Studies pivot to find what's different in kids that's fueling more aggressive and treatment-resistant behaviors
By the time Kristen Nadeau, MD, MS, began her fellowship in pediatric endocrinology at the University of Colorado School of Medicine in 2001, concern in her field over an emerging disease in youth had risen to the point that the National Institutes of Health was launching a major study.
As Nadeau and her colleagues began treating more youth with a form of type 2 diabetes (T2D) never seen in youth before the 1980s, they soon realized it was not the older persons' disease in younger bodies. Drugs effective in adults were failing in their pediatric patients, and the blood-sugar disorder was wreaking havoc on their health at unprecedented speed.
More studies were launched over the decades, confirming youth-onset T2D's aggressiveness, linking it with puberty and finding a significantly higher rate in girls and some ethnic minority groups.
"Most recent longer-term data are showing that people who developed diabetes in their youth are getting severe complications in their 20s and 30s, including heart attacks and kidney failure," said Nadeau, now a professor at the CU School of Medicine and pediatric endocrinologist with Children's Hospital Colorado.
"And this is a time in their lives when they should be at their healthiest - reproducing and being the breadwinners - not someone who's already declining."
Last month, Nadeau and colleagues published a review of that landmark study that launched early in her career and two other studies in a special issue of the journals of the American Diabetes Association (Diabetes and Diabetes Care). The journal editions recognized the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) on its 75th anniversary and signaled a transition point for youth-onset T2D research.
The study review also included CU Anschutz Medical Campus experts Phil Zeitler, MD, professor of pediatric-endocrinology at the CU School of Medicine, and senior author Dana Dabelea, MD, PhD, associate dean of research and Conrad M. Riley Distinguished Professor of Epidemiology at the Colorado School of Public Health.
Nadeau, lead author of the review, shared a list of highlights of what scientists have learned in the past two decades and the next step: a new study called DISCOVERY that will dig deeper into the youth version of the disease, in hopes of advancing a personalized and preventative medicine approach.
Puberty singled out as key player
With T2D, the pancreas produces insufficient amounts of insulin needed for sugar to enter the cells (and the cells can become resistant to insulin), resulting in persistent high blood glucose levels. Uncontrolled, the disease causes heart, kidney, eye and nerve damage. Experts attribute the rising rate in youth to a parallel rise in childhood obesity and sedentary lifestyle.
"Youth-onset T2D seems to have more rapid onset of pancreatic failure and the need for insulin treatment, and poorer responses to the medications that were studied than in adults," Nadeau said. Studies attribute puberty combined with obesity as a likely reason for aggressiveness.
"The pancreas has to make a lot more insulin because of puberty (which fuels increased growth hormone) on top of having obesity," Nadeau said. "We think the pancreas is just being pushed too hard to make enough insulin to overcome both challenges."
Nadeau likened it to gestational diabetes in pregnant women. "It's a different condition, but we think they actually happen for the same reason: That you have weight gain plus the insulin resistance that happens from growth hormone."
Some T2D cases in youth resolve after puberty, as gestational diabetes does after pregnancy, but most do not. "Usually, it seems that that hit is just too much, and that it causes permanent damage, and, in some kids, permanent diabetes."
In response to its severity, studies have looked at starting treatment earlier, during pre-diabetes, or using aggressive insulin treatment at diagnosis in hopes of halting or delaying early pancreas damage. But neither worked, Nadeau said.
Gaps in knowledge fuel research pivot
While drugs that can halt the disease in adults who have pre-diabetes clinical signs exist and continue to advance, scientists do not understand the newer youth-onset well enough to develop effective preventive treatments, Nadeau said.
"We don't even know what blood sugar values in this age group are actually of concern." Providers extrapolate adult data to youth to categorize pre-diabetes, but we don't know if the adult ranges apply to youth, she said.
Family matters: Youth-onset type 2 diabetes has a strong familial component, with 60% of patients having a parent or siblings with the disease. Add grandparents to the mix, and the rate jumps to 90%.
So rather than funding drug research with no clear target, the NIH is recruiting youth in early puberty with suspected risk factors for DISCOVERY, a national study across 15 universities aimed at better understanding the physiology behind the youth version of the disease to determine true risk.
"We don't usually see T2D before puberty," said Nadeau, national vice chair of DISCOVERY and local co-lead of the study's CU Anschutz arm along with pediatric endocrinologist Megan Kelsey, MD, MS. "So we'll follow them as they progress through puberty."
Some minority groups are hit notably harder
While overall, youth-onset T2D is rare compared with the adult version, it is not rare in some populations, Nadeau said.
"Prior to puberty, in the under-10 age group, almost every child with diabetes has type 1," Nadeau said of the autoimmune disorder that often strikes in youth and was once called juvenile diabetes. "But if you're looking at youth that are 10 to 19 years of age, now you're starting to see type 2 diabetes," she said, pointing to a bar graph.
"But what's interesting is when you separate by race and ethnicity."
For non-Hispanic White kids, most diabetes cases both before and after puberty are still type 1. "But then when you jump over to youth of American Indian/Alaska Native heritage, it's almost all type 2 diabetes after puberty," Nadeau said, noting that difference also holds true for youth of Asian Pacific Islander, Hispanic and non-Hispanic Black backgrounds.
"It's the main type of diabetes that's seen in those groups."
Rates of obesity tend to be higher in some of the minority groups, but the disparity remains, even when comparing youth who are equally obese, she said. One of the theories is that there's a genetic component in some minority populations that, when combined with obesity, inactivity and puberty, pushes T2D rates up. "Some groups might have more poor beta-cell function so that the pancreas doesn't function as well," Nadeau said.
Fat distribution plays chief role in body-weight connection
Obesity itself is not clearly a high-risk factor for youth-onset T2D. Non-obese youth do sometimes develop T2D, while not all youth with obesity get the disease, Nadeau said.
"It seems like there needs to be some degree of overweight. But what we think is happening is that there's certain people who are good at storing fat in the places that your body was made to store fat (legs, butt, hips) and are OK," she said.
"Something's changed about our whole society because this didn't happen in 1960 and 1970. … As a society, we need to work together to try to figure out cheaper, safer, easier ways for all kids to be able to access healthy food and exercise." - Kristen Nadeau, MD, MS
"But then there's other people that, even at a much lower weight, tend to store fat in their liver, or their visceral fat. It also gets inside of their muscle, and it causes those organs to work inappropriately." Those are the kids who develop T2D, Nadeau said, adding that there seems to be some racial and ethnic differences with that more dangerous fat distribution.
Bariatric surgery offers a ray of hope
Nadeau and Kelsey have done bariatric surgery studies in youth with T2D with positive outcomes. "It does seem to work in youth, possibly even better than it works in adults from the comparisons that we've been able to make so far." Yet, having a very high body mass index is a criteria for getting bariatric surgery, which some youth with T2D do not meet.
"And, we don't want to do surgery on every child," Nadeau said.
It's exciting, however, because it is working, and if researchers can understand what makes bariatric surgery successful in kids, then maybe new medications can mimic those mechanisms, Nadeau said.
"And we're getting there. The newest category of medicine are the GLP-1 receptor analogs, the ones that are in the news media for weight-loss medications. And they do have some of the hormones in them that change with bariatric surgery."
T2D: a sign of a broader issue?
Yet surgery or life-long medications for youth are not ideal solutions, Nadeau said. "What we really want is to get back to pre-1980s, when this wasn't happening at all," she said.
"Something's changed about our whole society because this didn't happen in 1960 and 1970. And so, it can't be just genetics, because that's not the way genetics works. It doesn't change that rapidly. As a society, we need to work together to try to figure out cheaper, safer, easier ways for all kids to be able to access healthy food and exercise," Nadeau said.
"This is the first time where kids born now are projected to have a shorter lifespan than their parents. We need to really pay attention to this, because all the other things that we're doing to deal with health aren't going to matter if people's baseline general health is declining, especially at these young ages."
