{beta}-Cell secretory capacity and demand in recipients of islet, pancreas, and kidney transplants

Abstract

Context: beta-Cell secretory capacity, a measure of functional beta-cell mass, is often impaired in islet transplant recipients, likely because of a low engrafted beta-cell mass, although calcineurin inhibitor toxicity is often cited as the explanation.

Objective: We sought to determine whether use of the calcineurin inhibitor tacrolimus was associated with reduced beta-cell secretory capacity or with increased beta-cell secretory demand independent of engrafted islet mass.

Design and participants: We compared metabolic measures in five intraportal islet recipients vs. 10 normal controls and in seven portally-drained pancreas-kidney and eight nondiabetic kidney recipients vs. nine kidney donor controls. All transplant groups received comparable exposure to tacrolimus, and each transplant group was matched for kidney function to its respective control group.

Intervention and main outcome measures: All participants underwent glucose-potentiated arginine testing where acute insulin responses to arginine (5 g) were determined under fasting (AIR(arg)), 230 mg/dl (AIR(pot)), and 340 mg/dl (AIR(max)) clamp conditions, and AIR(max) gives the beta-cell secretory capacity. Insulin sensitivity (M/I) and proinsulin secretory ratios (PISRs) were assessed to determine whether tacrolimus increased beta-cell secretory demand.

Results: Insulin responses were significantly lower than normal in the islet group for AIR(arg) (P < 0.05), AIR(pot) (P < 0.01), and AIR(max) (P < 0.01), whereas responses in the pancreas-kidney and kidney transplant groups were not different than in the kidney donor group. M/I and PISRs were not different in any of the transplant vs. control groups.

Conclusions: Impaired beta-cell secretory capacity in islet transplantation is best explained by a low engrafted beta-cell mass and not by a deleterious effect of tacrolimus.

Figure 1

Plasma insulin levels in response to bolus injections of arginine (arrows) administered under fasting, 230 mg/dl hyperglycemic clamp, and 340 mg/dl hyperglycemic clamp conditions. A, The AIRs to arginine were lower in the islet transplant compared with the normal control group. B and C, The AIRs to arginine were not different in either the pancreas-kidney or kidney transplant compared with the kidney donor control group. *, P < 0.05; **, P < 0.01.

Figure 2

AIRs to arginine as a function of the prestimulus plasma glucose concentration (18). The glucose-potentiation slope (GPS), calculated as the difference in the AIR at fasted and 230 mg/dl glucose levels divided by the difference in plasma glucose, is impaired in the islet vs. normal group (0.11 ± 0.01 vs. 0.76 ± 0.07; P < 0.0001; panel A), but not in the pancreas-kidney or kidney transplant vs. kidney donor group (0.71 ± 0.16 vs. 0.64 ± 0.04 vs. 0.90 ± 0.20; NS). β-Cell sensitivity to glucose is determined as the PG₅₀, the plasma glucose level at which half-maximal insulin secretion was achieved, using the y-intercept (b) of the GPS to solve the equation AIR_max/2 = GPS × PG₅₀ + b as represented by the dashed lines in panels A and B. Because the impairment of GPS in the islet group was proportional to the reduction in AIR_max, no difference existed in PG₅₀ between the islet vs. normal groups (134 ± 21 vs. 143 ± 9 mg/dl; NS; panel A), nor did any differences exist in PG₅₀ across the pancreas-kidney, kidney transplant, and kidney donor groups (148 ± 13 vs. 163 ± 10 vs. 148 ± 7 mg/dl; NS; panel B).

Figure 3

Plasma glucagon levels in response to bolus injections of arginine (arrows) administered under fasting, 230 mg/dl hyperglycemic clamp, and 340 mg/dl hyperglycemic clamp conditions. A, The AGRs to arginine were greater in the islet transplant compared with the normal control group under hyperglycemic clamp conditions. B and C, The AGRs to arginine were not different in either the pancreas-kidney or kidney transplant compared with the kidney donor control group. *, P < 0.05; **, P < 0.01.