Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations.

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6)%; 24 (13.5-36) months: 6.2 (5.7-8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41-0.62) units/kg; 24 (13.5-36) months: 0.20 (0-0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C-peptide: transported 788 (114-1764) pmol/L (n = 9); locally isolated 407 (126-830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Changes in RANKL/OPG/RANK gene expression in peripheral mononuclear cells following treatment with estrogen or raloxifene.

The RANKL/OPG/RANK pathway is the key mediator of osteoclastogenesis. Mononuclear cells may be implicated in post-menopausal osteoporosis. The effect of estrogen or raloxifene on bone resorption and the expression of RANKL/OPG/RANK in peripheral blood mononuclear cells (PBMCs) was examined. Twenty-nine women with post-menopausal osteoporosis were treated with estrogen (HRT) or raloxifene for 12 months. Bone mineral density (BMD) was measured at baseline and at 12 months at the spine and hip. Serum C-terminal telopeptide (CTX) and OPG were measured at baseline and at 1, 3, 6 and 12 months. PBMCs were isolated from 17 women and changes in RANKL, OPG and RANK mRNA were determined. The effects of estrogen or raloxifene in PBMCs in vitro were also assessed. BMD increased following treatment (lumbar spine % change mean [S.E.M.]: 4.3% [0.9], p<0.001). Serum CTX decreased (6 months: -43.7% [6.0], p<0.0001). Serum OPG declined gradually (12 months: -26.4% [4.4], p<0.001). RANKL, OPG and RANK gene expression decreased (6 months: RANKL 50.0% [24.8] p<0.001, OPG: 21.7% [28] p<0.001, RANK: 76.6% [10.2] p=0.015). Changes in OPG mRNA correlated with changes in BMD (r=-0.53, p=0.027) and CTX (r=0.7, p=0.0044). Down-regulation in RANKL, OPG, RANK mRNA and reduction in bone resorption was also seen in vitro. These results suggest that the expression of RANKL/OPG/RANK in PBMCs are responsive to the slowing in bone turnover/remodeling associated with treatment with estrogen or raloxifene. Further confirmatory studies are needed.