Early metabolic markers of islet allograft dysfunction

Abstract

Background: Islet transplantation can restore normoglycemia to patients with unstable type 1 diabetes mellitus, but long-term insulin independence is usually not sustained. Identification of predictor(s) of islet allograft dysfunction (IGD) might allow for early intervention(s) to preserve functional islet mass.

Methods: Fourteen islet transplantation recipients with long-term history of type 1 diabetes mellitus underwent metabolic testing by mixed meal tolerance test, intravenous glucose tolerance test, and arginine stimulation test every 3 months postislet transplant completion. Metabolic responses were compared between subjects who maintained insulin independence at 18 months (group 1; n=5) and those who restarted insulin within 18 months (group 2; n=9). Data were analyzed before development of islet graft dysfunction and while insulin independent.

Results: The 90-min glucose, time-to-peak C-peptide, and area under the curve for glucose were consistently higher in group 2 and increased as a function of time. At 12 months, acute insulin release to glucose in group 2 was markedly reduced as compared with baseline (5.62+/-1.21 microIU/mL, n=4 vs. 16.14+/-3.69 microIU/mL, n=8), whereas it remained stable in group 1 (22.36+/-4.98 microIU/mL, n=5 vs. 27.70+/-2.83 microIU/mL, n=5). Acute insulin release to glucose, acute C-peptide release to glucose (ACpRg), and mixed meal stimulation index were significantly decreased and time-to-peak C-peptide, 90-min glucose, and area under the curve for glucose were significantly increased when measured at time points preceding intervals where IGD occurred compared with intervals where there was no IGD.

Conclusions: The intravenous glucose tolerance test and mixed meal tolerance test may be useful in the prediction of IGD and should be essential components of the metabolic testing of islet transplant recipients.

Figure 1

Mixed Meal Tolerance Test glucose and C-peptide responses for Group-1 (A and B) and Group-2 (C and D).

Figure 2

Metabolic variables from the IVGTT (AIRg), AST (AIRarg) and MMTT (90min glucose and AUCglucose) separated by groups. The dark gray bars represent Group-1 and the light gray bars represent Group-2. Numbers above bars represent the sample size. A drop out of patients occurs due to reintroduction of insulin, problems with peripheral IV access, venous sampling or conditions that precluded the patient from undergoing the test at that time. * p<0.05 Group-1 vs. Group-2 (t-test).