The increase in the prevalence of obesity has contributed to the increased incidence of prediabetes and type 2 diabetes among youth and adults. Progressive β-cell function decline plays a pivotal role in the progression from normal to abnormal glucose tolerance, both in children and in adults.

The Restoring Insulin Secretion (RISE) study sought to test interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes. It was composed of three proof-of-principle randomized clinical trials, two of which are comparing medications:

1. a pediatric medication study (10-19 years), and

2. an adult medication study (20-65 years).

3. An adult study compared surgical vs. medical intervention known as the Adult Surgery (or BetaFat) study (22-65 years).

While the pediatric medication study has now been completed, the remaining two are expected to be completed in 2019. All studies included participants with IGT or recently diagnosed type 2 diabetes. The two medication studies sought to determine if ß-cell function could be preserved or improved in the 12 months during active treatment and three months after the withdrawal of therapy.¹ The last study sought to determine if ß-cell function could be preserved or improved in the 24 months following laparoscopic banding weight loss surgery.¹ The two coprimary outcomes selected for measuring the different components of ß-cell function included the 2nd phase, mean steady-state C-peptide response (measured at steady-state of the hyperglycemic clamp at ~200 mg/dl at 100 through 120 minutes of glucose infusion, and adjusted for insulin sensitivity measured at the same time), and the arginine-induced acute C-peptide response (ACPRmax) at maximal glycemic potentiation (i.e., at glucose >450 mg/dL also adjusted for insulin sensitivity, as a measure of β-cell secretory capacity).¹

For study medications, pediatric participants were allowed to be on metformin or glargine, whereas adult participants were drug naïve to diabetes medications. Exclusion criteria were minimal and excluded only participants with medical conditions unlikely to finish the trial. The pediatric medication protocol compared metformin (up to 1,000mg twice daily) taken for 12 months with insulin glargine used for 3 months followed by only metformin for 9 months. The adult medication protocol was a partially blinded clinical trial comparing metformin (up to 1,000mg twice daily) for 12 months, insulin glargine for 3 months followed by metformin for 9 months, the combination of liraglutide (up to 1.8 mg/day) and metformin for 12 months, or placebo for 12 months. Lastly, the adult surgery protocol was a randomized, unblinded, clinical trial comparing metformin (up to 1,000mg twice daily) for 24 months with laparascopic banding (within 4 weeks of randomization).¹ A total of 91, 267, and 88 patients were randomized to the pediatric study, adult study, and adult surgical study, respectively.

Overall retention, medication adherence and hyperglycemic clamp quality and reproducibility over time were excellent.

Primary ß-cell function showed a decline in insulin sensitivity in both treatment arms at both the 12- and 15-month time points for both steady-state C-peptide response and ACPRmax. The pattern of β-cell function loss was identical in youth with IGT.² Neither treatment arm showed any improvement while on study medication.

Results from the RISE pediatric study have demonstrated that insulin resistance and β-cell dysfunction in obese youth with IGT or early type 2 diabetes are unresponsive to metformin alone or glargine followed by metformin. Three months after the withdrawal of medication, β-cell dysfunction progressed and was worse than at baseline. These findings contrast with the previous studies completed in adults which demonstrate an improvement in β-cell function with metformin or insulin for diabetes prevention. As a consequence, the early treatment of children with IGT or type 2 diabetes may require other medications alone or in combination to combat insulin resistance and stall progressive loss β-cell function. Therefore, the results of the RISE Pediatric Medication Study call for further studies to identify safe and effective treatment options.