PDF(Pubmed)
Abstract：
BACKGROUND: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence.
METHODS: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT.
RESULTS: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females.
CONCLUSIONS: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment.
UNASSIGNED: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).
METHODS: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT.
RESULTS: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females.
CONCLUSIONS: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment.
UNASSIGNED: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).
摘要：
背景：在胰岛自体移植的全胰腺切除术中，成功的糖尿病结局受到即时血液介导的炎症反应导致的胰岛损失的限制.我们假设使用依那西普或α-1-抗胰蛋白酶阻断炎症反应将改善胰岛功能和胰岛素独立性。
方法：我们随机分配43名参与者接受A1AT（90mg/kgx6剂，n=13),或依那西普（50毫克，然后25毫克×5剂量，n=14),或标准护理(n=16)，旨在减少先天性炎症对早期胰岛存活的有害影响。使用混合膳食耐受性测试评估胰岛移植物功能，静脉葡萄糖耐量试验,葡萄糖增强精氨酸诱导的胰岛素分泌研究，HbA1c,TPIAT后3个月和1年的胰岛素剂量。
结果：我们观察到依那西普治疗组在TPIAT治疗后3个月最强烈的急性胰岛素反应（AIRglu）和急性C肽对葡萄糖的反应（ACRglu），但其他疗效指标无差异。两组在1年时总体上没有差异，但按性别调整后，女性有性别特异性治疗效果的趋势(AIRglup=0.05，ACRglup=0.06)，在A1AT治疗的女性中，胰岛素分泌指标最高。
结论：我们的随机试验支持依那西普在优化早期胰岛植入方面的潜在作用，但不清楚这种益处是否持续。需要进一步的研究来评估对这两种治疗可能的性别特异性反应。
UNASSIGNED：本研究是根据食品和药物管理局的研究新药申请（IND＃119828）进行的，并在clinicaltrials.gov（NCT＃02713997）上注册。
方法：我们随机分配43名参与者接受A1AT（90mg/kgx6剂，n=13),或依那西普（50毫克，然后25毫克×5剂量，n=14),或标准护理(n=16)，旨在减少先天性炎症对早期胰岛存活的有害影响。使用混合膳食耐受性测试评估胰岛移植物功能，静脉葡萄糖耐量试验,葡萄糖增强精氨酸诱导的胰岛素分泌研究，HbA1c,TPIAT后3个月和1年的胰岛素剂量。
结果：我们观察到依那西普治疗组在TPIAT治疗后3个月最强烈的急性胰岛素反应（AIRglu）和急性C肽对葡萄糖的反应（ACRglu），但其他疗效指标无差异。两组在1年时总体上没有差异，但按性别调整后，女性有性别特异性治疗效果的趋势(AIRglup=0.05，ACRglup=0.06)，在A1AT治疗的女性中，胰岛素分泌指标最高。
结论：我们的随机试验支持依那西普在优化早期胰岛植入方面的潜在作用，但不清楚这种益处是否持续。需要进一步的研究来评估对这两种治疗可能的性别特异性反应。
UNASSIGNED：本研究是根据食品和药物管理局的研究新药申请（IND＃119828）进行的，并在clinicaltrials.gov（NCT＃02713997）上注册。
