Prospective characterization of incident hepatic steatosis in pediatric and adolescent patients after total pancreatectomy with islet autotransplantation

BackgroundHepatic steatosis has been described as a common finding in adults following total pancreatectomy with islet autotransplantation (TPIAT) but it is unknown if this occurs in children and adolescents.ObjectivesTo define the frequency of post-TPIAT hepatic steatosis in a sample of children and adolescents and to identify clinical predictors of incident steatosis post-TPIAT.MethodsIn this prospective study, consecutive participants at least 1-month post-TPIAT underwent a liver MRI with proton density fat fraction (PDFF) and blood draw at our pediatric academic medical center between April 2021 and January 2022. Comparison clinical pre-TPIAT liver MRI or ultrasound and insulin use and graft function data were extracted from the medical record. T-tests were used for the comparison of means across continuous variables between participants with and without post-TPIAT steatosis.ResultsA total of 20 participants (mean: 13 ± 4 years; 12 female) were evaluated. Mean liver PDFF at research MRI was 7.4 ± 6.2% (range: 2–25%). Seven participants (35%) had categorical hepatic steatosis (PDFF>5%) post-TPIAT, five of whom had pre-TPIAT steatosis, reflecting a 13% (2/15; 95% CI: 2–40%) incidence of post-TPIAT steatosis. Participant characteristics were not significantly different between subgroups with and without post-TPIAT steatosis. Mean PDFF at research MRI was not different between graft function subgroups (7.5% optimal/good vs. 7.3% marginal/failure; p = .96).ConclusionOur study shows a moderate prevalence but low incidence of hepatic steatosis in a small sample of children and adolescents post-TPIAT. This study raises questions about a causal relationship between TPIAT and hepatic steatosis.     

参芪复方对2型糖尿病GK大鼠胰岛β细胞功能的影响

目的:以自发性2型糖尿病GK大鼠为研究对象,应用全基因组表达谱芯片技术,旨在探讨参芪复方调节胰岛细胞功能的分子机制,为中医药防治2型糖尿病提供理论依据。方法:GK大鼠每日给予高脂饲料喂养,连续4周,随机从GK大鼠中选取大鼠检测随机血糖,验证2型糖尿病模型成功。实验分为4组,空白组,模型组,参芪复方组(1.44 g?kg~(-1)),西格列汀组(16 mg·kg~(-1)),于灌胃前、灌胃4周、灌胃8周测早上8:00各组大鼠尾尖血糖;灌胃8周后,运用酶联免疫吸附测定(ELISA)检测大鼠血清胰岛素(INS)水平;采用原位末端标记(TUNEL)荧光法定量检测并观察胰岛β细胞凋亡情况;运用全基因组表达谱芯片技术对各组大鼠胰腺组织进行差异基因检测;采用实时荧光定量聚合酶链式反应(Real-time PCR)检测关键差异基因的mRNA转录水平。结果:与空白组比较,灌胃前、灌胃4周、灌胃8周,GK大鼠各组血糖显著升高(P0.01);灌胃4,8周,与模型组比较,各药物干预组大鼠血糖均显著较低(P0.01)。灌胃8周,与空白组比较,模型组大鼠INS水平显著较低(P0.01);与模型组比较,参芪复方组具有INS水平更高的趋势,西格列汀组INS水平显著较高(P0.01)。灌胃8周,与空白组比较,模型组大鼠胰岛β细胞凋亡数明显升高(P0.05);与模型组比较,参芪复方组、西格列汀组大鼠胰岛β细胞凋亡数均明显较低(P0.05,P0.01)。基因芯片及Real-time PCR检测均显示磷脂酰肌醇3-激酶受体1(PIK3R1)在参芪复方组/模型组中表达上调,在西格列汀组/模型组、模型组/空白组中表达下调;蛋白激酶B1(Akt1)在参芪复方组/模型组、西格列汀组/模型组中表达上调,在模型组/空白组中表达下调。结论:参芪复方可减少胰岛β细胞凋亡,增加胰岛素分泌,上调基因PIK3R1,Akt1的表达,推测具有养阴益气活血功效的参芪复方可能通过上调基因PIK3R1,Akt1的表达,抑制胰岛β细胞凋亡,改善胰岛β细胞功能,调节胰岛素分泌,从而防治2型糖尿病。     

A Registry Analysis of Damage to the Deceased Donor Pancreas During Procurement

Surgical injury to the pancreas is thought to occur commonly during procurement. The UK Transplant Registry was analyzed to determine the frequency of pancreatic injuries, identify factors associated with damage, and assess the impact of injuries on graft survival. Twelve hundred ninety‐six pancreata were procured from donation after brain death donors, with 314 (19.5%) from donation after circulatory death donors. More than 50% of recovered pancreata had at least one injury, most commonly a short portal vein (21.5%). Liver donation, procurement team origin, hepatic artery (HA) arising from the superior mesenteric artery (SMA), and increasing donor BMI were associated with increased rates of pancreas damage on univariate analyses; on multivariate analysis only the presence of an HA from the SMA remained significant (p = 0.02). Six hundred forty solid organ pancreas transplants were performed; 238 had some form of damage. Overall, there was no difference in graft survival between damaged and undamaged organs (p = 0.28); however, graft loss was significantly more frequent in pancreata with arterial damage (p = 0.04) and in those with parenchymal damage (p = 0.05). Damage to the pancreas during organ recovery is more common than other organs, and meticulous surgical technique and awareness of damage risk factors are essential to reduce rates of procurement‐related injuries.     

De Novo Donor‐Specific HLA Antibodies Are Associated With Rapid Loss of Graft Function Following Islet Transplantation in Type 1 Diabetes

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor‐specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed‐meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1–3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post–first transplant; two post–second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C‐peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300–1090); DSA positive 106(34–235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).     

Graft function 1 year after pregnancy in an islet‐transplanted patient

Pancreatic islet transplantation is a treatment option for patients with type 1 diabetes (T1D), but pregnancy has generally not been advised for women after receiving an islet allograft. We hereby describe what is to our knowledge the first successful pregnancy and persistent graft function in a woman 4 years after her initial islet transplantation. A 37‐year‐old woman with brittle type 1 diabetes was transplanted with two separate islet graft infusions, eventually becoming insulin independent. Ten months after her second transplantation, her immunosuppression was switched from tacrolimus and sirolimus to tacrolimus, azathioprine, and prednisolone, due to her wish to become pregnant. She became pregnant one year later, and after 38 weeks of uncomplicated pregnancy, she gave birth to a healthy child by C‐section. The current report suggests that pregnancy and childbirth can be accomplished after islet transplantation without loss of islet graft function.     

Evidence that cyclosporin A administration induces the formation of new cementum-like islets inside the gingival connective tissue

Two groups of 3 male Sprague-Dawley rats were given orally 30 mg/kg/d of vehicle (control group) or cyclosporin-A (experimental group) solution for 14 wk. The rats were anesthetized, tissues fixed by intracardiac perfusion of fixative solution and jaws dissected, demineralized, processed for Epon inclusion and cut by semi-thin serial sections. Histological examination revealed the presence of several islets located paravascularly inside the gingival connective tissue in the proximity of the root surfaces. The structure of these new cementum-like islets (NCLIs) was either compact and homogeneous or heterogeneous, but identical to that of the adjacent new cementum (NC) deposits. Histomorphometric evaluation indicated that the volume and the external surface of the NCLIs varied from 2354 to 679,497 μm³ and from 465 to 47,517 μm², respectively. These observations (a) suggest that CsA stimulates possibly paravascular progenitor cells which secrete in situ a NC-like material and (b) provides further evidence about the high potential of CsA to induce NC formation.     

The impact of islet mass,number of transplants,and time between transplants on graft function in a national islet transplant program

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3–8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291–15 417] vs. 6442 [5156–7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta ?0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.     

Islet autotransplantation improves glycemic control in patients undergoing elective distal pancreatectomy for benign inflammatory disease

Islet autotransplantation (IAT) is increasingly being performed to mitigate against the diabetic complications of pancreatic resection in patients with benign inflammatory pancreatic disorders; however, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine whether IAT improved glycemic outcomes in patients undergoing distal pancreatectomy for benign inflammatory disease. We performed a multicenter, retrospective case-control study of patients who underwent distal pancreatic resection with IAT at two U S tertiary care centers. The primary outcome was the mean change in pre- vs post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Nine patients requiring distal pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups. With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs post-operative HgA1c (0.42 vs 2.83, P = .004), and one case patient (14.3%) vs three control patients (23.1%) developed new post-operative diabetes (P = .581). We conclude that patients undergoing distal pancreatic resection for benign inflammatory disease should be considered for IAT, as long-term glycemic outcomes appear to be improved in those undergoing transplant.