Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on β-Cell Function: Comparison of Responses In Youth And Adults

Diabetes. 2019 Aug;68(8):1670-1680. doi: 10.2337/db19-0299. Epub 2019 Jun 9.


β-Cell dysfunction is central to the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes. Compared with adults, youth have hyperresponsive β-cells and their decline in β-cell function appears to be more rapid. However, there are no direct comparisons of β-cell responses to pharmacological intervention between the two age-groups. The Restoring Insulin Secretion (RISE) Adult Medication Study and the RISE Pediatric Medication Study compared interventions to improve or preserve β-cell function. Obese youth (n = 91) and adults (n = 132) with IGT or recently diagnosed type 2 diabetes were randomized to 3 months of insulin glargine followed by 9 months of metformin, or 12 months of metformin. Hyperglycemic clamps conducted at baseline, after 12 months of medication, and 3 months after medication withdrawal assessed β-cell function as steady-state and maximal C-peptide responses adjusted for insulin sensitivity. Temporal changes in β-cell function were distinctly different. In youth, β-cell function deteriorated during treatment and after treatment withdrawal, with no differences between treatment groups. In adults, β-cell function improved during treatment, but this was not sustained after treatment withdrawal. The difference in β-cell function outcomes in response to medications in youth versus adults supports a more adverse trajectory of β-cell deterioration in youth.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Blood Glucose / drug effects
  • C-Peptide / blood
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Glucose Intolerance / drug therapy
  • Glucose Tolerance Test
  • Humans
  • Insulin Glargine / therapeutic use
  • Insulin Resistance
  • Male
  • Metformin / therapeutic use*
  • Middle Aged


  • Blood Glucose
  • C-Peptide
  • Insulin Glargine
  • Metformin

Associated data

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