data from the type
05:57one Diabetes Exchange Clinic registry,
05:59which we participated in,
06:00of over 20,000 individuals
06:02with type one diabetes.
06:03And here we can see by age on
06:06the X axis and on the Y axis,
06:09the percent of individuals within body mass
06:12index in the overweight or obesity range.
06:14And they were.
06:15This data was collected at two
06:16time points and you could see
06:18that in the six to 18 year olds,
06:20at least a third of these young
06:22people with type one diabetes
06:23had an elevated body mass index,
06:25nearly half of the 18 to 26 year olds
06:28and 2/3 of those age 26 and above.
06:31So certainly this is a big problem
06:34and we know also that management of
06:36type one diabetes in adolescence
06:37is a big challenge.
06:38One of the reasons for that was
06:41previously elucidated by doctors
06:43Timberlane and Sherwin here using some
06:45of the Sentinel studies and they did
06:48insulin stimulated clamp techniques.
06:49And so here we could see that
06:52the adolescents with diabetes,
06:54with type one diabetes are in
06:56the bars here on the right.
06:58Those without diabetes are on the left.
07:01And we can see based on this X axis of
07:03glucose infusion rate that those with
07:05type one diabetes were more insulin
07:07resistant than the control population.
07:09And in particular those in the
07:11slashed lines that were in puberty
07:14had the worst insulin resistance,
07:16right.
07:16So now we're managing in these young
07:18people often times the insulin resistance
07:19in general related to type one diabetes,
07:22insulin resistance of puberty,
07:23and we're throwing obesity on top of that.
07:26And so we asked the question,
07:28how does adiposity impact insulin resistance
07:31in adolescence with type one diabetes?
07:33And I was awarded AK 23 grant
07:36to address 2 main questions.
07:38So how does adiposity impact
07:40the hepatic insulin resistance?
07:42Hepatic because we're very focused on that.
07:45And type one diabetes because to
07:48suppress hepatic glucose production,
07:51you actually have to over insulinize
07:52the periphery.
07:53But I can't get too much into
07:55that today and we're doing,
07:56we did that with the two step
07:58euglycemic hyperinsulinemic clamp
07:59technique with stable isotope infusion
08:02and our hypothesis there was that
08:04with elevated body mass index,
08:06insulin would be less effective at
08:08suppressing hepatic glucose production.
08:10The other aim was to examine
08:12how hepatic fat impacts insulin
08:14resistance in adolescence.
08:16And we expected that those with
08:18a higher body mass index would
08:20have higher hepatic fat and we did
08:23that by measuring abdominal.
08:25We did abdominal MRI to look
08:28at hepatic fat fraction.
08:29So here is the characteristics
08:32of the cohort studied.
08:33So age 2 is 12 to 16.
08:36You could see they were
08:37divided into lean BMI and
08:39overweight slash obesity BMI.
08:40And it's important to note that in
08:44Pediatrics the 85th to 94 point
08:469th percentile for age and sex is
08:48considered overweight BMI and 95th
08:50and above is considered obesity, BMI.
08:54We can see that the hepatic fat
08:58fraction was actually nice and low,
09:00so one point O nine in the lean
09:02and 1.98 in the overweight.
09:03Obesity, the cut off for metabolic associated
09:06steatotic liver disease is 5 or 5 1/2%.
09:08So none of the cohort had hepatic steatosis,
09:11which was in a very reassuring
09:15finding looking at some of the clamp
09:17findings in which you know you raise
09:19the insulin infusion to suppress
09:21endogenous glucose production and
09:22you see how well that happens.
09:24And that's a measure of hepatic
09:26insulin resistance.
09:27And so that we're looking at that
09:29suppression here on the Y axis and what we
09:31could see that in relation to BMI percentile,
09:34again the measure that we use in Pediatrics
09:36there was not any clear relationship.
09:38And here in orange we have the lean purple,
09:41the obesity and blue,
09:43the OR sorry purple,
09:44the overweight and blue,
09:45the obesity BMI cut offs and then
09:47looking at body fat percent as well.
09:50There really was not any clear relationship.
09:52So we looked further at potential
09:54other measures of adiposity that might
09:56provide more guidance and we use the
09:58VAT over the VAT set which is a measure
10:01of visceral adiposity as the visceral
10:03adipose tissue divided by visceral
10:05plus subcutaneous adipose tissue and
10:08that's obtained on abdominal MRI.
10:10And there we were able to see that
10:12as visceral adiposity increased
10:14there on the X axis,
10:16there was a rise in hepatic
10:18glucose production.
10:18So it may be that visceral adiposity
10:21is something that we can be looking at
10:23in type one diabetes in young people.
10:25So here we have some of the metabolic
10:28factors that we're studying related
10:30to cardiovascular risk.
10:31These empty ones just represent
10:33that there are many more.
10:34We cannot study all of them.
10:36So we had to limit it down.
10:38And why are we so interested in
10:41these factors and their potential
10:43role in cardiovascular risk.
10:45So we know that death from cardiovascular
10:47disease is the main cause of
10:49mortality and type one diabetes.
10:51This is data from the Swedish National
10:54Diabetes Register and you can see on
10:55the X axis from 1998 to 2013 and on
10:58the Y death from cardiovascular disease.
11:00The blue represents the individuals
11:02with type one diabetes and while
11:04that curve is declining nicely,
11:06it is well above that of the matched
11:08controls and here it is by age.
11:10So the group that was diagnosed
11:13with diabetes at less than age 10,
11:15here in the bottom of the the X axis,
11:17you know,
11:18they had the smallest expected
11:20median survival.
11:21And in fact for individuals
11:24diagnosed less than age 10,
11:26the expected life lost would be about
11:2918 years for women and 14 years for men.
11:31So you know,
11:33combining this information
11:34with knowing that obesity
11:35then is also a risk factor
11:37for cardiovascular disease.
11:38You know, we really want to understand how
11:41to improve health in these young people.
11:43And so we do know one of the
11:45tools that can help, right,
11:46the GLP one agonist medications,
11:48we know that those improved
11:50cardiovascular outcomes in adults
11:51with type 2 diabetes and with obesity.
11:54So our current work is kind of
11:56looking at whether you know if we
11:58treat the disease of obesity with
11:59GLP one agonists in these young
12:01people with type one diabetes,
12:03will it impact drivers
12:06of cardiovascular risk?
12:09And so to study this,
12:11I was awarded an RO one along
12:14with my wonderful colleagues,
12:15some of who are in the room today
12:18and we're asking the question,
12:19can GLP one agonist obesity treatment
12:21improve modifiable drivers of
12:23cardiometabolic risk in young adults
12:25with obesity and type one diabetes?
12:28And so we are doing Physiology
12:31based studies for this.
12:32The primary outcomes are all Physiology
12:35and we are studying young adults
12:37because the reviewers were not keen
12:39on the adolescent population to plan
12:42to study them in future iterations.
12:43And somagletite is FDA approved
12:45for treating the disease of
12:47obesity in age 12 and up.
12:49So one of the things we wanted
12:51to see was could there be
12:53improvements in visceral adiposity?
12:55So we hypothesized that compared to placebo,
12:58GLP one agonist treatment of
12:59obesity will promote loss of
13:01visceral adipose tissue measured
13:03by using the VAT over the VAT set.
13:05We want it to look at
13:07hepatic insulin resistance.
13:08So we want to see whether
13:09compared to placebo,
13:10whether treatment with GLP
13:12one agonist for obesity will
13:14reduce hepatic acetyl COA,
13:16which is a key driver of gluconeogenesis.
13:18And we're using a marker to measure that.
13:22And we also wanted to see you
13:24know what it would do in terms of
13:27atherogenic lipoproteinemia.
13:27And so we hypothesized that compared
13:30to placebo those receiving obesity
13:32treatment with smegletide will
13:33have a greater improvement in
13:35their postprandial triglycerides.
13:40So here is our study design
13:43at baseline participants.
13:44This is for the randomized
13:46controlled trial portion.
13:47We have two, two parts of the study.
13:49So a baseline participants are doing the
13:52two step euglycemic hyperinsulinemic clamp
13:54technique with stable isotope tracers
13:57as a measure of insulin resistance.
13:59They are doing abdominal MRI as well,
14:01so we're looking at abdominal
14:03adipose distribution,
14:04but we will also have measures
14:06of hepatic fat fraction in case
14:07that does become something we find
14:09in this slightly older cohort.
14:11They are having a high fat mixed meal
14:15tolerance test to look for atherogenic
14:17lipoproteins and see how that changes
14:19over the time period of the test.
14:21And this shake that they are
14:25drinking apparently is delicious.
14:27They're making everybody jealous.
14:28And then this they're doing a DEXA scan,
14:31right.
14:31So we really want to get the full
14:33body composition to see, you know,
14:35how that might impact these measures.
14:37And so we can do that with a with
14:40a DEXA scan rather than just the
14:42abdomen with the MRI and let's see.
14:44So after they complete
14:46these baseline studies,
14:48participants are being randomized 2
14:50to one ratio to 52 weeks of double
14:54blinded treatment with either some
14:56maglitide weekly titrated up to
14:592.44kg or or as high as tolerated
15:02or they're randomized to placebo.
15:05And then at 12 months while on treatment,
15:07we are repeating these initial
15:09baseline studies and looking to
15:11see you know the the differences
15:14between the placebo and the the
15:16treatment group in terms of of
15:19how how these measures changed.
15:22So so far,
15:23we have enrolled 5 participants in the study.
15:26We just got awarded this grant in
15:28September where I have a goal of 69
15:30and we look forward to sharing the
15:32results with you in a few years.
15:34So our path forward from here,
15:37we are really looking to remedy the
15:39positive of research in obesity
15:41and type one diabetes.
15:43They're the the medication studies
15:45In terms of GLP,
15:47one agonists are very focused on glycemia.
15:49But you know as we're hearing
15:51more about today,
15:52there are so many other potential ways
15:54that these medications may be helpful
15:57in people with diabetes and with obesity.
15:59And we are doing Physiology,
16:01Physiology based studies of these
16:02anti obesity medications because we
16:04really do want to understand what
16:05what are the pieces that change,
16:07where are these medications acting
16:08and how can we use these as a
16:11probe to understand more and move
16:12the field forward and and answer
16:14some of these knowledge gaps.
16:16And additionally I want to point out
16:18that we have a creative study design.
16:20I I often struggle when we're
16:22doing clinical trials.
16:22I'm like we could be getting so
16:24much more information that can
16:26help us develop other studies and
16:28and and move the field forward.
16:30So we will be obtaining clinical data
16:32that is secondary and exploratory outcomes,
16:35but it can help us to understand
16:36what next steps to take.
16:38So with that I will thank our
16:41research team. It takes a lot of
16:43people to do this, this human work,
16:45my mentorship team that has
16:46helped me over the years as well
16:48as our funders. And thank you.
16:57Wonderful, thank you Doctor Van
16:58name questions from the audience.
17:05Yeah this is great.
17:06I was I was wondering for for the
17:09from the studies that Kevin Harrell
17:10has done here with with anti CD3
17:13depletion and type one diabetes,
17:15those individuals obviously
17:16do not lose weight.
17:18I wonder whether a synergizing
17:21semaglottide in those individuals
17:24controls the the disease in a
17:26better fashion or or or delays
17:29the progression even more.
17:31Possibly there's a case report out
17:32on that where it appears to work,
17:34but we have not seen that in any
17:36sort of robust study design.
17:38Think also important we'll be seeing
17:41how some of the other medications that
17:43Anya had mentioned like the Amylin
17:45analogs combined with GLP ones or
17:48Glucagon combined with GLP ones might
17:50impact just based on some of the other
17:52Physiology we didn't talk about today.
17:59Thanks, Michelle,
18:00that was really nice one question.
18:03Is there any data in people,
18:05or or at least theoretically are
18:08are the pathways of wanting to eat
18:11when you're hypoglycemic versus the
18:13pathways that are hit by the drugs?
18:15Do they commingle at all?
18:17Is there an increased risk of
18:20hypoglycemia if you're trying to have
18:22tight control and also have people
18:24lose weight at the same time? As
18:27far as the pathways,
18:28I I do not have an answer for that one,
18:30but certainly there,
18:32you know the original studies of
18:35loraglitide looked specifically
18:36at glycemia and there was not
18:38enough of an improvement.
18:40There was the risk of hypoglycemia
18:42and also the side effects that
18:44come with these medications.
18:45So that's part of why we're thinking about,
18:48well, what about besides glycemia and
18:50we've also learned more how to use these
18:53medications in people with type one diabetes,
18:55how much to decrease the insulin.
18:56We have more opportunities in
18:58terms safety monitoring with use
19:01of continuous glucose monitoring.
19:03So certainly we are always
19:04thinking about hypoglycemia,
19:05but we have participants on the
19:07lookout for that and we are proactively
19:09lowering doses and following them
19:10very carefully at the time of dose
19:13escalations for the Simagmatite.
19:17Wonderful. Other questions,
19:19Yes, Doctor Kimmy,
19:25great presentation.
19:26So we know GLP One works on the brain, right?
19:30But it also works on the beta cell.
19:32Do you have any sense of of how
19:35there's a difference between
19:37subjects with obesity but without
19:39beta cells and beta cells,
19:41if they have a different response?
19:43That is, how much can we
19:45attribute the response to the
19:46brain alone versus the eyelid?
19:48Because at this point, I don't think
19:50we have an answer for that either,
19:51but we should work on that, right.
19:55And that's why we're here today
19:56for collaboration and networking.
19:58So wonderful. Thank you so much,
19:59Doctor Van Dame for a wonderful talk
20:02and we're going to keep moving along.