Researchers are racing to turn around troubling trends in the rise of child and adolescent diabetes
South Texas has become an epicenter for obesity and Type 2 diabetes, with about 16% of San Antonians — or one in six — living with Type 2 diabetes. And experts are seeing a disturbing trend of this disease among young people.
“The rates of Type 2 diabetes over the last 20 years have dramatically risen in children,” said Jane Lynch, MD, FAAP, pediatric endocrinologist and interim chief of the Division of Endocrinology in the Joe R. and Teresa Lozano Long School of Medicine. “In fact, of all our new onset children with diabetes, 50% are over the age of 10 and can present very sick.”
Five years ago, a child as young as five years old was diagnosed with Type 2 diabetes, Lynch added.
The growing rate of diabetes and prediabetes is a major public health issue, said Marzieh Salehi, MD, MS, FACP, an endocrinologist and a professor of medicine in the Long School of Medicine.
“If a child went to the emergency room 20 years ago and they had high glucose numbers, most definitely the diagnosis was Type 1 diabetes, meaning that the pancreas cannot produce the insulin,” Salehi said.
Now, particularly in adolescents with high glucose numbers, the diagnosis is just as likely to be Type 2 diabetes, Lynch said. While the initial intervention for adolescents is always to make lifestyle changes, the use of approved medications is sometimes appropriate to lower insulin resistance and appetite, added Lynch.
As experts in their fields — Lynch in pediatric endocrinology and Salehi in adult endocrinology — these two investigators are paving the way for improvements in the treatment of Type 2 diabetes through landmark research into medications that could help stem the tide of this growing epidemic.
The rise in Type 2 among youth
A number of factors have contributed to the rise in childhood Type 2 diabetes, including more sedentary lifestyles and increasing rates of obesity, said Lynch. With the hot summers, social deserts in which children may be disconnected from larger social networks and limited outdoor activities, the rate of obesity in South Texas continues to outpace the national average, she added.
“Obesity continues to rise in children,” Lynch said, adding that, nationally, from 2017 to 2020, it was estimated that 20% of adolescents in the United States were obese, with similar trends in other countries.
“For obesity, one of our biggest worries now is the high rates of hypertension, fatty liver and sleep apnea that go along with the weight gain and lead to adult complications at an earlier age,” Lynch said.
“In the U.S., the prediction i
s that about 60% of children will become obese by age 35, and if you’re a teenager, you have a 90% chance of staying obese in adulthood,” Lynch said.
Obesity, particularly when associated with increased stomach fat distribution and increased fat in the liver and skeletal muscle, is a major risk factor for prediabetes and Type 2 diabetes.
Developing Type 2 diabetes depends not only on body mass index and obesity, but also on one’s predisposition to insulin resistance, and this can be impacted by one’s ethnic and genetic background, Lynch said.
“You might have two kids with the same body mass index, but one who comes from a family with a high rate of Type 2 diabetes will be much more predisposed to having the disease than the other child,” Lynch said.
Puberty is a high-risk time
Type 2 diabetes is rooted in two disorders: The body can’t produce enough of the hormone insulin to lower blood sugar, and at the same time, the body is resistant to the action of insulin. Insulin resistance hinders the body’s ability to lower blood sugar levels and can increase the risk of developing Type 2 diabetes.
“We know that children who are obese by the age of 10 have become much more insulin resistant with pubertal hormones. Thus puberty, similar to pregnancy, creates a high-risk time for diabetes development in susceptible individuals,” Lynch said, adding that the first sign of insulin resistance is acanthosis, or darkening and thickening of the skin around the neck.
Interestingly, girls are more insulin resistant than boys, with two girls for every one boy diagnosed with Type 2 diabetes before the age of 18, Lynch said. Girls with insulin resistance are also at high risk for developing polycystic ovary syndrome — an endocrine disorder marked by a hormonal imbalance. Boys with insulin resistance are at high risk for fatty liver, Lynch added.
Lifestyle changes and bariatric surgery
Because obesity is a risk factor for developing Type 2 diabetes, the American Academy of Pediatrics recommends that children age 6 and over in the overweight or obese categories begin lifestyle treatments to limit sweet drinks and portion sizes and set activity goals. However, multiple studies have shown that lifestyle changes have been fairly ineffective, Lynch said, and many pediatricians may not have the time needed to devote to counseling.
Another treatment option for children with Type 2 diabetes is bariatric surgery, which changes the internal workings of the stomach to reduce food intake. However, this highly intensive surgery in children is considered only under strict criteria, and the decision process is more complex than for adults, Salehi said.
“The selection of candidates in this age group involves more stringent requirements and extensive multidisciplinary support,” Salehi said. “Parental involvement and commitment to the child’s long-term care and lifestyle changes are essential. Additionally, insurance coverage can vary and is often more limited for pediatric cases, which may further influence decision-making.”
As such, these surgeries remain relatively uncommon in children and are typically reserved for severe cases, Salehi said.
While bariatric surgery may not be the most-utilized option for children, the effectiveness of this surgery on both children and adults has played a role in the development of medications that have become increasingly popular not only for their antidiabetic and anti-obesity applications, but for their cardiovascular, cognitive, kidney and sleep apnea benefits. And researchers like Lynch and Salehi are at the forefront of this breakthrough research.
Game-changing medications
The diabetes and weight loss medications now sweeping the nation are made to mimic the action of two naturally made gut hormones: glucagon-like peptide 1, or GLP-1, and glucose-dependent insulinotropic polypeptide, or GIP. These gut hormones are released after eating and regulate blood sugar by stimulating insulin release.
Interestingly, the very first GLP-1 receptor agonist was discovered in the mid-1990s in the venom of a Gila monster, a lizard native to the southwestern United States and Mexico. According to the U.S. Department of Veterans Affairs, researchers found that the hormone in the Gila monster venom — called exendin-4 — stimulates the body’s insulin production and works like the GLP-1 hormone found in the digestive tract in humans. The discovery was licensed to a pharmaceutical company to develop into a drug, and a synthetic version of exendin-4 was approved for medical use by the U.S. Food and Drug Administration in 2005 and sold commercially.
Clinical trials leading up to the drug’s approval demonstrated improvements in glycemic control accompanied by weight loss and no risk of hypoglycemia, Salehi said. Since then, multiple GLP-1 and GIP-based medications have been developed not only for diabetes and obesity, but also for related complications such as cardiovascular disease, kidney disease, sleep apnea and neurodegenerative conditions like Alzheimer’s disease. Ongoing trials are underway to explore the metabolic benefits of molecules that mimic the action of other hormones involved in weight loss and liver metabolism in addition to those for GLP-1 and GIP medications.
“This is a new horizon for targeted treatment of various metabolic conditions and reduction of metabolic-related mortality,” Salehi said. In fact, Salehi is leading the first-of-its-kind clinical trial on the impact of a GLP-1 medication on the regulation of blood sugar in people with spinal cord injuries and Type 2 diabetes. This population has a two- to three-times higher rate of Type 2 diabetes, more metabolic conditions and much higher rates of fatty liver.
“The immediate impact would be that we are confirming the safety of this drug in this population,” Salehi said.
From research to new treatments
Researchers are now starting to mix GLP-1 medications with other gut hormones to enhance their effectiveness or reduce side effects for these drugs, Lynch said.
“That’s the future. These newer ‘cocktails’ of GLP-1 drugs mixed with other gut hormones — which also regulate insulin secretion and appetite — are also being studied for youth but not yet approved for those under 18,” Lynch said. She has been at the forefront of studies on the effectiveness and safety of GLP-1 medications to treat Type 2 diabetes and obesity in kids.
Lynch and collaborators initiated a study on treatment options for Type 2 diabetes in adolescents and youth, or TODAY. The university’s Health Science Center was one of 13 sites for this landmark National Institutes of Health study spanning over a decade, with an initial study from 2004 to 2011 to evaluate the effects of one of three treatments: the use of the frontline Type 2 diabetes medication metformin to reduce blood sugar levels, the use of metformin plus the antidiabetic drug rosiglitazone, or metformin plus an intensive lifestyle intervention. The initial study included 699 adolescent participants ages 10 to 17 with youth-onset Type 2 diabetes.
A follow-up, observational study was then conducted with 500 participants from 2011 to 2020. The multiyear study, published in the New England Journal of Medicine, highlighted the devastating outcomes for youth with the onset of Type 2 diabetes before reaching the age of 18 and brought awareness to the uniquely high risks and rapid progression of complications seen in youth from this age group, Lynch said.
“With this study, we realized the two-to-one ratio of girls to boys having Type 2 diabetes was national,” Lynch said. “We realized the complication rates for young-onset Type 2 youth were very accelerated. Due to pubertal hormones and insulin resistance, the onset of hypertension, fatty liver, eye disease, kidney disease and heart disease were very accelerated,” Lynch said.
Furthermore, “The pregnancy outcomes for girls were especially scary, with unexpectedly high rates of miscarriages and fetal anomalies, so we are very motivated to be aggressive in managing Type 2 diabetes,” Lynch added.
The next frontier: Prevention
Previously, Lynch participated in a study that led to the first FDA approval of a GLP-1 therapy for youth ages 10 to 18 and has been involved in studies of five categories of adult medications for kids, enabling the university to be on the frontlines of this research.
Currently, she is participating in three studies involving GLP-1 medications in youth and continues to be on the forefront of the GLP-1 research among youth with Type 2 diabetes.
Because of her participation in these landmark studies, Lynch likewise sits on multiple international committees to monitor safety in these types of trials for children. She credits these accomplishments and her participation in these groundbreaking studies to the expertise and skill of her research colleagues and the close collaboration between the pediatric endocrinologists and the adult diabetes unit at the university.
With the now widespread use of GLP-1 medications, researchers continue to modify and mix GLP-1 hormones with other related gut hormones to further enhance the effectiveness of Type 2 diabetes medications, Lynch said.
“While we realize there may be challenges in helping families to afford approved GLP-1 medications for youth, the ability to treat kids who have Type 2 diabetes with these approved medications has been a huge game changer,” Lynch said. “We now have begun to explore how to safely use these medications to prevent Type 2 diabetes and obesity-related complications, which has a lot of potential.”
The spinal cord injury correlation
A pioneering clinical trial explores a safe and effective treatment option for a population more prone to developing Type 2 diabetes
Those with traumatic spinal cord injuries — about 305,000 in the U.S., according to the National Spinal Cord Injury Statistical Center — have a two- to three-times higher rate of developing Type 2 diabetes and tend to die from metabolic diseases. Yet patients with spinal cord injury and diabetes are often underdiagnosed and undertreated, missing out on effective therapies for glucose control and weight management, said Marzieh Salehi, MD, MS, FACP, an endocrinologist and a professor of medicine at the Joe R. and Teresa Lozano Long School of Medicine and Medical Director of the Bartter Clinical Research Unit at the Audie L. Murphy Memorial Veterans Hospital.
Based on prior research conducted by Salehi and her team, individuals with spinal cord injuries and Type 2 diabetes are metabolically unique.
“There’s a breakdown in the communication between the gut, liver, pancreas and brain — a network that’s essential for keeping blood sugar levels in check,” Salehi explained. “Imagine what happens when that crosstalk is disrupted because neural signals can’t travel properly due to a spinal cord injury.”
This disconnect may explain why people with spinal cord injuries have a higher risk of diabetes, fatty liver disease and other metabolic conditions and are more likely to die from cardiovascular disease than from the spinal cord injury itself, Salehi said.
“Since there haven’t been any clinical trials in this population, physicians have been hesitant to prescribe newer medications that haven’t yet been proven effective for treating diabetes and related metabolic complications in people with spinal cord injuries,” Salehi added.
She hopes to change that with a groundbreaking clinical trial testing whether a GLP-1 receptor agonist can counter the harmful effects of spinal cord injury on blood sugar control and weight gain. The study — which received $3 million in funding from the National Institutes of Health —seeks not only to learn if this population will have any adverse effects from the medication, but also to shed more light on the underlying cause of diabetes and obesity in this population.
The five-year study is actively enrolling participants from San Antonio and community rehab clinics who have a spinal cord injury and Type 2 diabetes and are either managing their condition with the diabetes medication metformin or through diet alone.
Participants will first undergo detailed metabolic testing before being randomly assigned to receive either the GLP-1 receptor agonist medication or a placebo for 24 weeks, Salehi said.
The clinical trial model should allow researchers to better understand how blood sugar is processed in this population and how communication between organs influences blood sugar control and weight balance. Eventually, Salehi said, the study could pave the way for improved treatments and spark new drug development tailored to their unique metabolic needs.
“Our findings could provide critical insights to develop targeted treatments for the unique metabolic challenges faced by people with spinal cord injuries — ultimately improving their health and quality of life.”