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Dilemmas in Diabetes Mellitus in Youth
Dilemmas in Diabetes Mellitus in Youth
Dilemmas in Diabetes Mellitus in Youth
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This is supposed to be an interactive session. I always find these hard in these big rooms, but we'll try the best. That means that I have to try to be interactive and you guys have to try to be interactive, which nobody ever really wants to do and I get it. I never did when I was in these settings, but I really do would like people to feel comfortable asking questions. I have two cases with sort of two points to make that I consider to be dilemmas, but I am happy if something isn't making sense, I'm happy if you'd ask that question right at that moment. You don't necessarily need to wait till the end of the case, I'm okay with it. We'll get to both cases, but if we digress into areas of more interest to the group, I'm okay with that too. I think that's the point of these kind of sessions. Are the microphones on if people come up? Okay, yeah. So if you have a question that you really feel you don't wanna wait till the end of the case, because I've said something that's not clear, whatever, just hop up there and I'll call on you and we can see where the discussion goes. So I'm supposed to leave this up there for a moment so that if you want to enter the session that way, you can ask questions that way also. And I think apparently I will see them on this handy iPad if you do have questions, but don't wanna admit that you have a question. Okay. All right. Did everybody get it? Or did I need to go back for a second? Everybody all right? Okay. These are my disclosures. All right. So the objectives today are, and I picked two. I mean, obviously there are many dilemmas in diabetes in youth, but the two I picked were to understand the evaluation and management of pre-diabetes in youth. And I find this to be something that people aren't sure what to do. There's a lot of confusion about. And then the second one is to understand the management of new onset diabetes in an adolescent with obesity. I think these are major areas that people often struggle with. And I hope to give you just some insight into ways that you can approach these questions. So let's start with pre-diabetes in youth. So the first case is an at-risk youth with elevation of hemoglobin A1C. So JR is a 10-year-old African-American female who was seen by a new primary care provider who notes that she has had longstanding elevation in BMI greater than 98th percentile. She has moderate acanthosis nigricans, 10 or three breast and pubic hair on exam, and she's not yet had menarche. She has a family history of type two diabetes in her mother, who had diabetes during the pregnancy with JR, and the maternal grandmother. The primary care provider obtains a point of care with a hemoglobin A1C of 5.9%, tells the family she has pre-diabetes, and refers her to the diabetes center. So I'm just gonna have you raise your hands. I couldn't quite bring myself to do the polling. Seemed like an awful lot of effort for what we can do by hand raising. So you have a girl at risk. I think we'd all agree this isn't a girl with risk for development of dysglycemia, diabetes, et cetera, A1C of 5.9%. So of the following, I'll read them all, and then I'll have you vote. The next most important step is to draw a lipid panel, draw liver transaminases, refer for multidisciplinary lifestyle intervention, repeat the A1C to confirm pre-diabetes, or start metformin 500 milligrams a day. So who wants to vote for the lipid panel? Okay, one courageous person. Draw liver transaminases. Nobody, okay. Oh, you too, you wanna get both. Yeah, okay, that's the reality of life, isn't it? You don't get just one. Refer for multidisciplinary lifestyle intervention. Who wants to repeat the A1C to confirm the pre-diabetes? You just wanna get labs on everybody, yeah. Who wants to start metformin? Okay. Now, obviously, there's no one right answer here, but I will try to give you my thoughts on each of these possibilities. Personally, I agree with the majority that the right thing to do here is to refer this kid for a lifestyle intervention. How many people think this kid has pre-diabetes? Interesting, okay. What if the A1C was 6.1%? How many people think the kid has pre-diabetes? 6.3? 6.6? So a lot of you think that you can't have pre-diabetes in kids is what the implication is because 6.6 is diabetes, right? So the fact that most people didn't raise their hand says to me that most people think that you can't have pre-diabetes in kids. And I'll tell you right now, I agree with you. Not that you can't have it, but that we have no clue what it is. Okay, so it's important to remember that the criteria for diabetes have never been validated in youth. Right? There's nothing magic about a blood sugar of 200 or a fasting blood sugar of 126 or hemoglobin A1C of 6.5%, right? It's not God given. And these were all determined based on the observation that blood sugar or any measure of blood sugar over X increases your chance for complications. That is how it's defined, right? So there's nothing magic about a blood sugar of 200. The reason it matters is, does this work? Or does it just, okay. The reason it matters is because of studies like this that showed that when your fasting glucose gets above a certain point, when your hemoglobin, excuse me, when your two-hour glucose gets above a certain point, you start to have a sudden rise in risk for complications, right? That is how this is defined. Now, this was originally defined based on retinopathy. A lot of us are old enough to remember this sort of thing, but not everybody is. And people sometimes get lost in the number definitions rather than what it means to have diabetes. So back in 79, random glucose or GTT greater than 200 or a fasting glucose greater than 140 was defined as diabetes. Some of you may forget that it was 140 at one point. That was updated in 97 to be what we now know about, fasting glucose greater than 126 or a random or stimulated glucose greater than 200. Again, that was based on analysis of these kind of curves. And what does it take to generate a curve like this associating blood sugar and complications? What does it take to do that? Longitudinal, right? I mean, longitudinal observation of kids with enough data in it or people with enough data in it to be able to see these relationships. Do we have those for kids? No. So we actually can't define diabetes in the same way in kids that it was defined in adults. And I would have the courage to say it'll probably never happen. Because we can't leave, I mean, you're not gonna leave kids with A1Cs of nine. If it happens, it's gonna be kids who are poorly controlled and that's gonna have its own complications and interpretation, right? So we're a bit stuck. In 2009, very controversially, the ADA added an A1C of 6.5% as defining diabetes. Now, this was a huge controversy because people said there's all sorts of problems with this. It doesn't correlate well with the other parameters. However, and just to remind you, this required specific assay that was aligned with the National Hemoglobin Standardization Program and confirmed in asymptomatic patients, okay? Remember that when you're using A1C for defining. So even though it was well-recognized that these things didn't all correlate with each other, they all are associated with risk for retinopathy. So it doesn't make any sense to say that, well, the A1C is no good because it doesn't always agree with the fasting glucose and some people have diabetes by one and not the other because the definition of diabetes is based on this, not on 200 being magical. So it's really important to remember that. And they pointed out that A1C is at least as predictive as the other measures for the development of retinopathy. Now, where did the numbers come from? I mean, it's a little bit more sophisticated, but basically somebody said, oh, look, at an A1C of 6.5%, it's noticeably higher. Could it have been 6.35 or 6.45? Sure, right? So it's important to remember. I actually think this is a problem that we have in endocrinology in general is that numbers seem concrete, right? Your fellows are like, oh, the TSH is 2.6 as if that means something. When there's all sorts of things behind that, right? Things go wrong in assays all the time. So, but they feel concrete because it's a number. So it's important to remember. It does appear that both for A1C and for the other measures, it's not a continuum. There's a measure, there's a point below which there is no risk, but we just can't really define what that is. And so it's very simple to get lost in these numbers of 6.4 different than 6.6. Yes, it's across the ADA cutoff, but in reality, where's the difference? So it's important to keep this in mind. So this is sort of what diabetes is defined as and we don't have these data in kids, right? So diabetes in a child is extrapolated from the definition of diabetes in adults. Now, this is not a problem in type one, most of the time, occasionally, but most of the time kids with type one, they come in and they're clearly hyperglycemic. They're clearly have a disorder. This became more of a problem as we started seeing more kids with type two diabetes or obese kids with early type one, where now you're like, you're not diagnosing this based on the DKA at presentation. Now we're using these numbers and what we're trying to do essentially is to turn a continuous variable into a dichotomous one. Okay, so it's really important to keep this in mind. So now let's turn to prediabetes. Why even define prediabetes? In adults, the argument is that there are strong data supporting increased risk for the development of diabetes, okay? So the blood sugar between 100 and 126, fasting blood sugar, stimulated glucose between 140 and 200. These are shown in these observational longitudinal studies to be associated with increased risk of diabetes, right? So that's useful. You identify the patients who have increased risk of progressing. There are also strong data in adults demonstrating that treatment in patients like that can prevent diabetes, right? Do we have either of those in kids? No. Criteria for prediabetes, i.e. the glucose values that predict progression have never been validated in youth. So can we just use the adult data? Extrapolation of adult norms during puberty is probably not appropriate, and I'll show you why in a moment. And keep in mind that the definition of prediabetes is sort of a second degree extrapolation, right? You're extrapolating from adults the risk for progression to a disorder that we are extrapolating from adults. So I think it's really important to keep in mind that we really don't know what the progression is. Now, just a little bit about progression. This is a busy slide, and I apologize, but I wanna make just a couple of cases. This is a study from our, in Denver, the Safety Net Hospital, and they see a large number of patients, and they have been screening obese patients for many, many years for diabetes because there's somebody there interested in this issue. And so this was a study that was actually done initially. Is this working? Yeah. To look at the impact of adding A1C into the screening program. But what I wanna do is make use of the fact that we have these numbers. And what we found, these are large numbers, like 15,000, 17,000 kids a few years later. And what we see is a relatively small number of cases of type 2 diabetes. And many of you are aware of that. This is why we don't recommend routine screening for type 2 because it's quite rare in the population actually. But what's important from this is that we're actually able to look at a couple of things. And that is the progression rate. So these kids were followed for two years. And the question is, what predicted progression? How much progression was occurring? And what we see is that for a random glucose greater than 140, there were no kids that progressed to diabetes. For a fasting glucose greater than 100, about 18% progressed to diabetes. So pretty stringent, right? Not 126, greater than 100. A1c less than 6%, very little progression to diabetes. Whereas in this group, A1c between 6 and 6.4, about 20%. Now it's a small number, right? So if it was eight patients, it would be a bigger number. So be careful about the exact percentages here. But what I think this points out is that if you use relatively strict criteria, you can actually pick out the kids that are at risk for progression. But certainly not 5.9%. Those kids very rarely progress. Now, there's been a lot of argument about A1c in kids. Oh, it doesn't work very well. It doesn't correlate with glucose tolerance test. Granted, it doesn't. The other way to look at that is the glucose tolerance test don't correlate with the A1c. We don't actually know which one's right, right? It's not validated in kids. So which is the right one? We don't know. There's a lot of assuming that if it doesn't correlate with the glucose tolerance test, it must be wrong. But we don't know if the glucose tolerance test is right. Okay? And we also don't know that the glucose tolerance test is even reproducible. This is a study that Silver Arslanian's group did some years ago, just looking at kids who had glucose tolerance tests two weeks apart. And what you can see is the concordance is really not very good. Here's kids who had initial test, no diabetes. Some did on the repeat. Yes, diabetes. Many did not. Most did not on the repeat. And in total, it's about 27% concordance when you calculate it. So two glucose tolerance tests don't agree with each other. You have to wonder what the glucose tolerance test is telling us either. I said that maybe using these things during puberty is inappropriate. And this is one of the reasons that I say that. This is a study that we did. We realized that we had access to a large population of kids. This is from the Healthy Study. The Healthy Study was intended as a school intervention to deliver a multi-component obesity prevention program to schools. And the schools were randomized to receive the program or not receive the program. It kind of was, it didn't do much, honestly. But there's a lot of data from that study because kids had A1Cs, glucose tolerance tests, fasting glucose, in sixth grade and eighth grade. And we realized that the schools contained lots of otherwise healthy, lean, not obese kids that we could use to look at. And we wondered what A1C actually looks like in healthy kids. And so these are non-obese, these are lean kids. And what you see is about 2% of the non-obese kids have an A1C greater than 5.7%. Well, that's not too surprising, right? 2% on a normal curve is how we generally define normal ranges. But what's more important, if we look at the, by ethnicity and race, almost 10% of African-American kids had an A1C that would be by ADA criteria considered to be pre-diabetes. We don't really think that 7% of lean African-American kids have pre-diabetes. The only point here is that it, again, calls into question what's really happening to glycemia during puberty and whether you can extrapolate from adult data to these kids who probably have different glucose regulation going on, right? We also know that in kids, there's a great deal of reversion. So there's a study that Sonia Caprio did quite a number of years ago now, 102 obese kids, 30% of them had impaired glucose tolerance. She then looked at them for two years with no intervention. About 30% progressed to diabetes, but 30% went back to normal, right? So there may be changes in glycemia that are occurring during puberty that are actually just transient. Again, raising the question about what's the validity of making the diagnosis of pre-diabetes in puberty. So we can't make the diagnosis. Now, maybe we can come up with new criteria, maybe A1C over 6%, but there's probably more to that story. Maybe we could define risk for progression, but we don't know how to treat it. So what's the point? We know that there've been many trials of metformin in youth with obesity, but they've varied a lot. And they've been primarily limited to pubertal youth. They've differed in dose, they've differed in duration. For the most part, they haven't seen much. They see some modest improvements in BMI, but little to no improvement in insulin sensitivity compared to the placebo-treated controls. The longest published study was 18 months and showed BMI and cardiovascular risk improvement, but only in the prepubertal kids, not in the pubertal kids. So sub-class analysis, right? Which you always have to wonder about. We did a study in our program, Megan Kelsey did a longitudinal study called the HIP study or Health Influences of Puberty. And what she showed was steady decline in beta cell function, even in patients receiving metformin. So what appears to work in adults doesn't necessarily even work in kids. Huh, I just realized I didn't set the timer. It's okay, I see the clock. I won't hold you late, I promise. So maybe even though metformin works in adults, it's not gonna work in kids, which is a problem because I know a lot of people are starting kids like this on metformin. And I understand it. It's hard to not do something in a kid that you know is at risk, but I'm gonna try to show you that we have no evidence that metformin is actually beneficial. So this is the RISE study. I don't know how many of you are aware of this, but this has been a very important study. The reason it's been important is because this study included an adult cohort and a pediatric cohort with late prediabetes, early diabetes, by the definition of its inclusion. So the question that the study was done for was to see whether intervening with therapies to improve glucose metabolism would prevent beta cell deterioration and therefore make things better and maybe even get these people, individuals back to normal. But what's most important is that they were pediatric and adult cohorts treated in parallel, same meds, same laboratory, same techniques. Everything's the same, okay? Rigorous measures of insulin sensitivity and secretion using hyperglycemic clamp, glucose tolerance testing, body composition measurement, et cetera. And I just wanna show you a top line outcome of this. In order to do that, I wanna show you a cartoon first because the data are a little bit confusing. So what this cartoon is showing you is the relationship between insulin sensitivity and insulin secretion. And we all know that this is a hyperbolic relationship. As insulin sensitivity decreases, secretion rises in healthy people. So this point right here now is gonna be the population point for the cohort at the beginning. So the average point, that cohort has an average insulin sensitivity and an average insulin secretion, okay? So that's your starting point. There's two possibilities. Things can get better. So they go above the curve because insulin secretion's better, insulin sensitivity is better, or some combination, or they can go below the curve. Insulin sensitivity is, excuse me, insulin secretion deteriorated, insulin sensitivity deteriorated, or some combination, okay? So keep that in mind when I show you these next graphs. This is what the baseline looked in kids and adults. Here are the adults, here are the kids. What you can see here already is that the kids with the same inclusion criteria are much more insulin resistant. They're further to the left on the insulin sensitivity. And they're also making quite a bit more insulin, okay? So already you can see some of the major findings of rise in this one figure, this difference. They're on different lines. And at any degree of insulin sensitivity, the kids are making more insulin. So it's not just that they're more resistant, even at the same degree of resistance, they're making more insulin. They're hyper-secreting, if you will, okay? And that may be a clue to the difference between them. What happened? They were put on insulin to get the blood sugar down to 80 for three months, followed by metformin or metformin alone. There was also in the adult arm, a little ragletide arm in the adult part of this trial. What you see is that at 12 months, insulin sensitivity improved. Not much change in insulin secretion, but above the line, right? And then at 15 months, three months after treatment was taken away, they're pretty much back to where they were, but perhaps with somewhat better insulin sensitivity, right? What happened in the kids? Below the line, despite treatment. With aggressive insulin therapy or metformin, no improvement, and if anything, they are worse off a year despite, a year later, despite intervention. So I would argue that we have no data that shows that treatment of prediabetes in youth prevents type 2 diabetes at this point. Metformin does not improve insulin sensitivity or preserve beta cell function. If you do start metformin, when do you quit? And if you do start metformin, how do you know if they've developed diabetes and you need to start watching for complications? So I would argue that there's not a lot of evidence suggesting the use of metformin in kids at risk for diabetes. However we define that. Now, there may be things coming along that are gonna be much better, and I'm not saying we'll never have anything, but I think throwing metformin at these kids really is just throwing metformin at them because we feel like we need to do something. I think that's the last slide on this question. Oh, yeah, what can you do? Treat what you can treat, right? I mean, as you said, they have other problems, and in fact, diabetes is the most rare of all the things these obese kids get, right? They get lipid abnormalities. They get hydroglycerides. They get fatty liver. They get sleep apnea. They get depression. Those are all things that we know is valuable to intervene on, and sometimes I feel like, I'm gonna skip by this. We know that weight loss is beneficial. If you can get kids to lose weight, that is beneficial. So focus on what you can treat, and I want to just quickly show you, and anybody who went to the obese kids talk this morning will recognize these slides. These are from Meg and Kelsey, looking at weight loss, just weight loss medicines, as opposed to trying to treat diabetes, and what we see is that we have some pretty good weight loss medicines already, semaglutide in adults, quite substantial weight loss, phentermine, topiramate, cheap, really cheap to do, and you get substantial weight loss. Loraglutide is approved for kids. Not nearly as much weight loss as you get with phentermine and topiramate. I don't know, 100 times the cost. Oralistat's not even worth mentioning. Loraglutide, a BMI loss of 4%. No significant effect on cardiometabolic outcomes. She showed you this slide this morning. This is phentermine, topiramate, adult outcomes. My point is really the next one, which is the kid outcomes look just the same. Quite impressive weight loss for two generic medications taken once a day each. So don't forget, when you're thinking about pre-diabetes in these kids, don't forget to treat the weight loss if you need to. Questions about my rant on pre-diabetes? All right, yes, please. You know what, you can just say it and I'll repeat it. Yeah, so Bob, you're speaking from Washington. Oh, hi. Yeah, so, and I heard a lot of people with knowing sort of agreements there. People I think are well aware that there are concerns about what exactly the impact of race and ethnicity is on A1C. I don't really, that's sort of a different topic, but a few thoughts about it. I think it does add to the question about use of A1C, but what I've never seen answered to my satisfaction is whether the relationship between A1C and retinopathy or nephropathy is also shifted in race and ethnic groups that have a shift in their A1C. And that feels like the question that we really need to know is it may be that A1C means a different average glucose in an African-American person than it does in a white person. But we don't have data telling us what the relationship between that A1C and risk for complications is. I've never seen it, if it exists, because we don't have the longitudinal data in African-Americans and other racial groups to answer. I mean, it may very well be if the impact of glucose on the hemoglobin is different, maybe it's also different on the advanced glycation end products, right? So I just don't know what to do with that. Okay. So, the question was, does it mean something different if you find pre-diabetes or impaired, let's call it dysglycemia, how about that, okay. Is it different if they're prepubertal or pubertal? It's a really good question. It's quite uncommon in prepubertal kids. In general, it requires the additional impact of puberty to see that kind of dysglycemia. When you do see it, there's usually, in my experience, very strong family history, gestational diabetes, a lot of risk factors for that kid, extreme obesity. There's not enough of them to say, it means this in an eight-year-old and this in an 11-year-old. I would say that my take-home message would be, be humble about interpreting these kind of values in any non-adult, right, which we don't know where it's going to go. Okay, I'd like to switch gears totally. We may or may not finish, we'll see. Seventeen-year-old, white, non-Hispanic male, presenting to our practice after being lost to follow-up for two years. Saw the PCP because wasn't feeling well. Noted to have high blood pressure and HbA1c of 7% done on routine screening. Maybe the better term is case-finding. He was a high-risk kid, so blood tests were done. Weight gain of 75 pounds over the past year following sudden death of father due to a cardiac cause, family history of type 2 diabetes in the two grandparents, hypothyroidism in the same grandparents, strong history of hypertension and early heart disease. Exam, BMI is 56, blood pressure 150 over 70, no acanthosis, and the kid is 10 or 5. What type of diabetes do you think he has? Who says this is type 1? Who says this is type 2? Who thinks it's a MODY? You just want to draw in blood. Okay, we'll see. So classic features we're all aware of, type 1, typically white, typically non-Hispanic, limited family history, right, generally in families with type 1, lack of typical insulin resistance features, evidence for family autoimmunity. There's hypothyroidism in this family, right? Problem is, of course, these are all relatively common. Type 2, classically severe obesity, rapid weight gain, mild presentation like this kid picked up kind of by accident, strong family history, minority, race, ethnicity, etc. The incidence of youth type 2 is increasing by about 5% per year, but remember, it's still rare, right? So the a priori risk that any child actually has type 2 is relatively low, just in a population manner. 3,000 to 5,000 new kids a year, 35,000 to 50,000 in the U.S. by best estimates today. So that means that most kids are still have type 1 diabetes. And even among the highest ethnic groups, African Americans, 50% of adolescents have type 1. So it's easy to walk in the room and say, oh, overweight African American adolescent must be type 2. Well, what's the rate of obesity among adolescents? 20%, 30%, yeah? What do you think the obesity rate is among adolescents with type 1 diabetes? It's the same, right? So 30% of adolescents with type 1 diabetes are overweight or obese. So we've lost that as a distinguishing feature. Remember in the absence of frank hyperglycemia or signs and symptoms of diabetes, you must confirm the diagnosis of diabetes. I'm sure most of you know this. Because of those numbers, because a priori, most kids are going to have type 1, the recommendations are that all children for whom the diagnosis of type 2 is being considered should have antibody testing. And consider genetic evaluation for monogenic diabetes based on clinical and historical characteristics. And that's not been actually well worked out, the best, most efficient algorithms for doing so. So this patient was presumed to have type 2 diabetes, like most of you. Pancreatic autoantibodies were sent. Patient was started on metformin. One week later, two antibodies reported positive. Patient had excellent glycemic control on metformin, so the decision was made to start low-dose Glargine. I'll tell you, in our practice, we would never not start insulin on somebody who had a positive antibody. We've been burned too many times. So at least basal insulin for these patients. Patient decompensated and started on MDI a few months later. So type 1, right? You can't tell clinically who has type 1 and type 2. These are data from the TODAY study that looked at the screening. So kids were referred to the study, and then they were screened out if they had antibodies. So we have antibodies measured on 2,000 kids, whatever, 1,100 kids. And what we see is that the antibody-positive kids are leaner. They have lower C-peptide, they have a higher A1C. They have lipids that look more like type 1 than type 2. They have blood pressure that looks more like type 1 than type 2. But they overlap so completely that you can't use these things to distinguish between them. So you really need to have antibodies in all of these patients. And vice versa, occasionally somebody thinks somebody has type 1 and it turns out they're antibody negative. That's actually a more difficult clinical situation because they may have antibody negative type 1, right? So that's much harder than the kid who has a type 2 phenotype but really has type 1. So what next? What do you do next? This is a 13-year-old Hispanic female, BMI of 30. She goes to the ER. She's got symptoms, A1C greater than 14%, lots of type 2 diabetes, no autoimmunity, and she looks like she has type 2 diabetes. So after clearing ketones in the ED, what would you send her home on? A1C of 14. Long-acting insulin alone, long-acting insulin plus metformin, multiple daily injections, MDI plus metformin. So who votes for long-acting insulin alone? Insulin plus metformin? MDI? MDI plus metformin? Yeah, okay. This is what the ADA guidelines suggest. Youth with marked hyperglycemia, blood glucose greater than 250, or A1C greater than 8.5, I'll say 9. I was on this committee. I couldn't get people to move it up. Without acidosis, like this kid here, should be treated with basal insulin while metformin is initiated and titrated. I would argue to stay away from MDI in a patient like this because they won't do it, and you're just going to overwhelm the family. Just to remind you, these are the guidelines. Patient less than 8.5, start metformin, 8.5, greater than 8.5 but not decompensated, insulin plus metformin, and if they're decompensated, obviously insulin. You then get pancreatic antibodies, positive, they're type 1 and should be treated like type 1. Antibodies negative, continue the metformin, wean the insulin, and see where you can get. Is there any downside to short-acting insulin if the patient turns out to have type 2? Well, it can promote weight gain. Teaching required to start short-acting insulin may cause stress on the family that they end up not really needing to have undergone. Multiple daily injection regimens may cause confusion for families if the diagnosis is changed, and we've occasionally had families come back after the diagnosis has changed and they're taking their Umilog but not their Glargine. So they get confused, and so if we don't need to, there's no point in it. MDI does not treat the associated insulin resistance. An addition of metformin to long-acting insulin almost always results in ability to rapidly wean the insulin. Is there a downside to metformin if the patient has type 1? It's extremely safe. Youth with type 1 and obesity have similar cardiovascular risk to patients with type 2. Metformin is shown to benefit patients with type 2 by lowering insulin requirements and improving cardiovascular risk. This is a study looking at insulin sensitivity and weight per lean body mass, so these are lean controls, obese controls, patients with type 1 diabetes. So patients with type 1 diabetes are more insulin resistant than obese individuals without diabetes. So it's associated with insulin sensitivity. Insulin resistance is associated with a number of complications directly, and worst insulin sensitivity and obesity are known risk factors for cardiovascular disease. So what to do? And we just have one more minute, so I'm going to just give you an overview of a study that we've got going on in our group. This is actually a combination of two cohorts, but basically these are type 1 patients being treated with metformin, and the results show that in the patients with type 1 diabetes, there's progressively higher heart rate and blood pressure as weight increased from lean to overweight to obese, and the highest rates of hypertension were seen in the group with type 1 and obesity, and significantly higher than those with type 2. Arterial stiffness testing was increased in type 1 diabetes. Exercise testing showed decreased cardiovascular exercise tolerance as BMI increased, and there were a number of hormone markers consistent with worsening of insulin resistance. In a placebo-controlled trial, metformin did not improve glycemia, and there's been multiple of these trials now, and the word on the street is metformin's not useful. It depends what you're worrying about. It reduces ascending aorta stiffness. It reduces ascending aorta wall shear stress. It reduces carotid intima media thickness, a measure of atherosclerotic burden. It improves left ventricular end-systolic and end-diastolic volume, dis-synchrony, and longitudinal strain, so metformin has no improvement in A1c, but it is improving a number of other cardiovascular risks, and likely, this isn't just metformin, right? This is probably true for many of the drugs we think of as being type 2 drugs are very likely to show benefits if you ask the right question in patients with type 1 diabetes. Bromocriptine, for example, improves blood pressure. It improves central aortic stiffness and distensibility. It improves ventricular pressure hemodynamics. It improves renal hyperfiltration. SGLT2 inhibitors lower blood pressure and lower urine albumin excretion. GLP-1 receptors reduce epicardial fat tissue, improve blood pressure and lipids, lower rates of cardiovascular and renal events in adults with type 2, and in an individual with type 1, improves endothelial function, muscle perfusion, and angiogenesis, and this was just to remind you about phentermine and topiramate. Weight loss in type 1 is probably beneficial, and we should not ignore it because they have type 1 diabetes. Obese kids with type 1 diabetes are at increased risk for many things, and terzapatide, maybe. We'll see. And with that, I'll stop. I'm happy to take questions, but the time is up.
Video Summary
The video discusses two cases related to diabetes. The first case involves a 10-year-old girl with a family history of type 2 diabetes who is diagnosed with pre-diabetes. The speaker emphasizes that the criteria for diagnosing pre-diabetes in youth have not been validated, and there is no known way to prevent progression to diabetes in these cases. The use of metformin as a treatment option is questioned, as studies have shown limited improvement in insulin sensitivity and beta cell function. The speaker suggests focusing on treating the weight-related issues and comorbidities instead. <br /><br />In the second case, a 17-year-old boy is diagnosed with type 2 diabetes, but later found to have pancreatic autoantibodies. The speaker highlights the importance of antibody testing in distinguishing type 1 and type 2 diabetes in youth, as clinical features are not sufficient for an accurate diagnosis. The boy's treatment is changed to insulin therapy, and the speaker recommends starting with basal insulin while initiating metformin. <br /><br />Overall, the video highlights the challenges in diagnosing and managing diabetes in youth, particularly in distinguishing between type 1 and type 2 diabetes. The speaker emphasizes the need for antibody testing and individualized treatment plans based on the specific characteristics of each case.
Keywords
diabetes
pre-diabetes
type 2 diabetes
metformin
insulin sensitivity
beta cell function
pancreatic autoantibodies
type 1 diabetes
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