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

  • Stefano Benedini
  • Federica Ermetici
  • Silvia Briganti
  • Roberto Codella
  • Ileana Terruzzi
  • Paola Maffi
  • Rossana Caldara
  • Antonio Secchi
  • Rita Nano
  • Lorenzo Piemonti
  • Rodolfo Alejandro
  • Camillo Ricordi
  • Livio Luzi
Original Article

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

Pancreatic islet allotransplantation Insulin sensitivity C-peptide Euglycemic hyperinsulinemic clamp mTOR 

Abbreviations

BMI

Body mass index

DIR

Daily insulin requirement

GCMS

Gas chromatography–mass spectrometry

IL-2

Interleukin-2

ITx

Islet transplantation

mTOR

The mechanistic target of rapamycin

mTORC

mTOR complex

SD

Standard deviation

SE

Standard error

SUITO

Secretory Unit of Islet Transplantation Objects

T1DM

Type 1 diabetes mellitus

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

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Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Stefano Benedini
    • 1
    • 2
  • Federica Ermetici
    • 1
  • Silvia Briganti
    • 1
  • Roberto Codella
    • 2
  • Ileana Terruzzi
    • 3
  • Paola Maffi
    • 4
  • Rossana Caldara
    • 4
  • Antonio Secchi
    • 4
    • 6
  • Rita Nano
    • 4
  • Lorenzo Piemonti
    • 4
    • 6
  • Rodolfo Alejandro
    • 5
  • Camillo Ricordi
    • 5
  • Livio Luzi
    • 1
    • 2
  1. 1.Endocrinology and MetabolismIRCCS Policlinico San DonatoSan Donato Milanese (Milan)Italy
  2. 2.Department of Biomedical Sciences for HealthUniversità degli Studi di MilanoMilanItaly
  3. 3.Diabetes Research Institute, Metabolism, Nutrigenomics and Cellular Differentiation UnitSan Raffaele Scientific InstituteMilanItaly
  4. 4.Department of Internal Medicine, Transplant Medicine UnitSan Raffaele Scientific InstituteMilanItaly
  5. 5.Diabetes Research InstituteUniversity of Miami Miller School of MedicineMiamiUSA
  6. 6.Vita Salute San Raffaele UniversityMilanItaly

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