Tacrolimus-induced diabetes in rats courses with suppressed insulin gene expression in pancreatic islets.
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.
Hernández-Fisac
I
I
Biochemistry Department, Medical School, Complutense University, Madrid-28040, Spain.
Pizarro-Delgado
J
J
Calle
C
C
Marques
M
M
Sánchez
A
A
Barrientos
A
A
Tamarit-Rodriguez
J
J
D000818:Animals; D001835:Body Weight; D004247:DNA / Q000032:analysis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000633:toxicity*
D007328:Insulin; D004247:DNA; D016559:Tacrolimus