Building a Legacy of Impactful Type 2 Diabetes Research

Why is youth-onset Type 2 diabetes a growing public health crisis, and how has research helped us understand and respond to it?

For the first time in generations, kids are predicted to have shorter lifespans than their parents. After decades of medical progress and rising life expectancy, this reversal is startling. One of the factors driving this shift is a rapid, widespread surge in youth-onset Type 2 diabetes. This disease is striking earlier, progressing faster and proving far harder to treat than in adult populations.

The endocrinology team at Children's Hospital Colorado and the Lifecourse Epidemiology of Adiposity & Diabetes (LEAD) Center at the Colorado School of Public Health have played a pivotal role in addressing this emerging narrative. As a leading site for groundbreaking, federally funded studies on youth-onset Type 2 diabetes, Children’s Colorado helped uncover how and why the disease behaves so differently in children. The researchers behind these studies were among the first to show that standard adult treatments often fail in youth, that complications appear earlier and that existing definitions of diabetes may not even apply to pediatric cases. This work will inform the next generation of diabetes research.

The impact of this research has been so great that several Children’s Colorado-led studies — including TODAY, SEARCH, RISE and the ongoing DISCOVERY study — were recently recognized as the most groundbreaking set of Type 2 diabetes research findings in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 75th anniversary publication.

Founded in 1950 and housed within the National Institutes of Health, the NIDDK has led the nation’s scientific response to diabetes. Through decades of funding research and infrastructure, the institute has uncovered mechanisms, risks and treatments for both Type 1 and Type 2 diabetes (T2D). The four Children’s Colorado-led youth-onset T2D studies highlighted in the NIDDK’s anniversary collection exemplify that mission.

From helping define the problem, to reshaping treatment protocols, to now leading prevention-focused studies like DISCOVERY, Children’s Colorado has been at the forefront of every stage in the fight against youth-onset T2D.

TODAY: A wake-up call for pediatric diabetes care

The Treatment Options for Type 2 Diabetes in Adolecents and Youth (TODAY) study began enrolling kids ages 10 to 17 in 2004 to determine how well conventional treatments worked in pediatric populations. Philip Zeitler, MD, a nationally recognized leader in pediatric endocrinology, chaired the study. His foundational role helped establish a concern for rising rates of T2D in pediatrics.

Researchers from TODAY enrolled nearly 700 teens and randomized them into three treatment arms: metformin alone (the standard first-line treatment for adult-onset diabetes), metformin combined with intensive lifestyle intervention such as exercise, and metformin combined with rosiglitazone, another oral diabetes medication. The goal was to see how these approaches could help patients maintain blood sugar control.

According to Kristen Nadeau, MD, pediatric endocrinologist and principal investigator of RISE and DISCOVERY, the TODAY study’s findings were stunning: Most teens lost blood sugar control rapidly, regardless of treatment. Even combining two medications didn’t guarantee success, and lifestyle interventions weren’t enough. A central takeaway from this research was that compared to adults, youth had higher failure rates and increased resistance to insulin.

TODAY tracked long-term outcomes as patients aged into their 20s and 30s — and what they found was perhaps even more alarming. As they aged, patients with youth-onset T2D began to experience serious complications far earlier than expected: heart attacks, strokes, kidney failure and other life-altering events that typically don’t occur until much later in life. “These complications are occurring at a time when you’d expect people to be the healthiest in their lives and possibly reproducing,” says Megan Kelsey, MD, pediatric endocrinologist and site principal investigator for DISCOVERY.

There were also notable differences between the sexes: Boys responded better to lifestyle interventions than girls did. Dr. Nadeau noted that part of that difference may stem from puberty timing. Since girls generally enter puberty about a year earlier than boys, their window for early intervention may be even shorter.

One of the most unsettling findings emerged from pregnancy-related outcomes. Young women who developed T2D in their youth experienced higher rates of birth defects during pregnancy, particularly congenital heart anomalies in their babies. This not only increased the child’s own risk of developing diabetes but also introduced a generational cycle of metabolic risk and poor outcomes.

TODAY was one of the first large-scale controlled studies to definitively show that youth-onset T2D is not just an adult condition on a younger timeline — it’s more aggressive, less responsive to treatment and tied to earlier and more severe complications. It proved that rising rates of T2D in youth were in fact not a mere coincidence, but a crisis.

SEARCH: Mapping the epidemic

Distinguished professor Dana Dabelea, MD, PhD, was the principal investigator of SEARCH at the University of Colorado Anschutz Medical Campus, one of six clinical sites that participated, and Co-Chair of the Steering Committee. This was the first large-scale study to track Type 1 and Type 2 diabetes in American youth. Launched in 2000, SEARCH provided foundational data on prevalence, complications and disparities across racial, ethnic and socioeconomic groups for T2D. It remains one of the most comprehensive epidemiological efforts in pediatric diabetes research.

“It was probably the first study in the world that, at a population-based level, compared rates and trends in Type 1 and Type 2 diabetes side by side,” Dr. Dabelea says. “It provided some of the most solid evidence on how much diabetes exists in U.S. kids in the first two decades of this century.”

The study revealed stark health disparities. Kids from low-income communities or underrepresented racial or ethnic groups were not only more likely to develop T2D, but also more likely to suffer early complications. Dr. Dabelea explains that SEARCH also showed that these kids were generally treated less aggressively and met fewer quality of care metrics, in addition to having less access to nutritional food.

“It highlights the role of social drivers of health,” says Dr. Dabelea. “Everything we do as individuals is in the context of our environment, and if our environment is not conducive of making lifestyle changes, they won’t be successful.”

Another key finding from SEARCH was that serious complications — including hypertension, kidney disease (nephropathy) and nerve damage (neuropathy) — began developing within just a few years of diagnosis. These complications occurred earlier and more frequently in youth with T2D than in those with Type 1, despite similar levels of blood sugar control. “There must be other factors, perhaps related to obesity or inflammation, that explain this higher burden of complications,” Dr. Dabelea notes.

SEARCH’s findings emphasized that youth-onset Type 2 diabetes is not only more aggressive than Type 1 in many cases, but it also reflects and reinforces broader public health equity concerns. The study continues to serve as a foundational evidence base for pediatric diabetes prevention and policy.

RISE: Youth and adults respond differently to treatment

The Restoring Insulin Secretion (RISE) study offered something previous trials couldn’t: a direct, head-to-head comparison of Type 2 diabetes in adolescents and adults using the same treatment under identical study conditions. Adult and child participants were matched up to create pairings with similar weights and glucose levels so that the researchers could home in on differences caused by age.

Dr. Nadeau led the pediatric arm of the multicenter trial, which enrolled youth ages 10 to 19 years old alongside adults who had either impaired glucose tolerance (prediabetes) or early Type 2 diabetes. Dr. Nadeau’s analysis focused on two treatment approaches: metformin alone and a three-month course of insulin therapy followed by metformin.

While adult participants generally maintained or improved pancreatic beta cell function under both regimens, youth had the opposite result. Their beta cell function — which is typically the process by which insulin is produced and secreted by the pancreas — was maintained or deteriorated, and their blood glucose worsened. “We had more kids who progressed from prediabetes to diabetes, or who lost control of their diabetes and needed to go on insulin,” Dr. Nadeau says.

In addition to poor treatment responses, youth exhibited stark physiological differences. Compared to adults, adolescents were twice as insulin resistant, requiring double the insulin to control blood sugar. They also produced more insulin, but it simply didn’t work as effectively.

Researchers believe that the hormonal changes of puberty, especially rising hormone levels, plus the effects of obesity, can push the pancreas past its limit. While puberty-induced insulin resistance is temporary in healthy adolescents, it creates a dangerous threshold when combined with poor pancreatic function.

RISE also challenged assumptions carried over from adult diabetes research. For example, because metformin had worked to delay or prevent diabetes in adults with prediabetes, many believed it would do the same in youth. But this study proved otherwise.

“That changed clinical care,” Dr. Nadeau says. “We don’t use metformin anymore to prevent diabetes in kids because it isn’t effective.”

RISE solidified that youth-onset T2D is not just adult diabetes on fast-forward — it’s a fundamentally different disease with different treatment needs. It also laid the groundwork for more targeted trials, such as DISCOVERY.

DISCOVERY: Identifying future risks

With so much research showing that youth-onset diabetes progresses quickly and responds poorly to treatment, the NIH chose to shift focus away from intervention and toward understanding why groups are at risk. That goal gave rise to Discovery of Risk Factors for Type 2 Diabetes in Youth (DISCOVERY) — a national, longitudinal study to identify which children are most at risk for T2D and why.

Dr. Kelsey and Dr. Nadeau are the principal site investigators for the CU Anschutz Medical Campus, with Dr. Nadeau stepping into the role of co-chair of the entire DISCOVERY study. Dr. Dabelea is also a principal investigator of a CU Anschutz – American Indian site to study T2D in indigenous communities.

Now in its first year of recruiting, DISCOVERY plans to enroll 3,600 youth across 15 sites in the U.S., with a particular focus on underrepresented populations. Children are recruited in early puberty, since T2D most often begins to emerge during this developmental window.

Researchers are collecting detailed data on each child’s family history, body mass index, insulin sensitivity, body composition, pubertal hormones, lifestyle behaviors and glucose metabolism, as well as biospecimens for future analysis. The goal is not only to identify who is most likely to develop diabetes, but also to determine why some at-risk youth go on to develop the disease while others do not.

“We’re not just collecting data — we’re building for future breakthroughs,” Dr. Nadeau says. “The samples we’re collecting now may tell us things five or 10 years from now that we don’t yet know to ask.”

While DISCOVERY focuses on identifying risk, it also sets the stage for intervention. Data from this study may help inform early warning systems, define new diagnostic thresholds for children or even create the design of future clinical trials aimed at prevention. This study is a direct response to gaps revealed by SEARCH, TODAY and RISE.

“DISCOVERY is a prevention-focused study,” Dr. Kelsey says. “We’re not trying to treat kids once they have diabetes. We’re trying to figure out how they get it in the first place.”

Continuing to push diabetes treatment forward

From TODAY to DISCOVERY, the trajectory of these NIDDK-funded studies illustrates an unfortunate truth: Youth-onset T2D is increasing rapidly and often resists the treatments that work for adults. These aren’t just statistics — they are real children facing a serious, lifelong disease at the very stage of life when they should be the healthiest.

That reality has changed the way pediatric endocrinologists treat and approach T2D in youth. “In a pretty short period of time, this research has enormously changed our management,” Dr. Kelsey says. “Without it, we’re at a loss. We can’t just go based on research done in adults.”

Studies like these are possible because of long-term investment from the NIDDK. Thanks to these findings, researchers are focusing on goals with a different mindset moving forward — identifying early risk factors and having earlier interventions. For instance, there has been a focus toward understanding what glucose regulation and other factors look like in healthy kids during puberty.

Additional studies have shown that youth-onset T2D responds well to bariatric surgery, although this is a drastic step in care. Remission rates after surgery have revealed that youth, particularly teens, may actually have better rates than adults. That said, Dr. Nadeau points out that we should focus more on prevention rather than turning to such an extreme level of care.

Prevention remains the long-term goal. Even though newer medications and surgical approaches offer better control, many youth still end up on multiple medications and insulin by their early twenties, facing a lifetime of complicated care. “It’s a huge burden of treatment for these young people,” Dr. Kelsey says.

And no matter how promising a medical intervention may be, it can only go so far without addressing the larger social and environmental context. Families need access to healthy food, safe neighborhoods, quality care and systems that make healthy choices realistic. Whether it’s DISCOVERY or SEARCH, the ultimate vision is to transform how we care for, and protect, the next generation.