Tacrolimus-induced Diabetes in Rats Courses With Suppressed Insulin Gene Expression in Pancreatic Islets

Am J Transplant. 2007 Nov;7(11):2455-62. doi: 10.1111/j.1600-6143.2007.01946.x. Epub 2007 Aug 24.

Abstract

An animal model of post-transplant diabetes was induced in rats by treating them daily with 0.1 mg/kg body weight of tacrolimus (FK506) in two i.p. injections. Rats developed hyperglycaemia and glucose intolerance after 9 days of treatment. Pancreatic islets, isolated from treated rats on different days, showed a decreased capacity to secrete insulin in response to 20 mM glucose at days 7 and 14. This suppression of insulin secretion was preceded by a reduction of the islet insulin content on day 5 that was progressively decreasing until the end of the treatment (day 14). Islet content of insulin mRNAs, transcribed from rat insulin genes 1 and 2, was strongly suppressed, similar to the insulin content, at days 7 and 14. Islet mass was not strikingly modified by tacrolimus treatment: the DNA content was slightly decreased at the end (day 14) and the rate of islet cell apoptosis slightly increased. Tacrolimus-induced diabetes in the rat seems to be mainly provoked by a decreased insulin gene transcription with little or no alteration of islet mass. This explains that the observed suppression of all the islet and animal parameters studied was completely reversed 2 weeks after interrupting tacrolimus treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • DNA / analysis
  • DNA / genetics
  • Diabetes Mellitus, Experimental / etiology*
  • Diabetes Mellitus, Experimental / genetics
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Insulin / genetics*
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiopathology*
  • Male
  • Rats
  • Rats, Wistar
  • Tacrolimus / toxicity*

Substances

  • Insulin
  • DNA
  • Tacrolimus