Study Overview
Children born small for gestational age (SGA) are smaller than expected for their gestational age at birth. Many catch up in growth during infancy or early childhood, but some do not and may later receive growth hormone (GH) treatment to improve height. At the same time, both SGA status and GH therapy have been linked to changes in glucose and insulin regulation, raising questions about long-term metabolic safety.
This study examined whether children born SGA who were receiving GH therapy had a different glucose-insulin profile from children with isolated growth hormone deficiency (iGHD), children with obesity, and lean controls. The main focus was insulin resistance, which is the body’s reduced response to insulin and a key early sign of future metabolic risk.
Why This Question Matters
Growth hormone is widely used in pediatrics for short stature caused by specific conditions, including SGA without catch-up growth and iGHD. Although GH helps promote growth, it can also reduce insulin sensitivity. In other words, the body may need to produce more insulin to keep blood sugar normal.
This is especially relevant in children born SGA because they may already have a higher baseline risk of insulin resistance, altered body composition, and later metabolic disease. Understanding whether GH therapy further increases this risk is important for balancing the benefits of improved height against possible metabolic consequences.
How the Study Was Done
The investigators analyzed 1,252 children and adolescents across several groups:
134 children born SGA without catch-up growth who were receiving GH therapy, called the SGA-GHT group
27 untreated SGA children with catch-up growth, called the SGA-CUG group
308 children with isolated growth hormone deficiency receiving GH therapy
427 children with obesity
356 lean controls
To assess glucose-insulin metabolism, the researchers used both fasting measures and oral glucose tolerance test results. These included:
Fasting glucose
HOMA-IR, a common marker of insulin resistance based on fasting glucose and insulin
Matsuda index, which reflects insulin sensitivity during an oral glucose tolerance test
Insulin area under the curve (AUC), which shows how much insulin the body releases after a glucose load
HbA1c, a marker of average blood sugar over the previous 2 to 3 months
The analysis was adjusted for sex, age, and body mass index (BMI) using matching and multivariable regression to make the groups more comparable.
Main Findings
Before treatment, children with SGA who were receiving GH therapy already showed a less favorable metabolic profile than children with iGHD. Specifically, they had:
Higher insulin AUC
Higher HOMA-IR
Lower Matsuda index
These findings indicate greater insulin resistance and poorer insulin sensitivity. Importantly, their values were closer to those seen in the obesity group than in the iGHD group.
During GH therapy, HbA1c was slightly but significantly higher in the SGA-GHT and iGHD groups than in lean controls. Although the average values remained in a near-normal range, the difference suggests a measurable shift toward higher glucose burden.
The degree of insulin resistance in the SGA-GHT group approached that of children with obesity, reinforcing the idea that SGA children receiving GH may have a metabolic profile more similar to obesity than to other GH-treated short-stature conditions.
Prediabetes and Post-Treatment Findings
One of the most clinically important results was the frequency of prediabetes. The highest prevalence was found in children born SGA and receiving GH therapy, at 11.11%. This was notably higher than in children with iGHD at 1.59% and in children with obesity at 3.13%.
After GH treatment was stopped, the SGA-GHT group still showed elevated markers of impaired glucose metabolism. Prediabetes remained present in 4.65% of these children, and insulin resistance remained higher than in controls and iGHD patients. Their profile was similar to that of children with obesity, where prediabetes prevalence was 6.38%.
No cases of overt type 2 diabetes were observed in this study, which is reassuring. However, the persistence of abnormal metabolic markers suggests that risk does not disappear immediately after GH is discontinued.
What These Results Mean
This study suggests that children born SGA may have a built-in vulnerability to insulin resistance, and GH treatment can further worsen that tendency. The key message is not that GH should be avoided, but that its use requires careful monitoring.
In clinical terms, the results support the following ideas:
Children born SGA, especially those without catch-up growth, should be considered a metabolically higher-risk group.
GH therapy may improve height outcomes, but it can also increase insulin resistance and raise the likelihood of prediabetes.
Routine metabolic follow-up is important during treatment and after treatment ends.
Children with SGA may need monitoring that is similar in intensity to that used in pediatric obesity care.
Clinical Significance
GH therapy remains an important and often beneficial treatment for children born SGA who fail to catch up in growth. Improved final height can have meaningful physical and psychological benefits. However, this study highlights the need for a balanced approach.
Monitoring should typically include:
Fasting glucose and insulin, where appropriate
HbA1c
Oral glucose tolerance testing in selected patients
Regular assessment of BMI, waist circumference, and pubertal stage
Attention to family history of diabetes or metabolic disease
If early signs of insulin resistance appear, clinicians may consider closer follow-up, lifestyle counseling, and reassessment of GH dosing and overall risk-benefit balance. The study does not provide a specific treatment algorithm, but it clearly supports proactive surveillance.
Possible Biological Explanation
The findings fit with known biology. Growth hormone has anti-insulin effects, meaning it can reduce the body’s ability to take up glucose into muscle and fat tissue. This is one reason GH can temporarily raise insulin levels.
Children born SGA may already have altered fat distribution, reduced insulin sensitivity, and long-term metabolic programming related to fetal growth restriction. When GH is added, the combined effect may amplify insulin resistance. This helps explain why the SGA-GHT group looked metabolically closer to the obesity group than to the iGHD group.
Strengths and Limitations
A major strength of this study is the relatively large sample size and the inclusion of several comparison groups. Using both fasting and post-glucose-load measures provided a more complete picture of metabolism than fasting values alone.
There are also limitations. This was an observational analysis, so it cannot prove that GH therapy directly caused the metabolic differences. The number of untreated SGA children with catch-up growth was small, which limits comparisons in that subgroup. In addition, metabolic risk can be influenced by puberty, nutrition, physical activity, and family history, factors that may not be fully captured in any single study.
Practical Takeaway for Families and Clinicians
For families, the main message is that GH treatment can still be appropriate and helpful for selected children born SGA, but it should not be viewed as a purely growth-focused therapy. Metabolic health matters too.
For clinicians, this study supports routine attention to glucose-insulin metabolism in children born SGA, especially those receiving GH. The absence of overt diabetes is reassuring, but the higher rates of prediabetes and insulin resistance indicate that these children deserve structured follow-up.
Conclusion
Children born small for gestational age who receive growth hormone therapy show an impaired glucose-insulin metabolism that resembles the pattern seen in children with obesity. This impairment appears to worsen during GH treatment and may persist even after therapy ends. While no type 2 diabetes was observed, the elevated risk of prediabetes and insulin resistance supports close metabolic monitoring throughout care.
