Tacrolimus‐Induced Diabetes in Rats Courses with Suppressed Insulin Gene Expression in Pancreatic Islets

• Published in: American journal of transplantation Vol. 7; no. 11; pp. 2455 - 2462
• Main Authors: Hernández‐Fisac, I., Pizarro‐Delgado, J., Calle, C., Marques, M., Sánchez, A., Barrientos, A., Tamarit‐Rodriguez, J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2007; Blackwell
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Body Weight; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - genetics; Diabetes. Impaired glucose tolerance; Disease Models, Animal; DNA - analysis; DNA - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation; Insulin - genetics; Insulin - metabolism; Insulin genes; Insulin Secretion; Islets of Langerhans - metabolism; Islets of Langerhans - physiopathology; Male; Medical sciences; pancreatic islets; Pharmacology. Drug treatments; post‐transplant diabetes; Rats; Rats, Wistar; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; tacrolimus; Tacrolimus - toxicity; Endocrinopathy; Pancreatic hormone; Calcineurin inhibitor; Rat; Gene; Genetics; Protein synthesis inhibitor; Endocrine pancreas; Postoperative; Diabetes mellitus; Rodentia; Langerhans islet; post- transplant diabetes; Lactone; Gene expression; Macrolide; Insulin; Immunomodulator; Vertebrata; Mammalia; Tacrolimus; Insulin genes; Animal; Immunosuppressive agent; Antibacterial agent; pancreatic islets
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2007.01946.x

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. Insulin and pro‐insulin mRNAs, as well as the secretory response to glucose were decreased in islets isolated from rats treated daily with tacrolimus.