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Posttransplant diabetes mellitus (PTDM) has gained widespread attention due to the micro and macro-vascular complications that increase the morbidity and mortality of patients receiving solid organs. The higher incidence of PTDM has been mainly attributed to the immunosuppressive therapy. Therefore, this study compares the metabolic side effects of low dose maintenance therapy of FK-506 and Cyclosporin A (CsA) in 14 patients 1 year after orthotopic liver transplant and analyzes possible factors that contribute to the development of PTDM.Two groups (n=7) differing in their immunosuppressive regimen (FK506 or CsA) were matched to eight control subjects and compared to each other. The effects of in vivo insulin action were assessed by means of the euglycemic hyperinsulinemic clamp technique. Arginine stimulation tests at normo- (5.5 mM) and hyperglycemic (15 mM) levels were performed and the acute insulin, C-peptide, and glucagon response (2-5 min) to arginine were determined.Insulin sensitivity (total glucose disposal) was statistically lower in patients treated with FK-506 and CsA (5.05±0.47 and 5.05±0.42 mg/kg/min) as compared to controls (6.62±0.38 mg/kg/min) (P<0.02), with a significantly higher nonoxidative glucose disposal for the control group (P<0.01), and lower free fatty acid levels (P<0.05). Absolute values for acute insulin response were higher but not significantly different for the transplanted groups. The lower percentage of increase of insulin release after arginine stimulation observed in the FK-506 and CsA groups as compared with controls (754%±100, 644%±102 vs. 1191%±174) (P<0.03 and 0.02, respectively), suggests a reduced β cell secretory reserve in both treated groups. Also, the acute glucagon response to arginine during hyperglycemia declined less in the FK-506 (28%) and CsA groups (29%) compared with controls (48%) (P<0.05) indicating a defect in the pancreatic β cell-α cell axis.There are no major metabolic differences on low maintenance doses between FK-506 and CsA. Both immunosuppressant agents contribute to the development of PTDM at different levels.