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 language | English (US) |
|---|---|
| Pages (from-to) | 1-8 |
| Number of pages | 8 |
| Journal | Acta Diabetologica |
| DOIs | |
| State | Accepted/In press - Apr 13 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
Cite this
Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation. / Benedini, Stefano; Ermetici, Federica; Briganti, Silvia; Codella, Roberto; Terruzzi, Ileana; Maffi, Paola; Caldara, Rossana; Secchi, Antonio; Nano, Rita; Piemonti, Lorenzo; Alejandro, Rodolfo; Ricordi, Camillo; Luzi, Livio.
In: Acta Diabetologica, 13.04.2018, p. 1-8.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation
AU - Benedini, Stefano
AU - Ermetici, Federica
AU - Briganti, Silvia
AU - Codella, Roberto
AU - Terruzzi, Ileana
AU - Maffi, Paola
AU - Caldara, Rossana
AU - Secchi, Antonio
AU - Nano, Rita
AU - Piemonti, Lorenzo
AU - Alejandro, Rodolfo
AU - Ricordi, Camillo
AU - Luzi, Livio
PY - 2018/4/13
Y1 - 2018/4/13
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 [6,6-2H2] 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.
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 [6,6-2H2] 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.
KW - C-peptide
KW - Euglycemic hyperinsulinemic clamp
KW - Insulin sensitivity
KW - mTOR
KW - Pancreatic islet allotransplantation
UR - http://www.scopus.com/inward/record.url?scp=85045274246&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045274246&partnerID=8YFLogxK
U2 - 10.1007/s00592-018-1141-z
DO - 10.1007/s00592-018-1141-z
M3 - Article
C2 - 29654388
AN - SCOPUS:85045274246
SP - 1
EP - 8
JO - Acta Diabetologica
JF - Acta Diabetologica
SN - 0940-5429
ER -