Restoring Insulin Secretion (RISE): design of studies of β-cell preservation in prediabetes and early type 2 diabetes across the life span

Abstract

Objective: The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.

Research design and methods: β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95-125 mg/dL (5.3-6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c 5.8-7.0% (40-53 mmol/mol), and BMI 25-40 kg/m(2). Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30-40 kg/m(2), HbA1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m(2), 10-19 years of age, and diabetes <6 months.

Results: Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.

Conclusions: RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01763346 NCT01779362 NCT01779375.

Figure 1

Time lines for screening, run-in, treatment, and washout for RISE protocols involving medications in adults and children (A) and surgery in adults (B).