The effects of maintenance doses of FK506 versus cyclosporin a on glucose and lipid metabolism after orthotopic liver transplantation

Luis A. Fernandez, Roger Lehmann, Livio Luzi, Alberto Battezzati, Maria C. Angelico, Camillo Ricordi, Andreas Tzakis, Rodolfo Alejandro

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Abstract

Background. Posttransplant diabetes mellitus (PTDM) has gained widespread attention due to the micro and macro-vascular complications that increase the morbidity and mortality of patients receiving solid organs. The higher incidence of PTDM has been mainly attributed to the immunosuppressive therapy. Therefore, this study compares the metabolic side effects of low dose maintenance therapy of FK-506 and Cyclosporin A (CsA) in 14 patients 1 year after orthotopic liver transplant and analyzes possible factors that contribute to the development of PTDM. Methods. Two groups (n=7) differing in their immunosuppressive regimen (FK506 or CsA) were matched to eight control subjects and compared to each other. The effects of in vivo insulin action were assessed by means of the euglycemic hyperinsulinemic clamp technique. Arginine stimulation tests at normo- (5.5 mM) and hyperglycemic (15 mM) levels were performed and the acute insulin, C-peptide and glucagon response (2-5 min) to arginine were determined. Results. Insulin sensitivity (total glucose disposal) was statistically lower in patients treated with FK-506 and CsA (5.05±0.47 and 5.05±0.42 mg/kg/min) as compared to controls (6.62±0.38 mg/kg/min) (P<0.02), with a significantly higher nonoxidative glucose disposal for the control group (P<0.01), and lower free fatty acid levels (P<0.05). Absolute values for acute insulin response were higher but not significantly different for the transplanted groups. The lower percentage of increase of insulin release after arginine stimulation observed in the FK-506 and CsA groups as compared with controls (754%±100, 644%±102 vs. 1191%±174) (P<0.03 and 0.02, respectively), suggests a reduced β cell secretory reserve in both treated groups. Also, the acute glucagon response to arginine during hyperglycemia declined less in the FK-506 (28%) and CsA groups (29%) compared with controls (48%) (P<0.05) indicating a defect in the pancreatic β cell-α cell axis. Conclusions. There are no major metabolic differences on low maintenance doses between FK-506 and CsA. Both immunosuppressant agents contribute to the development of PTDM at different levels.

Original languageEnglish
Pages (from-to)1532-1541
Number of pages10
JournalTransplantation
Volume68
Issue number10
StatePublished - Nov 27 1999

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Tacrolimus
Lipid Metabolism
Liver Transplantation
Cyclosporine
Glucose
Arginine
Diabetes Mellitus
Immunosuppressive Agents
Insulin
Glucagon
Glucose Clamp Technique
C-Peptide
Nonesterified Fatty Acids
Hyperglycemia
Statistical Factor Analysis
Blood Vessels
Insulin Resistance
Morbidity
Transplants
Control Groups

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

The effects of maintenance doses of FK506 versus cyclosporin a on glucose and lipid metabolism after orthotopic liver transplantation. / Fernandez, Luis A.; Lehmann, Roger; Luzi, Livio; Battezzati, Alberto; Angelico, Maria C.; Ricordi, Camillo; Tzakis, Andreas; Alejandro, Rodolfo.

In: Transplantation, Vol. 68, No. 10, 27.11.1999, p. 1532-1541.

Research output: Contribution to journalArticle

Fernandez, LA, Lehmann, R, Luzi, L, Battezzati, A, Angelico, MC, Ricordi, C, Tzakis, A & Alejandro, R 1999, 'The effects of maintenance doses of FK506 versus cyclosporin a on glucose and lipid metabolism after orthotopic liver transplantation', Transplantation, vol. 68, no. 10, pp. 1532-1541.
Fernandez, Luis A. ; Lehmann, Roger ; Luzi, Livio ; Battezzati, Alberto ; Angelico, Maria C. ; Ricordi, Camillo ; Tzakis, Andreas ; Alejandro, Rodolfo. / The effects of maintenance doses of FK506 versus cyclosporin a on glucose and lipid metabolism after orthotopic liver transplantation. In: Transplantation. 1999 ; Vol. 68, No. 10. pp. 1532-1541.
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abstract = "Background. Posttransplant diabetes mellitus (PTDM) has gained widespread attention due to the micro and macro-vascular complications that increase the morbidity and mortality of patients receiving solid organs. The higher incidence of PTDM has been mainly attributed to the immunosuppressive therapy. Therefore, this study compares the metabolic side effects of low dose maintenance therapy of FK-506 and Cyclosporin A (CsA) in 14 patients 1 year after orthotopic liver transplant and analyzes possible factors that contribute to the development of PTDM. Methods. Two groups (n=7) differing in their immunosuppressive regimen (FK506 or CsA) were matched to eight control subjects and compared to each other. The effects of in vivo insulin action were assessed by means of the euglycemic hyperinsulinemic clamp technique. Arginine stimulation tests at normo- (5.5 mM) and hyperglycemic (15 mM) levels were performed and the acute insulin, C-peptide and glucagon response (2-5 min) to arginine were determined. Results. Insulin sensitivity (total glucose disposal) was statistically lower in patients treated with FK-506 and CsA (5.05±0.47 and 5.05±0.42 mg/kg/min) as compared to controls (6.62±0.38 mg/kg/min) (P<0.02), with a significantly higher nonoxidative glucose disposal for the control group (P<0.01), and lower free fatty acid levels (P<0.05). Absolute values for acute insulin response were higher but not significantly different for the transplanted groups. The lower percentage of increase of insulin release after arginine stimulation observed in the FK-506 and CsA groups as compared with controls (754{\%}±100, 644{\%}±102 vs. 1191{\%}±174) (P<0.03 and 0.02, respectively), suggests a reduced β cell secretory reserve in both treated groups. Also, the acute glucagon response to arginine during hyperglycemia declined less in the FK-506 (28{\%}) and CsA groups (29{\%}) compared with controls (48{\%}) (P<0.05) indicating a defect in the pancreatic β cell-α cell axis. Conclusions. There are no major metabolic differences on low maintenance doses between FK-506 and CsA. Both immunosuppressant agents contribute to the development of PTDM at different levels.",
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T1 - The effects of maintenance doses of FK506 versus cyclosporin a on glucose and lipid metabolism after orthotopic liver transplantation

AU - Fernandez, Luis A.

AU - Lehmann, Roger

AU - Luzi, Livio

AU - Battezzati, Alberto

AU - Angelico, Maria C.

AU - Ricordi, Camillo

AU - Tzakis, Andreas

AU - Alejandro, Rodolfo

PY - 1999/11/27

Y1 - 1999/11/27

N2 - Background. Posttransplant diabetes mellitus (PTDM) has gained widespread attention due to the micro and macro-vascular complications that increase the morbidity and mortality of patients receiving solid organs. The higher incidence of PTDM has been mainly attributed to the immunosuppressive therapy. Therefore, this study compares the metabolic side effects of low dose maintenance therapy of FK-506 and Cyclosporin A (CsA) in 14 patients 1 year after orthotopic liver transplant and analyzes possible factors that contribute to the development of PTDM. Methods. Two groups (n=7) differing in their immunosuppressive regimen (FK506 or CsA) were matched to eight control subjects and compared to each other. The effects of in vivo insulin action were assessed by means of the euglycemic hyperinsulinemic clamp technique. Arginine stimulation tests at normo- (5.5 mM) and hyperglycemic (15 mM) levels were performed and the acute insulin, C-peptide and glucagon response (2-5 min) to arginine were determined. Results. Insulin sensitivity (total glucose disposal) was statistically lower in patients treated with FK-506 and CsA (5.05±0.47 and 5.05±0.42 mg/kg/min) as compared to controls (6.62±0.38 mg/kg/min) (P<0.02), with a significantly higher nonoxidative glucose disposal for the control group (P<0.01), and lower free fatty acid levels (P<0.05). Absolute values for acute insulin response were higher but not significantly different for the transplanted groups. The lower percentage of increase of insulin release after arginine stimulation observed in the FK-506 and CsA groups as compared with controls (754%±100, 644%±102 vs. 1191%±174) (P<0.03 and 0.02, respectively), suggests a reduced β cell secretory reserve in both treated groups. Also, the acute glucagon response to arginine during hyperglycemia declined less in the FK-506 (28%) and CsA groups (29%) compared with controls (48%) (P<0.05) indicating a defect in the pancreatic β cell-α cell axis. Conclusions. There are no major metabolic differences on low maintenance doses between FK-506 and CsA. Both immunosuppressant agents contribute to the development of PTDM at different levels.

AB - Background. Posttransplant diabetes mellitus (PTDM) has gained widespread attention due to the micro and macro-vascular complications that increase the morbidity and mortality of patients receiving solid organs. The higher incidence of PTDM has been mainly attributed to the immunosuppressive therapy. Therefore, this study compares the metabolic side effects of low dose maintenance therapy of FK-506 and Cyclosporin A (CsA) in 14 patients 1 year after orthotopic liver transplant and analyzes possible factors that contribute to the development of PTDM. Methods. Two groups (n=7) differing in their immunosuppressive regimen (FK506 or CsA) were matched to eight control subjects and compared to each other. The effects of in vivo insulin action were assessed by means of the euglycemic hyperinsulinemic clamp technique. Arginine stimulation tests at normo- (5.5 mM) and hyperglycemic (15 mM) levels were performed and the acute insulin, C-peptide and glucagon response (2-5 min) to arginine were determined. Results. Insulin sensitivity (total glucose disposal) was statistically lower in patients treated with FK-506 and CsA (5.05±0.47 and 5.05±0.42 mg/kg/min) as compared to controls (6.62±0.38 mg/kg/min) (P<0.02), with a significantly higher nonoxidative glucose disposal for the control group (P<0.01), and lower free fatty acid levels (P<0.05). Absolute values for acute insulin response were higher but not significantly different for the transplanted groups. The lower percentage of increase of insulin release after arginine stimulation observed in the FK-506 and CsA groups as compared with controls (754%±100, 644%±102 vs. 1191%±174) (P<0.03 and 0.02, respectively), suggests a reduced β cell secretory reserve in both treated groups. Also, the acute glucagon response to arginine during hyperglycemia declined less in the FK-506 (28%) and CsA groups (29%) compared with controls (48%) (P<0.05) indicating a defect in the pancreatic β cell-α cell axis. Conclusions. There are no major metabolic differences on low maintenance doses between FK-506 and CsA. Both immunosuppressant agents contribute to the development of PTDM at different levels.

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