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

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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.

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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

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Funding

This work was funded by Telethon-JDRF JT01Y01.

Author information

Author notes

  1. Stefano Benedini and Federica Ermetici have contributed equally to this work.

Authors and Affiliations

  1. Endocrinology and Metabolism, IRCCS Policlinico San Donato, Via Morandi 30, 20097, San Donato Milanese (Milan), Italy

    Stefano Benedini, Federica Ermetici, Silvia Briganti & Livio Luzi

  2. Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy

    Stefano Benedini, Roberto Codella & Livio Luzi

  3. Diabetes Research Institute, Metabolism, Nutrigenomics and Cellular Differentiation Unit, San Raffaele Scientific Institute, Milan, Italy

    Ileana Terruzzi

  4. Department of Internal Medicine, Transplant Medicine Unit, San Raffaele Scientific Institute, Milan, Italy

    Paola Maffi, Rossana Caldara, Antonio Secchi, Rita Nano & Lorenzo Piemonti

  5. Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    Rodolfo Alejandro & Camillo Ricordi

  6. Vita Salute San Raffaele University, Milan, Italy

    Antonio Secchi & Lorenzo Piemonti

Authors
  1. Stefano Benedini
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  2. Federica Ermetici
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  3. Silvia Briganti
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  4. Roberto Codella
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  5. Ileana Terruzzi
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  8. Antonio Secchi
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  9. Rita Nano
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  11. Rodolfo Alejandro
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  13. Livio Luzi
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Corresponding author

Correspondence to Stefano Benedini.

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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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Managed by Massimo Porta.

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Benedini, S., Ermetici, F., Briganti, S. et al. Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation. Acta Diabetol 55, 715–722 (2018). https://doi.org/10.1007/s00592-018-1141-z

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  • DOI: https://doi.org/10.1007/s00592-018-1141-z

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