GROWTH HORMONE LINKS TO WORSE T2D CONTROL IN ADOLESCENTS

Type 2 diabetes manifests in a more severe form among young people compared to adults, and growth hormones associated with puberty may contribute to this. Certain growth hormones, such as insulin-like growth factor 1 (among others), are thought to affect insulin sensitivity and the function of beta cells.^[1] Type 2 diabetes diagnoses are related to several complications at an early age. For instance, the TODAY study found that at least one complication occurred in 60% of analyzed study participants (N = 500). Cumulative incidence for hypertension, dyslipidemia, diabetic kidney disease, nerve disease, and retinal disease were elevated.^[2]

In a new analysis of the TODAY study, which included 310 participants, plasma levels of three proteins involved in growth hormone activity showed significant association with the controllability of type 2 diabetes in adolescents, a finding that suggests these proteins may serve as risk markers for incidents of type 2 diabetes and may help identify kids who could benefit from aggressive preventive care.^[1]

"Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes," said Chang Lu, MD, at the at the recent American Diabetes Association's 83rd Scientific Sessions. "Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset."

Another potential application is to "leverage these data to find predictive markers" that could identify adolescents with type 2 diabetes "at risk for particularly aggressive disease and target them for more intervention," added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston, Massachusetts.

Does Growth Hormone Cause Incident T2D at Puberty?

Changes in levels of growth hormone-associated peptides during puberty "could potentially explain why children with type 2 diabetes have a more aggressive course" of the disorder, added Dr. Lu, also a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital. Puberty-associated changes in growth hormone and related peptides "could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10," said Dr. Isganaitis in an interview.

A current hypothesis is that "high levels of growth hormone are a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin, and so they do not develop diabetes," commented Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver. "But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition" to developing type 2 diabetes, Nadeau said in an interview.

Drs. Lu, Isganaitis, and their co-authors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study,^[3] which randomly assigned 699 kids aged 10 to 17 years with type 2 diabetes into 1 of 3 anti-diabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.

The primary outcome showed a 39% to 52% incidence of failure during 5 years of follow-up, depending on the specific treatments the study participants received.^[3]

Growth Hormone Correlates of Glycemic Failure

The new analyses focused on 310 study participants from the TODAY study who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline. After 3 years they assessed these changes relative to the endpoint of glycemic failure. The results showed that an increase in insulin-like growth factor-1 was significantly associated with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.^[3]

In contrast, increasing plasma levels of growth hormone receptor were significantly associated with an increased rate of glycemic failure, hyperglycemia, insulin resistance, and diminished beta-cell function. Also, an increase in insulin-like growth factor binding protein-1 was significantly associated with glycemic failure and hyperglycemia at 36 months, with higher insulin sensitivity at baseline. All of these analyses adjusted for baseline differences in several demographic and clinical variables; "However," cautioned Lu, "these post-hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure."^[3]

Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Lu said. Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in kids identified as having a higher risk.

Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Lu said.

ANTENATAL CORTICOSTEROIDS: A LIFE-SAVING INTERVENTION FOR PRETERM INFANTS, BUT ARE THERE LATER CHILDHOOD EFFECTS?

Antenatal corticosteroids are considered a key intervention for pregnant people who are at risk of preterm delivery earlier than 34 weeks. The drugs reduce the risk for perinatal and neonatal death and decrease the risk of developing respiratory distress syndrome. However, how these drugs affect these infants into childhood has been less widely studied, according to a new systematic review and meta-analysis of 1.6 million infants.^[4]

The study, which was published in the BMJ, found that babies who were exposed to antenatal corticosteroids are at an increased risk of adverse health outcomes later on.^[4]

Approximately 40% of infants exposed to the steroids before 34 weeks of gestation were born at full term, but were more likely to have a neonatal intensive care admission, be intubated, have a reduced head circumference, and develop long-term neurodevelopmental or behavioral disorders in childhood. Study authors wrote that clinicians need to more carefully assess the risks and benefits for individual pregnant patients. They also noted the future need for better ways to help predict preterm birth, as well as for assessments for clinicians to use when considering prescribing antenatal corticosteroids.

"Steroids are powerful medications,” said Sarah McDonald, MD, professor and maternal-fetal medicine specialist in the Department of Obstetrics and Gynecology at McMaster University, Hamilton, Canada, and lead study author. "With power comes responsibility. As physicians, we want to use steroids to help those who need it (the smallest babies) but avoid using them if birth is unlikely to be very early as there may be developmental harms associated with steroids.”

Study Findings and Potential Future Risks

McDonald and colleagues analyzed data from 7 randomized controlled trials and 10 population-based cohort studies that included data on infants with exposure to antenatal corticosteroids born before 34 weeks, between 35 and 36 weeks, and those born at term (≥ 37 weeks).

The researchers found that around 40% of infants who were exposed to antenatal corticosteroids before 24 weeks were born at term, but with associated risk for short- and long-term effects. These risks, they found, included neonatal intensive care admission (adjusted odds ratio, 1.49 [95% CI: 1.19, 1.86]), intubation (unadjusted relative risk, 2.59), reduced head circumference (adjusted mean difference, −0.21 [95% CI: −0.29, −0.13]), and long-term neurodevelopmental or behavioral disorders (adjusted hazard ratio [AHR], 1.47; [95% CI: 1.36, 1.60]). The researchers found similar results in over half of exposed infants born at term or late preterm.

The findings align with a second study published online in the BMJ that compared more than 45,000 exposed infants in Taiwan to almost 2 million infants with no exposure.^[5] Exposure to one course of antenatal corticosteroids (compared with no exposure) increased the risk for overall serious infections (AHR, 1.32 [95% CI: 1.18, 1.47], P < .001 ), acute gastroenteritis (AHR, 1.35 [95% CI: 1.10, 1.65]; P < .001), sepsis (AHR, 1.74 [95% CI: 1.16, 2.61]; P = .01), and pneumonia (AHR, 1.39 [95% CI: 1.17, 1.65]; P < .001) in the first 12 months of life.

The findings create a better understanding of potential future risks, according to G. Thomas Ruiz, MD, ob/gyn lead at MemorialCare Orange Coast Medical Center in Fountain Valley, California, who was not affiliated with the research. He said the findings may not change current clinical practice immediately because of the absence of predictive tools that can inform clinicians of specific risk to a patient.

"Sometimes you have to use steroids, especially for infants at risk of being born very prematurely,” Ruiz said. "There are too many good studies that demonstrate benefits.” He added that the study also did not demonstrate whether the negative health outcomes directly resulted from the use of corticosteroids alone, or if other factors may play a role.

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