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

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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.

Original languageEnglish
Pages (from-to)715-722
Number of pages8
JournalActa Diabetologica
Volume55
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

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Keywords

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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