Endocrine Abstracts

The efficacy of human islet transplantation is reduced by loss of islets directly after transplantation. Ischemia is likely to be an important contributing factor to the observed islet loss. Diazoxide inhibits insulin secretion by beta cells and has been shown to exhibit anti-apoptotic and anti-ischemic effects. We hypothesized that preincubation of human islets with diazoxide leads to improved islet survival and graft function.

Methods: Isolated human pancreatic islets were incubated in CMRL1066 culture medium with or without diazoxide 260 μmol/l for 72 h. After incubation, a sample was taken to assess islet viability (FDA-PI staining) and function (glucose stimulated insulin secretion, GSIS). Islets (3000 IEQ) were transplanted under the kidney capsule of NOD-SCID mice which had been rendered diabetic by intraperitoneal injection with streptozotocin. Fourteen days after islet transplantation, the mice underwent an intraperitoneal glucose tolerance test (IPGTT) to assess endogenous human C-peptide production and glucose tolerance.

Results: 83.2±4.0% of islets pretreated with diazoxide were viable compared to 76.0±4.2% of islet incubated without diazoxide (P<0.001). Islet function in vitro did not differ (GSIS ratio 2.2±0.8 for treated islets versus 1.8±0.8 for untreated islets, P=0.2). The IPGTT demonstrated a higher glucose excursion in untreated mice as compared to treated mice (AUC glucose: 1273 mmol/120min for treated mice versus 2804 mmol/120 min for untreated mice, P=0.03). Also, the IPGTT stimulated human C-peptide excursion was greater in mice who received islets treated with diazoxide than in mice who received islets without diazoxide exposure (0.34±0.23 nmol/l vs 0.056±0.10 nmol/l at 60 min, respectively, P=0.03).

Conclusion: Diazoxide pretreatment of isolated human islets improves pancreatic islet survival in vitro and leads to improved islet graft function in diabetic mice.