Cardiovascular disease is the number one killer of people with diabetes. And managing cardiovascular risk is even more important in youth-onset diabetes than in adult-onset disease, according to Kristen J. Nadeau, MD, MS, recipient of the 2021 Outstanding Scientific Achievement Award.

“Youth-onset diabetes is more aggressive and more treatment-resistant than in adults,” said Dr. Nadeau, Professor of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus. “Youth-onset of type 1 and type 2 diabetes have both unique and overlapping features, and youth onset has unique features from adult-onset. Youth-onset of diabetes leads to earlier complications and earlier increases of cardiovascular disease risk.”

Dr. Nadeau presented her award lecture, Unique Cardiometabolic Mechanisms and Consequences of Youth-Onset Type 1 and Type 2 Diabetes, on Monday, June 28. The presentation can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Dr. Nadeau’s research focuses on understanding the mechanisms of youth-onset diabetes, obesity, and insulin resistance, including sex differences and racial/ethnic disparities, to prevent long-term diabetes complications. Through her roles as pediatric chair of the Restoring Insulin Secretion (RISE) study of beta-cell preservation in youth and adults, and as a cardiorenal/metabolic outcomes leader of the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial of youth-onset type 2 diabetes, Dr. Nadeau has demonstrated that youth-onset type 2 diabetes is more aggressive and treatment-resistant than in adults.

RISE, TODAY, and other trials counter six common myths that prevent CVD risk reduction in diabetes, Dr. Nadeau said.

The first myth claims the phenotype of youth-onset type 1 diabetes complications centers on beta-cell failure and hyperglycemia. The reality is that muscle insulin resistance (IR) is a prominent feature of youth-onset type 1 diabetes. Muscle IR worsens with obesity.

“The severity of this insulin resistance should sound an alarm to the type 1 provider regarding the importance of managing diet and exercise in type 1 youth,” Dr. Nadeau said.

While muscle IR is high in youth with type 1 and type 2 diabetes, the causes are different, she continued. In youth with type 2 diabetes, muscle IR is related to intramyocellular lipids. In youth with type 1 diabetes, it correlates with mitochondrial dysfunction in muscle tissue. The end result is similar: increasing vascular dysfunction.

The second myth claims IR is always accompanied by features of metabolic syndrome. The reality is that metabolic syndrome is not always present in youth with type 1 diabetes, even in obese youth.

Hepatic IR is common in youth with type 1 diabetes, but does not correlate with intra-abdominal fat. Instead, hepatic IR correlates with increased growth hormone. There are greater correlations with hypoglycemia than hyperglycemia and an absence of hepatic fat in youth with type 1 diabetes.

The third myth claims glucose elevation drives cardiovascular dysfunction. Diabetes significantly reduces cardiopulmonary fitness in youth with type 1 and type 2 diabetes. Reductions in fitness are tightly correlated with both IR and decreasing vascular function.

“The heart rate and blood pressure measures become worse in obese youth with type 1 diabetes than in type 2 diabetes, stressing the importance of addressing healthy diet and exercise, and interventions that lower insulin dosing in youth with type 1 diabetes,” Dr. Nadeau said.

The fourth myth claims decreasing glycemia with insulin is the only approach to treating youth with type 1 diabetes. Recent work suggests that non-insulin interventions can provide significant benefits for youth with type 1 diabetes.

A small trial of metformin vs. placebo in adolescents with type 1 diabetes showed decreased weight, fat mass, and body mass index in the metformin group, as well as improved insulin sensitivity, improved endothelial function, and reduced insulin dosing. Benefits were more pronounced in obese youth with type 1 diabetes, but lean type 1 diabetes adolescents showed clinically significant improvements.

There is also evidence that once-daily bromocriptine quick release (BCQR) in the morning can reset the circadian close to an insulin-sensitive state by decreasing sympathetic activity.

The first study of BCQR vs. placebo in type 1 diabetes included 40 adolescents and 40 adults. At baseline, youth with type 1 diabetes were more insulin-resistant and had worse glycemic control than adults. BCQR improved blood pressure in both type 1 diabetes youth and adults. Aortic MRI showed that youth with type 1 diabetes had improved vascular health.

“Obesity is driving insulin resistance and cardiovascular risk in youth with type 1 diabetes, demanding approaches beyond insulin,” Dr. Nadeau said. “We need longer-term studies of metformin, BCQR, and other adjunctive agents.”

The fifth myth claims that youth-onset type 2 diabetes is just an earlier version of adult-onset type 2 diabetes.

“Youth-onset looks different,” Dr. Nadeau said. “Females predominate in youth with type 2 diabetes, but not in adult disease. This prevalence starts early in puberty and worsens in the later teen years.”

There are also differences in responses to antidiabetic agents. In adults, thiazolidinedione agents improve glycemia by decreasing visceral adiposity and improving insulin sensitivity. In the TODAY trial, youth improvements in glycemia with rosiglitazone were not mediated by changes in visceral or subcutaneous adipose tissue, both of which increased.

The final myth holds that interventions used in adult-onset type 2 diabetes are too aggressive for youth-onset type 2 diabetes. Trial data suggest that youth may benefit even more than adults from aggressive interventions. Glucose failure occurs more rapidly in youth than adults. And complications—including hyperfiltration, proteinuria, hypertension, and cardiac hypertrophy—appear earlier in youth-onset type 2 diabetes.

In both TODAY and ADOPT (A Diabetes Outcome Progression Trial), more youth than adults failed metformin treatment than adults. In TODAY, girls responded best to rosiglitazone while boys responded best to lifestyle changes.

There are also important age differences in gestational diabetes. Adolescent and adult women who became pregnant during the TODAY study had similar rates of large-for-gestational-age, short-for-gestational-age, and preterm births. But 21% of adolescent offspring had major congenital anomalies, half of them cardiac, nearly five times the reported rate in adults with type 2 diabetes.

The RISE trial showed that youth make more C-peptide and more insulin than adults in response to similar glycemic stimuli, Dr. Nadal noted. Glucose control in youth requires more insulin—a mean of 70 units daily at 11 to 12 weeks—which is associated with more weight gain than in adults.

Glycemic worsening was more common in youth than in adults in the RISE trial. And while all ages showed lower beta-cell responses, youth had higher glycemia while adults had lower insulin sensitivity.

Response to bariatric surgery also changes by age. Small trials show similar weight loss in adults and youth, but youth had more type 2 diabetes and hypertension remission than adults. These initial results came largely from Roux-en-Y procedures, which have largely been replaced by the better-tolerated vertical sleeve gastrectomy. The Surgical or Medical Treatment for Pediatric Type 2 Diabetes (ST₂OMP) trial, currently underway, is seeking to explore youth outcomes following the newer procedure.