Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation

Acta Diabetol. 2018 Jul;55(7):715-722. doi: 10.1007/s00592-018-1141-z. Epub 2018 Apr 13.

Abstract

Background: The immunosuppressive drug rapamycin may influence insulin sensitivity in insulin-responsive tissues.

Aims: This study aimed at evaluating the effectiveness of rapamycin pre-treatment before pancreatic islet allotransplantation (ITx) in patients with type 1 diabetes mellitus (T1DM).

Methods: Forty-one T1DM patients were studied. Thirteen patients with poor glycemic control underwent a short-term rapamycin treatment before ITx (Group 1), and they were compared to 28 patients undergoing ITx without rapamycin pre-treatment (Group 2). Outcomes were daily insulin requirement (DIR), fasting blood glucose, HbA1c, C-peptide and the SUITO index of beta-cell function. A subgroup of patients pre-treated with rapamycin before ITx underwent euglycemic hyperinsulinemic clamp with [6,6-2H2] glucose before and after ITx to evaluate insulin sensitivity.

Results: We found a significant reduction in DIR after rapamycin pre-treatment (- 8 ± 6 U/day, mean ± SD, p < 0.001) and 1 year after ITx. DIR reduction 1 year after ITx was greater in Group 1 as compared to Group 2 (- 37 ± 15 vs. - 19 ± 13 U/day, p = 0.005) and remained significant after adjusting for gender, age, glucose and baseline HbA1c (beta = 18.2 ± 5.9, p = 0.006). Fasting glucose and HbA1c significantly decreased 1 year after ITx in Group 1 (HbA1c: - 2.1 ± 1.4%, p = 0.002), while fasting C-peptide (+0.5 ± 0.3 nmol/l, p = 0.002) and SUITO index increased (+57.4 ± 39.7, p = 0.016), without differences between the two groups. Hepatic glucose production decreased after rapamycin pre-treatment (- 1.1 ± 1.1 mg/kg/min, p = 0.04) and after ITx (- 1.6 ± 0.6 mg/kg/min, p = 0.015), while no changes in peripheral glucose disposal were observed.

Conclusions: Rapamycin pre-treatment before ITx succeeds in reducing insulin requirement, enhancing hepatic insulin sensitivity. This treatment may improve short-term ITx outcomes, possibly in selected patients with T1DM complicated by insulin resistance.

Clinical trial: Clinicaltrials.gov NCT01060605; NCT00014911.

Keywords: C-peptide; Euglycemic hyperinsulinemic clamp; Insulin sensitivity; Pancreatic islet allotransplantation; mTOR.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / surgery*
  • Drug Administration Schedule
  • Female
  • Humans
  • Insulin / therapeutic use*
  • Islets of Langerhans Transplantation*
  • Male
  • Middle Aged
  • Sirolimus / administration & dosage*
  • Time Factors
  • Transplantation Conditioning / methods*
  • Treatment Outcome
  • Young Adult

Substances

  • Blood Glucose
  • Insulin
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT01060605
  • ClinicalTrials.gov/NCT00014911