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01-07-2018 | Original Article

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

Authors: 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

Published in: Acta Diabetologica | Issue 7/2018

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.

Shapiro AM, Pokrywczynska M, Ricordi C (2017) Clinical pancreatic islet transplantation. Nat Rev Endocrinol 13:268–277CrossRefPubMed

Codella R, Adamo M, Maffi P, Piemonti L, Secchi A, Luzi L (2017) Ultra-marathon 100 km in an islet-transplanted runner. Acta Diabetol 54:703–706CrossRefPubMed

Pellegrini S, Cantarelli E, Sordi V, Nano R, Piemonti L (2016) The state of the art of islet transplantation and cell therapy in type 1 diabetes. Acta Diabetol 53:683–691CrossRefPubMed

Fiorina P, Folli F, Bertuzzi F et al (2003) Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. Diabetes Care 26(4):1129–1136CrossRefPubMed

Fiorina P, Folli F, Maffi P et al (2003) Islet transplantation improves vascular diabetic complications in patients with diabetes who underwent kidney transplantation: a comparison between kidney-pancreas and kidney-alone transplantation. Transplantation 75(8):1296–1301CrossRefPubMed

Shapiro AM, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238CrossRefPubMed

Benedini S, Ruffini E, Terruzzi I, Mancuso M, Luzi L (2008) Glucose and leucine metabolism in lung transplanted patients on low dose of steroids for immunosuppressive therapy. Transplant Proc 40:1566–1571CrossRefPubMed

Shapiro AM, Ricordi C, Hering BJ et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330CrossRefPubMed

Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15:155–162CrossRefPubMed

10.

Um SH, D’Alessio D, Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3:393–402CrossRefPubMed

11.

Shigeyama Y, Kobayashi T, Kido Y et al (2008) Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol 28:2971–2979CrossRefPubMedPubMedCentral

12.

Yu Y, Yoon SO, Poulogiannis G et al (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332:1322–1326CrossRefPubMedPubMedCentral

13.

Hsu PP, Kang SA, Rameseder J et al (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–1322CrossRefPubMedPubMedCentral

14.

Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293CrossRefPubMedPubMedCentral

15.

Luzi L, Hering BJ, Socci C et al (1996) Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus. J Clin Invest 97:2611–2618CrossRefPubMedPubMedCentral

16.

Takita M, Matusmoto S (2012) SUITO index for evaluation of clinical islet transplantation. Cell Transplant 21:1341–1347CrossRefPubMedPubMedCentral

17.

Benedini S, Fiocchi R, Battezzati A et al (2002) Energy metabolism in diabetic and nondiabetic heart transplant recipients. Diabetes Care 25:530–536CrossRefPubMed

18.

Steele R (1959) Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 82:420–430CrossRefPubMed

19.

Collaborative Islet Transplant Registry. Eighth annual report. CITR 2014 www.citregistry.org. Accessed 8 Dec 2016

20.

D’Addio F, Maffi P, Vezzulli P et al (2014) Islet transplantation stabilizes hemostatic abnormalities and cerebral metabolism in individuals with type 1 diabetes. Diabetes Care 37(1):267–276CrossRefPubMed

21.

Fiorina P, Gremizzi C, Maffi P et al (2005) Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients. Diabetes Care 28(6):1358–1365CrossRefPubMed

22.

Matsumoto S, Takita M, Chaussabel D et al (2011) Improving efficacy of clinical islet transplantation with iodixanol-based islet purification, thymoglobulin induction, and blockage of IL-1β and TNF-α. Cell Transplant 20:1641–1647CrossRefPubMed

23.

Citro A, Cantarelli E, Maffi P et al (2012) CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. J Clin Invest 122:3647–3651CrossRefPubMedPubMedCentral

24.

Rachdi L, Balcazar N, Osorio-Duque F et al (2008) Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc Natl Acad Sci USA 105:9250–9255CrossRefPubMedPubMedCentral

25.

Pende M, Kozma SC, Jaquet M et al (2000) Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 408:994–997CrossRefPubMed

26.

Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA (2011) Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 60:827–837CrossRefPubMedPubMedCentral

27.

Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor/mTOR complex. Science 307:1098–1101CrossRefPubMed

28.

Lamming DW, Ye L, Katajisto P et al (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:1638–1643CrossRefPubMedPubMedCentral

29.

Li J, Kim SG, Blenis J (2014) Rapamycin: one drug, many effects. Cell Metab 19:373–379CrossRefPubMedPubMedCentral

30.

Krebs M, Brunmair B, Brehm A et al (2007) The mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 56:1600–1607CrossRefPubMed

31.

Fraenkel M, Ketzinel-Gilad M, Ariav Y et al (2008) mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57:945–957CrossRefPubMed

32.

Houde VP, Brule S, Festuccia WT et al (2010) Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59:1338–1348CrossRefPubMedPubMedCentral

33.

Johnston O, Rose CL, Webster AC, Gill JS (2008) Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 19:1411–1418CrossRefPubMedPubMedCentral

34.

Piemonti L, Maffi P, Monti L et al (2011) Beta cell function during rapamycin monotherapy in long-term type 1 diabetes. Diabetologia 54:433–439CrossRefPubMed

Title: Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation
Authors: 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
Publication date: 01-07-2018
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 7/2018
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-018-1141-z

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

Abstract

Background

Aims

Methods

Results

Conclusions

Clinical Trial

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Abstract

Background

Aims

Methods

Results

Conclusions

Clinical Trial

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