medwireNews: The RISE trial investigators have found that increased insulin resistance and hyperresponsive beta cells may explain the rapid progression of type 2 diabetes in children.
However, early intervention with insulin did not preserve beta cell function in children with prediabetes or early diabetes, the team reported at the ADA’s 78th Scientific Sessions in Orlando, Florida, USA. The results are also published in Diabetes Care.
The researchers had hoped that insulin would slow the children’s beta cell function decline because of research showing that it can do so in adults, when oral antidiabetic agents cannot. Their primary outcomes therefore reflected the response of beta cells to acute and prolonged stimulation (arginine-induced acute C-peptide response at maximum glucose and steady-state C-peptide response, respectively), corrected for insulin sensitivity.
However, both of these measures worsened during 12 months of treatment. “Thus, neither group improved in their beta cell function while on active treatment,” said Kristen Nadeau (University of Colorado Anschutz Medical Campus, Aurora, USA), who presented the medication findings.
This was true for the 41 children who took 3 months of insulin glargine followed by 9 months of metformin and for the 43 who took metformin for the full 12 months. The findings were similar after an additional 3 months of medication washout.
There were also no differences between the groups to indicate that the 6 months of glargine might have helped to preserve beta cell function relative to metformin alone, and this remained the case in a separate analysis of the 54 patients with impaired glucose tolerance, who Nadeau noted might have “more room for improvement” than those with overt diabetes.
The study participants were aged an average of 14.9 and 13.9 years in the glargine and metformin groups, respectively. About 40% had diabetes, with the rest having impaired glucose tolerance, and they had an average glycated hemoglobin (HbA1c) of 5.7% and average BMI of 37 kg/m2.
The lack of effect on beta cell function was despite participants being largely adherent to medication – 68% and 86–89% of patients were more than 80% adherent to glargine and metformin, respectively – and despite both groups achieving significant HbA1c reductions.
Presenting the secondary outcomes, Silva Arslanian (Children’s Hospital of Pittsburgh, Pennsylvania, USA) noted that HbA1c rose after treatment withdrawal to become almost 0.5% higher than at baseline, consistent with progressive beta cell decline despite active treatment.
And although around 50% of the participants taking glargine achieved their blood glucose goal, by the end of follow-up they were using an average dose of around 71 U/day, which is “a relatively large amount of insulin,” said Arslanian, noting that some participants required up to 100 U/day.
The RISE study is also looking at treatment (medication or surgery) in 355 adults, the results of which are yet to be reported, but the baseline findings allowed for a direct comparison with the child participants, specifically the 66 who had not previously used metformin.
This revealed that pediatric and adult participants had similar oral glucose tolerance test profiles. However, the children had around a 50% reduction in insulin sensitivity relative to the adults, coupled with greater compensatory responses from their beta cells. Specifically, they had larger acute C-peptide responses to intravenous glucose and arginine, and larger C-peptide and insulin responses to oral glucose.
The compensatory beta cell responses were proportionally larger in the children than the adults, said Arslanian, which may help to explain why diabetes progresses so fast in children.
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