Normalization of insulin sensitivity and glucose homeostasis in type I diabetic pancreas transplant recipients: a 48-month cross-sectional study--a clinical research center study

Despite the establishment of heterotopic, whole cadaveric, pancreas-kidney transplantation as an effective form of therapy for type I diabetes with chronic renal insufficiency, uncertainty remains regarding the potentially deleterious effects of severe peripheral hyperinsulinemia and long-term immunosuppressive therapy on insulin sensitivity (SI) and, subsequently, on beta-cell function and maintenance of euglycemia over years. To examine the alterations in SI that may occur over time and their impact on glucose homeostasis, beta-cell function, SI, and glucose effectiveness (SG) were measured using the frequently sampled iv glucose tolerance test (FSIGTT) and minimal model method in 39 glucose-tolerant type I diabetic pancreas-kidney transplant recipients in a cross-sectional manner at 3, 6, 12, 24, 36, and 48 months post transplantation. Mean basal and poststimulation (oral glucose tolerance test and FSIGTT) serum glucose responses were similar among the groups from 3-48 months. Plasma insulin response during the FSIGTT was higher (P < 0.001, repeated measures ANOVA) at 6 months vs. 12-48 months. Incremental integrated areas under the curve for 1st phase, glucose-stimulated, tolbutamide-stimulated, and total insulin responses tended to be higher (P = NS) at 6 months. Glucose disappearance rate constant, kG, did not differ significantly from 3-48 months. Mean +/- SE S1 in the pancreas-kidney recipients was 4.25 +/- 1.6 x 10(-4) min-1/microU.mL-1 at 3 months (group 1, n = 7) (vs. 7.9 +/- 0.9 x 10(-4) normal reference), decreased to 2.95 +/- 0.6 at 6 months (group 2, n = 11), improved to baseline values of 4.6 +/- 1.0 at 12 months (group 3, n = 10), and normalized at 24 months (group 4, n = 6) to 7.5 +/- 1.7 (P = 0.008). The normalisation in SI was sustained at 36 months (group 5, n = 3, 8.0 +/- 3.7, P = 0.03), and up to 48 months (group 6, n = 5, 6.1 +/- 1.6, P = 0.04) in the type I diabetic pancrease allograft recipients. Corresponding SG tended to increase but did not differ significantly from 3 (1.69 +/- 0.2 x 10(-2)/min), 6 (2.33 +/- 0.39), 12 (1.9 +/- 0.2), 24 (1.9 +/- 0.4), 36 (1.98 +/- 0.15), and 48 months (2.27 +/- 0.3). Hepatic insulin extraction did not differ among the groups. SI correlated significantly with prednisone dose (r = -0.45, P = 0.002). In summary, after successful whole cadaveric, heterotopic, pancreas-kidney transplantation in type I diabetic recipients: 1) euglycemia remains relatively stable over 48 months; 2) SI is diminished early after transplantation (3-6 months), possibly caused by the effects of initially high doses of prednisone and hyperinsulinemia. However, this is compensated by a normal SG and by hyperinsulinemia to maintain euglycemia; 3) SI improves by 12 months and normalizes from 24-48 months, after transplantation, despite hyperinsulinemia and long-term immunosuppressive therapy. The time-dependent decrease in poststimulation insulin response after successful pancreas-kidney transplantation in type I diabetic recipients, therefore, is not caused by gradual beta-cell decline but rather is a response to normalization of SI. However, longitudinal studies pre-and post pancreas transplantation over an extended period of time will be necessary to confirm the present findings.