Effects of Cyclosporine and Sirolimus on Insulin-Stimulated Glucose Transport and Glucose Tolerance in a Rat Model

• Cyclosporine (CsA) and sirolimus (SRL) have been associated with undesirable side effects, including posttransplantation diabetes and hyperlipidemia, but the molecular mechanisms underlying these effects remain to be elucidated. Animal studies focusing on clinically relevant doses are advised. This study sought to compare the metabolic effects on isolated rat adipocytes treated with either CsA or SRL ex vivo and after long-term in vivo treatment in Wistar rats. We assessed the ex vivo effects of CsA (0.5–30 μmol/L) and SRL (1–250 μmol/L) on insulin-stimulated 14C-glucose uptake in epididymal adipocytes (n = 6–9). In parallel, rats (n = 12) were treated with either vehicle, CsA (5 mg/kg/d) or SRL (1 mg/kg/d) for either 3 or 9 weeks. At the end of the treatment, glucose tolerance test (GTT) and insulin-stimulated 14C-glucose uptake as well as biochemical parameters were analyzed. A significant reduction in the insulin-stimulated glucose uptake over basal was observed among isolated adipocytes, whether exposed ex vivo or in vivo to CsA or SRL treatment. Furthermore, the SRL group showed significantly lighter fat pads and smaller adipocytes at 3 weeks with a smaller gain in body weight throughout the study compared with either the vehicle or CsA cohorts. Glucose intolerance was observed after a GTT, at the end of the treatment with either drug. Additionally, at 9 weeks serum triglycerides were increased by CsA compared with vehicle or SRL treatment. Interestingly, although SRL-treated animals presented higher fed and fasted insulin levels compared with either group, suggesting insulin resistance, the CsA group presented lower fed and fasted insulin values, suggesting a defect in insulin secretion at 9 weeks. These results suggested that either ex vivo treatment of fat cells or in vivo treatment of rats with CsA or SRL impaired insulin-stimulated glucose uptake by adipocytes. Both drugs caused glucose intolerance, which altogether could be responsible for the development of posttransplantation diabetes. The introduction of calcineurin inhibitors, like cyclosporine (CsA), has been important to save lives and improve the safety of organ transplantations. However, the use of these drugs is followed by the emergence of a number of side effects that impact the patient's quality of life. One of the most important is new-onset diabetes mellitus after transplantation (NODAT),1, 2 and 3 which is usually associated with an increased risk of cardiovascular diseases and consequently decreased patient survival.3, 4 and 5 CsA, a peptide of fungal origin, CsA, forms a complex with cyclophilins, which then inhibits calcineurin, preventing the movement of transcription factors into the nucleus, thus blocking interleukin (IL)-2 production and, consequently, proliferation and differentiation of T cells.6 and 7 Studies on purified islets and insulin-producing beta cells have proposed various diabetogenic actions of CsA. Therefore, CsA decreases insulin content of the beta cell, reversibly inhibiting insulin gene transcription and ultimately insulin secretion,8 although the mechanisms that lead to these effects are not well understood.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

hmg-coa reductase

renal-transplantation

immunosuppressive agents

calcineurin inhibitors

kidney-transplantation

mtor inhibition

adipose-tissue

rapamycin

tacrolimus

resistance

land

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)