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

S Benedini, F Ermetici, S Briganti, R Codella, I Terruzzi, P Maffi, R Caldara, A Secchi, R Nano, L Piemonti, R Alejandro, C Ricordi, L Luzi

Research output: Contribution to journalArticle

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- 2 H 2 ] 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. © 2018 Springer-Verlag Italia S.r.l., part of Springer Nature
Original languageEnglish
Pages (from-to)715-722
Number of pages8
JournalActa Diabetologica
Volume55
Issue number7
DOIs
Publication statusPublished - 2018

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Islets of Langerhans Transplantation
Sirolimus
Insulin
Insulin Resistance
Glucose
Type 1 Diabetes Mellitus
Fasting
C-Peptide
Therapeutics
Glucose Clamp Technique
Liver
Immunosuppressive Agents
Islets of Langerhans
Blood Glucose
pre-rapamycin
Clinical Trials
Pharmaceutical Preparations

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Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation. / Benedini, S; Ermetici, F; Briganti, S; Codella, R; Terruzzi, I; Maffi, P; Caldara, R; Secchi, A; Nano, R; Piemonti, L; Alejandro, R; Ricordi, C; Luzi, L.

In: Acta Diabetologica, Vol. 55, No. 7, 2018, p. 715-722.

Research output: Contribution to journalArticle

Benedini, S ; Ermetici, F ; Briganti, S ; Codella, R ; Terruzzi, I ; Maffi, P ; Caldara, R ; Secchi, A ; Nano, R ; Piemonti, L ; Alejandro, R ; Ricordi, C ; Luzi, L. / Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation. In: Acta Diabetologica. 2018 ; Vol. 55, No. 7. pp. 715-722.
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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- 2 H 2 ] 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. {\circledC} 2018 Springer-Verlag Italia S.r.l., part of Springer Nature",
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AU - Benedini, S

AU - Ermetici, F

AU - Briganti, S

AU - Codella, R

AU - Terruzzi, I

AU - Maffi, P

AU - Caldara, R

AU - Secchi, A

AU - Nano, R

AU - Piemonti, L

AU - Alejandro, R

AU - Ricordi, C

AU - Luzi, L

PY - 2018

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N2 - 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- 2 H 2 ] 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. © 2018 Springer-Verlag Italia S.r.l., part of Springer Nature

AB - 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- 2 H 2 ] 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. © 2018 Springer-Verlag Italia S.r.l., part of Springer Nature

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