medwireNews: Glucose–insulin impairment in small-for-gestational-age (SGA) children is comparable to that found in children with obesity and worsened by use of growth hormone (GH) therapy, say German researchers.
Recognising that glucose–insulin metabolism impairment is documented in children born SGA and in children with isolated growth hormone deficiency (iGHD) who are treated with GH therapy, the team investigated the impact of GH therapy on oral glucose tolerance and fasting parameters in children born SGA who had not achieved catch-up growth in their first 4 years.
Antje Körner (University of Leipzig) and co-workers collated data from 442 children and adolescents attending a medical centre between 1994 and 2022, and 810 participants of the LIFE Child cohort. The patients were aged 0–21 years and had records of at least one fasting glucose or insulin sample, while 377 and 686, respectively, had one or more oral glucose tolerance test (OGTT) results.
Overall, the study population included 134 SGA patients without catch-up growth who were undergoing GH therapy, 27 SGA patients who achieved catch-up growth without GH therapy, 308 patients undergoing GH therapy for iGHD, 427 children with obesity, and 356 lean children.
SGA was defined as a birthweight or length below –2 standard deviation score (SDS), while obesity was defined as a BMI–SDS of 1.88 or above and lean as a BMI–SDS of less than 1.28. The researchers explain that, to allow for data analysis, matched cohorts were created based on a similar distribution of age, sex, pubertal stage, and, except for the children with obesity, BMI–SDS.
Metabolism before GH therapy
Children born SGA without catch-up growth, children with iGHD and lean controls had comparable fasting glucose levels, glycated haemoglobin (HbA1c) and 2-hour glucose levels on their OGTT, whereas children with obesity had significantly higher fasting glucose levels than the other four groups.
But children born SGA without catch-up growth were more insulin resistant than their iGHD counterparts, as indicated by significantly higher insulin area under the curve (AUC) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) measures, and a significantly lower Matsuda index for whole-body insulin sensitivity. Moreover, children born SGA had higher HOMA-IR and Matsuda index values than lean children, and similar values to those with obesity.
“Overall, glucose-insulin metabolism was diminished in treatment-naïve children born SGA compared to lean controls, whereas iGHD patients had a comparable glucose-insulin metabolism to lean controls”, the authors summarize.
Metabolic changes during GH therapy
Compared with children with iGHD, patients born SGA who underwent GH therapy did so for longer (7.5 vs 5.8 years) and received a significantly higher dose (34.34 vs 29.97 µg/kg), the researchers write in The Journal of Clinical Endocrinology & Metabolism.
During GH therapy, both children born SGA and those with iGHD “showed a shift toward an impaired glucose metabolism in comparison to lean controls”, say Körner and colleagues.
Specifically, children born SGA had significantly higher glucose AUC, and 1-hour glucose levels than lean controls during GH therapy, and significantly higher HbA1c levels than both lean children and those with obesity. Children born SGA also had higher insulin AUC than the iGHD patients given GH therapy, as well as a significantly higher HOMA-IR score and significantly lower Matsuda index.
Of note, insulin sensitivity and secretion levels in the children born SGA undergoing GH therapy “approached” those of children with obesity, the researchers say, although this SGA group were less likely to have pathological age-adjusted HOMA-IR than the obesity group.
Nevertheless, children born SGA given GH therapy did not have significantly different glucose and insulin measures than the children born SGA who achieved catch-up growth without treatment.
Metabolic differences after GH therapy cessation
To determine whether potential GH therapy-related changes in glucose metabolism were reversible, the team compared the born SGA and iGHD groups an average 8 months after finishing GH therapy with age-, sex- and BMI-matched groups of lean children and those with obesity.
The authors report that “glucose metabolism in iGHD patients returned to normal.”
By contrast, children born SGA who finished GH therapy continued to have significantly higher fasting glucose, 1-hour glucose and 2-hour glucose levels than lean children, and they had similar levels to those of children with obesity, although HbA1c levels were comparable among the three groups.
Children born SGA given GH therapy also had significantly higher insulin AUC and lower Matsuda index values than lean children, as well as a higher rate of pathological HOMA-IR, a finding that was also noted for children with obesity.
Findings were comparable between children born SGA who had received GH therapy and those who spontaneously achieved catch-up growth, although there was a trend towards lower insulin resistance in the former.
Using the American Diabetes Association diagnosis of diabetes as pathological values for at least two out of glycated haemoglobin, insulin resistance and impaired glucose tolerance, the highest prevalence of prediabetes occurred in children born SGA during GH therapy, at 11.1% versus 3.1% of age- and sex-matched children with obesity. However, this reversed after GH therapy was discontinued (4.7 vs 6.4%). None of the children developed overt diabetes, defined as two or more simultaneous measurements in the diabetic range, the researchers observe.
Metabolic monitoring advised
“We recommend that children born SGA treated with GH should receive similar metabolic monitoring as children with obesity, which may comprise annual measures of HbA1c, fasting glucose, fasting insulin, and lipid status”, Körner et al conclude.
“In cases with elevated fasting indices or additional risk factors (such as overweight or obesity, family history of diabetes, ethnicity at risk for diabetes, acanthosis nigricans) we recommend using OGTT”, they continue.
The team also recommends that SGA patients who develop insulin resistance or prediabetes during GH therapy should receive similar lifestyle interventions as those given to children with obesity, such as diet and physical exercise, and, where needed, insulin-sensitising agents such as metformin, adding that “lowering the dose of GH should be considered first before initiating further pharmacotherapy.”
By Lynda Williams
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