Abstract

BACKGROUND. Tacrolimus-sirolimus immunosuppression has improved islet graft survival but may affect islet function. METHODS. We studied the effects of tacrolimus, sirolimus, or both in normal adult male Sprague Dawley rats. Glucose and insulin response to oral glucose load and pancreas pathology were evaluated after two weeks of daily tacrolimus (1-8 mg/kg/day), sirolimus (0.08-8 mg/kg/day), or low-dose sirolimus (0.08 mg/kg/day) plus tacrolimus (1 mg/kg/day) treatment compared to controls. RESULTS. Tacrolimus and sirolimus each caused dose-dependent hyperglycemia with hyperinsulinemia in response to oral glucose compared to controls, suggesting insulin resistance. At the highest doses of sirolimus, fasting insulin concentrations were high and did not increase with oral glucose suggesting loss of first phase insulin release. The combination of low doses of tacrolimus and sirolimus, at concentrations used in clinical transplantation, resulted in hyperglycemia without hyperinsulinemia after oral glucose administration. The combination of tacrolimus and sirolimus decreased islet size, and increased islet apoptosis more than either medication alone, or controls. CONCLUSIONS. In summary, short-term therapy with either tacrolimus or sirolimus causes insulin resistance in normal rats. Combination tacrolimus-sirolimus causes greater islet changes suggesting early islet failure.

Original languageEnglish (US)
Pages (from-to)466-470
Number of pages5
JournalTransplantation
Volume82
Issue number4
DOIs
StatePublished - Aug 1 2006

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Tacrolimus
Sirolimus
Sprague Dawley Rats
Insulin Resistance
Glucose
Hyperinsulinism
Insulin
Hyperglycemia
Graft Survival
Immunosuppression
Oral Administration
Pancreas
Fasting
Transplantation
Apoptosis
Pathology

Keywords

  • Insulin resistance
  • Sirolimus
  • Tacrolimus

ASJC Scopus subject areas

  • Transplantation

Cite this

Tacrolimus and sirolimus cause insulin resistance in normal Sprague Dawley rats. / Larsen, Jennifer Lynn; Bennett, Robert G; Burkman, Tab; Ramirez, Ana Lisa; Yamamoto, Sakura; Gulizia, James; Radio, Stanley J; Hamel, Frederick G.

In: Transplantation, Vol. 82, No. 4, 01.08.2006, p. 466-470.

Research output: Contribution to journalArticle

Larsen, Jennifer Lynn ; Bennett, Robert G ; Burkman, Tab ; Ramirez, Ana Lisa ; Yamamoto, Sakura ; Gulizia, James ; Radio, Stanley J ; Hamel, Frederick G. / Tacrolimus and sirolimus cause insulin resistance in normal Sprague Dawley rats. In: Transplantation. 2006 ; Vol. 82, No. 4. pp. 466-470.
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AU - Radio, Stanley J

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