Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes

Diabetes Care. 2019 Sep;42(9):1742-1751. doi: 10.2337/dc19-0556. Epub 2019 Jun 9.


Objective: The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve β-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of <12 months duration.

Research design and methods: A total of 267 adults with IGT (n = 197, 74%) or recently diagnosed type 2 diabetes (n = 70, 26%) were studied. Participants were randomized to receive 12 months of metformin alone, 3 months of insulin glargine with a target fasting glucose <5 mmol/L followed by 9 months of metformin, 12 months of liraglutide combined with metformin, or 12 months of placebo. β-Cell function was assessed using hyperglycemic clamps at baseline, 12 months (on treatment), and 15 months (3 months off treatment). The primary outcome was β-cell function at 15 months compared with baseline.

Results: All three active treatments produced on-treatment reductions in weight and improvements in HbA1c compared with placebo; the greatest reductions were seen in the liraglutide plus metformin group. At 12 months, glucose-stimulated C-peptide responses improved in the three active treatment groups and were greatest in the liraglutide plus metformin group, but the arginine-stimulated incremental C-peptide response was reduced in the liraglutide plus metformin group. Despite on-treatment benefits, 3 months after treatment withdrawal there were no sustained improvements in β-cell function in any treatment group.

Conclusions: In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved β-cell function during active treatment failed to produce persistent benefits after treatment withdrawal. These observations suggest that continued intervention may be required to alter the progressive β-cell dysfunction in IGT or early type 2 diabetes.

Trial registration: NCT01779362.

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

  • Adult
  • Arginine
  • B-Lymphocytes / metabolism*
  • Blood Glucose / metabolism*
  • Body Weight
  • C-Peptide / blood
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Fasting / blood
  • Female
  • Glucose Intolerance / blood*
  • Glucose Intolerance / drug therapy
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Insulin Glargine / administration & dosage
  • Insulin Resistance / physiology
  • Liraglutide / administration & dosage
  • Male
  • Metformin / administration & dosage
  • Middle Aged
  • Withholding Treatment


  • Blood Glucose
  • C-Peptide
  • Hypoglycemic Agents
  • Insulin Glargine
  • Liraglutide
  • Metformin
  • Arginine

Associated data