Differential loss of β-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study

Diabetes Res Clin Pract. 2021 Aug;178:108948. doi: 10.1016/j.diabres.2021.108948. Epub 2021 Jul 15.


Aims: To compare OGTT-derived estimates of β-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE.

Methods: Youth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and β-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm.

Results: After treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, β-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, β-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline β-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms.

Conclusions: After treatment withdrawal youth demonstrated progressive decline in β-cell function after stopping treatment with either G/M or MET. In contrast, β-cell function in adults remained stable despite an increase in HbA1c over time. ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.

Keywords: Impaired glucose tolerance; Insulin secretion; Metformin; Type 2 diabetes; Youth; β-cell function.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Blood Glucose
  • Diabetes Mellitus, Type 2* / drug therapy
  • Glucose Intolerance*
  • Glucose Tolerance Test
  • Humans
  • Insulin / metabolism
  • Insulin Resistance*
  • Insulin Secretion


  • Blood Glucose
  • Insulin

Associated data

  • ClinicalTrials.gov/NCT01779375
  • ClinicalTrials.gov/NCT01779362