1. Islet transplantation increases insulin sensitivity in Type 1 diabetics, acting at both the liver and skeletal muscle.
2. Post-transplant immunosuppression with low-dose tacrolimus and sirolimus does not induce insulin resistance.
Evidence rating level: 2 (Good)
Study Rundown: Type 1 Diabetes (T1D) is characterized by frequent periods of hyperglycemia and increased free fatty acids, leading to insulin resistance. Islet transplantation corrects these deficits and therefore may restore insulin sensitivity. However, mouse studies have suggested that immunosuppression following transplant with tacrolimus and sirolimus may actually contribute to insulin resistance. Therefore, the authors of this study sought to determine whether improved metabolic control post-transplant would improve insulin sensitivity despite immunosuppression, and whether improved sensitivity would be due to effects at the liver, skeletal muscle, or both.
The results of this study suggest that islet transplantation does improve insulin sensitivity in patients with T1D. Furthermore, the authors suggest that appropriately dosed, glucocorticoid-free immunosuppression does not induce insulin resistance. These conclusion are supported by the use of euglycemic clamp technique. However, it should be noted that this study was a case control, and involved a very small sample size (12 diabetic patients). T1D subjects also lost weight after the transplant, though adjusting for BMI did not significantly reduce the positive effect of islet transplantation on insulin sensitivity.
In-Depth [controlled before-and-after study]: The authors of this study enrolled 12 T1D patients with a history of long-standing disease and severe hypoglycemia events who had received intrahepatic islet transplants. These procedures were followed by maintenance immunosuppression with low-dose tacrolimus and sirolimus. Controls included 14 healthy, non-diabetic subjects from prior and ongoing studies. The T1D subjects then underwent hyperinsulinemic, euglycemic clamps before and between 6 and 7 months post-transplant. Primary outcomes measured included serum glucose and insulin, and hepatic and skeletal muscle insulin sensitivity were calculated from these results. At the conclusion of the study, the authors found that glycosylated hemoglobin was reduced post-transplant from 7.0% to 5.6% (P < 0.01), and that total, hepatic, and peripheral insulin sensitivity increased (P < 0.05 for all). Furthermore, hepatic insulin sensitivity was less in T1D pre- than post-transplant subjects and controls (P < 0.05). The T1D subjects’ insulin requirement was also significantly reduced (P < 0.01), though basal glucose levels did not change before and after the transplant. Adjusting for BMI with a linear mixed model did not significantly affect insulin sensitivity measures.
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