Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation
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The immunosuppressive drug rapamycin may influence insulin sensitivity in insulin-responsive tissues.
This study aimed at evaluating the effectiveness of rapamycin pre-treatment before pancreatic islet allotransplantation (ITx) in patients with type 1 diabetes mellitus (T1DM).
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.
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.
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.
Clinicaltrials.gov NCT01060605; NCT00014911.
KeywordsPancreatic islet allotransplantation Insulin sensitivity C-peptide Euglycemic hyperinsulinemic clamp mTOR
Body mass index
Daily insulin requirement
Gas chromatography–mass spectrometry
The mechanistic target of rapamycin
Secretory Unit of Islet Transplantation Objects
Type 1 diabetes mellitus
This work was funded by Telethon-JDRF JT01Y01.
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.
- 19.Collaborative Islet Transplant Registry. Eighth annual report. CITR 2014 www.citregistry.org. Accessed 8 Dec 2016