Endocrine Abstracts

Introduction: Islet transplantation (ITx) is a therapeutic option for patients with Type 1 diabetes. However there is attrition of graft function and the majority of patients require exogenous insulin injections and/or further transplants, within five years. Mouse models help elucidate mechanisms of islet graft failure and the NOD/Lt-scid IL2rγ^null (NSG) mouse is useful to study human islet engraftment but few published studies exist. As different numbers of islets are necessary to render different mouse strains euglycaemic, our aim was to determine differences in transplant success based on number of islet equivalents (IEQ) in this specific mouse model.

Methods: Either 2000 (n=4) or 4000 (n=3) human IEQs were transplanted under the kidney capsule of male streptozotocin-induced diabetic NSG mice. Blood glucose levels were monitored for 6-weeks post-ITx, glucose tolerance tests (GTT) performed at 2 weeks (2 g glucose/kg body weight, i.p.) with human c-peptide level measurements, before histological processing of kidney capsule for islets/insulin staining.

Results: Mice transplanted with 4000 IEQs returned to normoglycaemia (non-fasting blood glucose <12 mmol/l) after (mean±S.E.M.) 6.3±1.8 days, but those receiving 2000 IEQs had not after six weeks. Following the GTT, glucose concentrations were diminished and stimulated human c-peptide concentrations greater with 4000 vs 2000 IEQs (600±138 vs 2769±326 mmol/l×min (P<0.001) and 1447.8±1039.8 vs 24.8±13.2 pmol/l respectively). Histology showed the presence of islets and positive insulin staining under the kidney capsule.

Discussion: We have demonstrated that the number of islets transplanted is critical to transplant success and a return to normoglycaemia. In our study, the large number of islets transplanted suggests the NSG mouse is highly resistant to insulin, compared to other mouse models. This should be taken into account in further studies, and further human islet ‘dose’ finding studies performed to determine the optimal number for ITx success.