Islet damage during isolation as assessed by miRNAs and the correlation of miRNA levels with posttransplantation outcome in islet autotransplantation

High‐quality pancreatic islets are essential for better posttransplantation endocrine function in total pancreatectomy with islet autotransplantation (TPIAT), yet stress during the isolation process affects quality and yield. We analyzed islet‐enriched microRNAs (miRNAs) ‐375 and ‐200c released during isolation to assess damage and correlated the data with posttransplantation endocrine function. The absolute concentration of miR‐375, miR‐200c, and C‐peptide was measured in various islet isolation steps, including digestion, dilution, recombination, purification, and bagging, in 12 cases of TPIAT. Posttransplantation glycemic control was monitored through C‐peptide, hemoglobin A_1c, insulin requirement, and SUITO index. The amount of miR‐375 released was significantly higher during enzymatic digestion followed by the islet bagging (P < .001). Mir‐200c mirrored these changes, albeit at lower concentrations. In contrast, the C‐peptide amount was significantly higher in the purification and bagging steps (P < .001). Lower amounts of miR‐375 were associated with a lower 6‐month insulin requirement (P = .01) and lower hemoglobin A_1c (P = .04). Measurement of the absolute quantity of miRNA‐375 and ‐200c released during islet isolation is a useful tool to assess islet damage. The quantity of released miRNA is indicative of posttransplantation endocrine function in TPIAT patients.     

Utility of arginine stimulation testing in preoperative assessment of children undergoing total pancreatectomy with islet autotransplantation

Metabolic outcomes after total pancreatectomy with islet autotransplantation (TPIAT) are influenced by the islet mass transplanted. Preclinical and clinical studies indicate that insulin and C‐peptide levels measured after intravenous administration of the beta cell secretagogue arginine can be used to estimate the available islet mass. We sought to determine if preoperative arginine stimulation test (AST) results predicted transplanted islet mass and metabolic outcomes in pediatric patients undergoing TPIAT. We evaluated the association of preoperative C‐peptide and insulin responses to AST with islet isolation metrics using linear regression, and with postoperative insulin independence using logistic regression. Twenty‐six TPIAT patients underwent preoperative AST from 2015 to 2018. The acute C‐peptide response to arginine (ACRarg) was correlated with isolated islet equivalents (IEQ; r = 0.59, P = 0.002) and islet number (IPN; r = 0.48, P = 0.013). The acute insulin response to arginine (AIRarg) was not significantly correlated with IEQ (r = 0.38, P = 0.095) or IPN (r = 0.41, P = 0.071). Neither ACRarg nor AIRarg was associated with insulin use at 6 months postoperatively. Preoperative C‐peptide response to arginine correlates with islet mass available for transplant in pediatric TPIAT patients. AST represents an additional tool before autotransplant to provide counseling on likely islet mass and to inform quality improvements of islet isolation techniques.     

In‐hospital and 90‐day outcomes after total pancreatectomy with islet autotransplantation for pediatric chronic and acute recurrent pancreatitis

Total pancreatectomy with islet autotransplantation (TPIAT) is used to treat debilitating chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) that has failed medical and endoscopic therapy. We performed a retrospective review of TPIAT patients at a free‐standing children's hospital to evaluate perioperative outcomes. Twenty patients (median age 13, 65% female) underwent TPIAT (2015 through 2017). Of the 20 patients, 95% had CP and 1 patient (5%) had ARP alone. Seventy‐five percent of the patients had a pancreatitis‐associated genetic mutation; 40% had pancreas divisum. The median surgical time was 757 (IQR 657 to 835) minutes. Median islet equivalents per kg of body weight (IEQ/kg) were 6404 (IQR 5018 to 7554). At 90 days postoperatively vs preoperatively, significantly fewer patients were receiving parenteral nutrition (0% vs 25%, P = .006) and opioids (45% vs 75%, P = .01). Short Form 36‐Item Health Survey (SF‐36) physical health module scores and total scores improved (34.0 preoperatively vs 54.6 at 90 days, P = .008, and 47.1 vs 65.3, P = .007, respectively); SF‐10 physical health scores also improved (13.4 vs 33.1, P = .02). Insulin requirement decreased from 0.5 unit/kg/day to 0.4 unit/kg/day between discharge and 90 days (P = .02). TPIAT is an effective option when debilitating disease persists despite maximal medical and endoscopic therapy. Opioid, parenteral nutrition, and exogenous insulin use can successfully be weaned within 90 days after TPIAT, with gains in health‐related quality of life.     

Unmethylated Insulin DNA Is Elevated After Total Pancreatectomy With Islet Autotransplantation: Assessment of a Novel Beta Cell Marker

Beta cell death may occur both after islet isolation and during infusion back into recipients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis. We measured the novel beta cell death marker unmethylated insulin (INS) DNA in TPIAT recipients before and immediately after islet infusion (n = 21) and again 90 days after TPIAT, concurrent with metabolic functional assessments (n = 25). As expected, INS DNA decreased after pancreatectomy (p = 0.0002). All TPIAT recipients had an elevated unmethylated INS DNA ratio in the first hours following islet infusion. In four samples (three patients), INS DNA was also assessed immediately after islet isolation and again before islet infusion to assess the impact of the isolation process: Unmethylated and methylated INS DNA fractions both increased over this interval, suggesting death of beta cells and exocrine tissue before islet infusion. Higher glucose excursion with mixed‐meal tolerance testing was associated with persistently elevated INS DNA at day 90. In conclusion, we observed universal early elevations in the beta cell death marker INS DNA after TPIAT, with pronounced elevations in the islet supernatant before infusion, likely reflecting beta cell death induced by islet isolation. Persistent posttransplant elevation of INS DNA predicted greater hyperglycemia at 90 days.     

Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized,Placebo‐Controlled Study

Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of postprocedure beta cell apoptosis. Endogenous glucagon‐like peptide‐1 and glucose‐dependent insulinotropic peptide, which are increased by dipeptidyl peptidase 4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitagliptin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n = 54) or placebo (n = 29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs. 45%, p = 0.82) or 18 months (36% vs. 44%, p = 0.48). At 12 months, insulin dose was 9.0 (standard error 1.7) units/day and 7.9 (2.2) units/day in the sitagliptin and placebo groups, respectively (p = 0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) units/day, respectively (p = 0.32). Hemoglobin A_1c levels and insulin secretory measures were similar in the two groups, as were adverse events. In conclusion, sitagliptin could be safely administered but did not improve metabolic outcomes after TPIAT.     

Development of Autoimmune‐Mediated β Cell Failure After Total Pancreatectomy With Autologous Islet Transplantation

Total pancreatectomy with islet autotransplantation (TPIAT) is performed for definitive treatment of chronic pancreatitis; patients are not diabetic before surgery, or have C‐peptide positive pancreatogenous diabetes. Thus, TPIAT recipients are not traditionally considered at risk for autoimmune loss of the islet graft. We describe a 43‐year‐old female who underwent TPIAT with high mass islet graft of 6031 IEQ/kg, with no evidence of presurgical β cell autoimmunity who developed type 1 diabetes within the first year after TPIAT, resulting in complete loss of beta cell function. The patient had positive GAD and insulin autoantibodies at 1 year and 18 months after TPIAT, not present prior, and undetectable C‐peptide after mixed meal and intravenous glucose tolerance testing at 18 months. Glucagon secretion was preserved, suggesting the transplanted alpha cell mass was intact. HLA typing revealed a DR3/DR4 class II haplotype. This case highlights the need to consider de novo type 1 diabetes in patients with unexpected islet graft failure after TPIAT.     

Low prevalence of diabetes distress following total pancreatectomy with islet autotransplantation

Diabetes distress (DD), or psychological fatigue associated with diabetes management, is common in type 1 and 2 diabetes mellitus and is associated with poor glycemic control. Diabetes distress has never been evaluated in patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We analyzed DD after TPIAT in 260 patients (average age 34.3 [standard deviation 15], 75.5% F) undergoing TPIAT between 2006 and 2014. Each patient completed 1 or more diabetes distress scale (DDS) questionnaires from 1 to 7 years post‐TPIAT (631 total). We examined changes in DD over 7 years and also patient characteristics associated with DD 1 year post‐TPIAT (n = 189). One year after TPIAT, 151 of 189 (80%) reported no or low distress (DD<2). Diabetes distress increased over time by an average of 0.084 (SE 0.017) points per year, an average 0.59 point increase from years 1 to 7 (P < .0001). Insulin‐dependent patients had significantly greater DD 1 year post‐TPIAT compared to insulin‐independent patients (P < .0001). Higher DD was associated with poorer glycemic control as indicated by HbA1c (P < .0001). Prevalence of DD is low but increases over time after TPIAT. Insulin dependence and poorer glycemic control are associated with higher levels of DD.     

Combination of Obesity with Hyperglycemia is a Risk Factor for the Presence of Vertebral Fractures in Type 2 Diabetic Men

Although patients with type 2 diabetes show no bone mineral density (BMD) reduction, fracture risks are known to increase. It is unclear why the patients have an increased risk of fracture despite sufficient BMD. We investigated the relationships of body mass index (BMI), HbA_1c, and urinary C-peptide (uC-peptide) versus BMD, bone metabolic markers, serum adiponectin, and prevalent vertebral fracture (VF). A total of 163 Japanese type 2 diabetic men were consecutively recruited, and radiographic and biochemical data were collected. BMI was positively correlated with BMD at the whole body, lumbar spine, and femoral neck (P < 0.05) and negatively correlated with osteocalcin and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) (P < 0.01). HbA_1c was negatively correlated with osteocalcin (P < 0.01) but not BMD at any site. Subjects were classified into four groups based on BMI and HbA_1c (group LL BMI < 24 and HbA_1c < 9, group LH BMI < 24 and HbA_1c ≧ 9, group HL BMI ≧ 24 and HbA_1c < 9, group HH BMI ≧ 24 and HbA_1c ≧ 9). Serum adiponectin, osteocalcin, and uNTX were lower and the incidence of VF was higher despite sufficient BMD in the HH group. Multivariate logistic regression analysis adjusted for age, duration of diabetes, uC-peptide, and estimated glomerular filtration rate showed that the HH group was associated with the presence of a VF and multiple VFs (odds ratio [OR] = 3.056, 95% confidence interval [CI] 1.031–9.056, P = 0.0439, and OR = 5.415, 95% CI 1.126–26.040, P = 0.0350, respectively). Combination of obesity with hyperglycemia was a risk factor for VF despite sufficient BMD in diabetic men.     

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.     

Fasting parameters for estimation of stimulated β cell function in islet transplant recipients with or without basal insulin treatment

In order to assess β cell secretory capacity after islet transplantation, standardized mixed meal stimulation tests are often used. But these tests are cumbersome and the effect of exogenous insulin on the test results is unclear. The aim of our study was to determine to what extent fasting glycemic indices can estimate stimulated β cell function in islet transplant recipients with and without basal insulin. In total 100 mixed meal stimulation tests, including 31 with concurrent basal insulin treatment, were performed in 36 islet transplant recipients. In a multivariate model, fasting C-peptide and fasting glucose together estimated peak C-peptide with R² = .87 and area under the curve (AUC) C-peptide with a R² = .93. There was a larger increase of glucose during tests in which exogenous insulin was used (+7.9 vs +5.3 mmol/L, P < .001) and exogenous insulin use was associated with a slightly lower estimated peak C-peptide (relative change: −15%, P = .02). In islet transplant recipients the combination of fasting C-peptide and glucose can be used to accurately estimate stimulated β cell function after a mixed meal stimulation test, whether exogenous basal insulin is present or not. These data indicate that graft function can be reliably determined during exogenous insulin treatment and that regular islet graft stimulation tests can be minimized.     

Defining outcomes for β‐cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop

β‐cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas & Islet Transplant Association (IPITA) and European Pancreas & Islet Transplantation Association (EPITA) held a workshop to develop consensus for an IPITA/EPITA Statement on the definition of function and failure of current and future forms of β‐cell replacement therapy. There was consensus that β‐cell replacement therapy could be considered as a treatment for β‐cell failure, regardless of etiology and without requiring undetectable C‐peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA_1c) and the occurrence of severe hypoglycemia. Optimal β‐cell graft function is defined by near‐normal glycemic control [HbA_1c ≤ 6.5% (48 mmol/mol)] without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C‐peptide. Good β‐cell graft function requires HbA_1c < 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C‐peptide production. Marginal β‐cell graft function is defined by failure to achieve HbA_1c < 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C‐peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β‐cell graft is defined by the absence of any evidence for clinically significant C‐peptide production. Optimal and good functional outcomes are considered successful clinical outcomes.     

Predicting endocrine function after total pancreatectomy and islet cell autotransplantation: A novel approach utilizing computed tomography texture analysis

BackgroundIslet cell autotransplantation is an effective method to prevent morbidity associated with type IIIc diabetes after total pancreatectomy. However, there is no valid method to predict long-term endocrine function. Our aim was to assess computed tomography texture analysis as a strategy to predict long-term endocrine function after total pancreatectomy and islet cell autotransplantation.MethodsAll patients undergoing total pancreatectomy and islet cell autotransplantation from 2007 to 2020 who had high-quality preoperative computed tomography imaging available for texture analysis were included. The primary outcome was optimal long-term endocrine function, defined as stable glycemic control with <10 units of insulin/day.ResultsSixty-three patients met inclusion criteria. Median yield was 6,111 islet equivalent/kg body weight. At a median follow-up of 64.2 months, 12.7% (n = 8) of patients were insulin independent and 39.7% (n = 25) demonstrated optimal endocrine function. Neither total islet equivalent nor islet equivalent/kg body weight alone were associated with optimal endocrine function. To improve endocrine function prediction, computed tomography texture analysis parameters were analyzed, identifying an association between kurtosis (odds ratio, 2.32; 95% confidence interval, 1.08–4.80; P = .02) and optimal endocrine function. Sensitivity analysis discovered a cutoff for kurtosis = 0.60, with optimal endocrine function seen in 66.7% with kurtosis ≥0.60, compared with only 26.2% with kurtosis <0.60 (P < .01). On multivariate logistic regression including islet equivalent yield, only kurtosis ≥0.60 (odds ratio, 5.61; 95% confidence interval, 1.56–20.19; P = .01) and fewer small islet equivalent (odds ratio, 1.00; 95% confidence interval, 1.00–1.00; P = .02) were associated with optimal endocrine function, with the whole model demonstrating excellent prediction of long-term endocrine function (area under the curve, 0.775).ConclusionComputed tomography texture analysis can provide qualitative data, that when used in combination with quantitative islet equivalent yield, can accurately predict long-term endocrine function after total pancreatectomy and islet cell autotransplantation.     

Successful Application of Closed‐Loop Artificial Pancreas Therapy After Islet Autotransplantation

Total pancreatectomy with islet autotransplantation (TPIAT) may relieve the pain of chronic pancreatitis while avoiding postsurgical diabetes. Minimizing hyperglycemia after TPIAT limits beta cell apoptosis during islet engraftment. Closed‐loop (CL) therapy combining an insulin pump with a continuous glucose monitor (CGM) has not been investigated previously in islet transplant recipients. Our objective was to determine the feasibility and efficacy of CL therapy to maintain glucose profiles close to normoglycemia following TPIAT. Fourteen adult subjects (36% male; aged 35.9 ± 11.4 years) were randomized to subcutaneous insulin via CL pump (n = 7) or multiple daily injections with blinded CGM (n = 7) for 72 h at transition from intravenous to subcutaneous insulin. Mean serum glucose values were significantly lower in the CL pump group than in the control group (111 ± 4 vs. 130 ± 13 mg/dL; p = 0.003) without increased risk of hypoglycemia (percentage of time <70 mg/dL: CL pump 1.9%, control 4.8%; p = 0.46). Results from this pilot study suggest that CL therapy is superior to conventional therapy in maintaining euglycemia without increased hypoglycemia. This technology shows significant promise to safely maintain euglycemic targets during the period of islet engraftment following islet transplantation.     

A randomized,phase 1b study of the pharmacokinetics,pharmacodynamics, safety,and tolerability of bleselumab,a fully human,anti‐CD40 monoclonal antibody,in kidney transplantation

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUC_inf, C_max, and AUC_last. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUC_inf and AUC_last demonstrated a more than dose‐proportional increase in the range of 50‐500 mg, and C_max increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment‐emergent anti‐bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose‐dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).     

Lower bone mineral density in children with type 1 diabetes is associated with poor glycemic control and higher serum ICAM-1 and urinary isoprostane levels

The purpose of the study was to investigate bone mineral density (BMD) in children with type 1 diabetes (DM1) and to establish the relationships between BMD, physical activity, glycemic control, and markers of systemic oxidative stress and inflammation. We studied 30 children with DM1, aged 4.7–18.6 years, and 30 healthy subjects, matched by sex, age, and body mass index (BMI). Mean duration of DM1 was 5.4 ± 3.4 years and mean glycosylated hemoglobin (HbA_1c) level over 12 months was 9.8 ± 1.5%. Lumbar and total bone mineral density (BMD, g/cm²) were measured by dual-energy X-ray absorptiometry (DXA). We calculated the apparent volumetric lumbar BMD (BMDvol, g/cm³) and total mineral content adjusted for age and height (BMCadj), and measured plasma intercellular adhesion molecule-1 (ICAM-1), high sensitivity C-reactive protein (hs-CRP), and urinary 8-iso-prostaglandin F_2a (F₂-IsoPs). Calcium (Ca) intake was assessed by questionnaire and physical activity by questionnaire and accelerometer (ActiGraph, count/h). Total BMCadj and lumbar BMDvol were significantly lower in children with DM1 than in controls (101.8 ± 7.7 vs. 107 ± 5.7%, P = 0.005; 0.32 ± 0.08 vs. 0.36 ± 0.09 g/cm³, P = 0.05, respectively). These differences were mostly caused by the differences in boys. Plasma ICAM-1 and hs-CRP levels were significantly higher in the DM1 group compared to the controls. Ca intake and urine F₂-IsoPs levels were similar between the groups. Diabetic boys were less active than controls (18231 ± 6613 vs. 24145 ± 7449 count/h, P = 0.04). In the DM1 group, lumbar BMDvol correlated inversely with urinary F₂-IsoPs (r = −0.5; P = 0.005) and plasma ICAM-1 levels (r = −0.4; P = 0.02), and also with HbA_1c levels after adjustment for age (r = −0.45; P < 0.05). Total BMCadj correlated inversely with HbA_1c levels (r = −0.4; P = 0.02). We conclude that children with DM1, particularly boys, have lower BMD. Poor glycemic control, elevated markers of oxidative stress, and inflammation are associated with lower BMD.     

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66–0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66–0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = −0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.     

BMX‐001, a novel redox‐active metalloporphyrin,improves islet function and engraftment in a murine transplant model

Islet transplantation has become a well‐established therapy for select patients with type 1 diabetes. Viability and engraftment can be compromised by the generation of oxidative stress encountered during isolation and culture. We evaluated whether the administration of BMX‐001 (MnTnBuOE‐2‐PyP⁵⁺ [Mn(III) meso‐tetrakis‐(N‐ b ‐butoxyethylpyridinium‐2‐yl)porphyrin]) and its earlier derivative, BMX‐010 (MnTE‐2‐PyP [Mn(III) meso‐tetrakis‐(N‐methylpyridinium‐2‐yl)porphyrin]) could improve islet function and engraftment outcomes. Long‐term culture of human islets with BMX‐001, but not BMX‐010, exhibited preserved in vitro viability. Murine islets isolated and cultured for 24 hours with 34 μmol/L BMX‐001 exhibited improved insulin secretion (n = 3 isolations, P < .05) in response to glucose relative to control islets. In addition, 34 μmol/L BMX‐001–supplemented murine islets exhibited significantly reduced apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling, compared with nontreated control islets (P < .05). Murine syngeneic islets transplanted under the kidney capsule at a marginal dose of 150 islets revealed 58% of 34 μmol/L BMX‐001–treated islet recipients became euglycemic (n = 11 of 19) compared with 19% of nontreated control islet recipients (n = 3 of 19, P < .05). Of murine recipients receiving a marginal dose of human islets cultured with 34 μmol/L BMX‐001, 92% (n = 12 of 13) achieved euglycemia compared with 57% of control recipients (n = 8 of 14, P = .11). These results demonstrate that the administration of BMX‐001 enhances in vitro viability and augments murine marginal islet mass engraftment.     

BETA‐2 score is an early predictor of graft decline and loss of insulin independence after pancreatic islet allotransplantation

This study aimed to evaluate whether the BETA‐2 score is a reliable early predictor of graft decline and loss of insulin independence after islet allotransplantation. Islet transplant procedures were stratified into 3 groups according to clinical outcome: long‐term insulin independence without islet graft decline (group 1, N = 9), initial insulin independence with subsequent islet graft decline and loss of insulin independence (group 2, N = 13), and no insulin independence (group 3, N = 13). BETA‐2 was calculated on day 75 and multiple times afterwards for up to 145 months posttransplantation. A BETA‐2 score cut‐off of 17.4 on day 75 posttransplantation was discerned between group 1 and groups 2 and 3 (area under the receiver operating characteristic 0.769, P = .005) with a sensitivity and negative predictive value of 100%. Additionally, BETA‐2 ≥ 17.4 at any timepoint during follow‐up reflected islet function required for long‐term insulin independence. While BETA‐2 did not decline below 17.4 for each of the 9 cases from group 1, the score decreased below 17.4 for all transplants from group 2 with subsequent loss of insulin independence. The reduction of BETA‐2 below 17.4 predicted 9 (1.5‐21) months in advance subsequent islet graft decline and loss of insulin independence (P = .03). This finding has important implications for posttransplant monitoring and patient care.     

Factors related to renal haemodynamics in young type-1 diabetes mellitus patients

The influence of metabolic control (HbA_1c), noradrenaline (NA) and insulin-like growth factors (IGF-I and IGF-II) on renal function and size was investigated in 11 insulin-dependent diabetes mellitus patients aged 11–17 years. Renal function was evaluated in terms of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal size was determined as renal parenchymal volume (RPV) by ultrasonography. The patients' HbA_1c values ranged from 8.2% to 12.9% (normal range 5.5–8.5%) and their GFR and ERPF were higher than normal. Their IGF-II values were higher, and NA and IGF-I levels were lower than those of healthy controls. Inverse correlations between NA and GFR (r=–0.66) and NA and ERPF (r=–0.63) were found. No correlation was found between serum IGF-I and renal functional parameters. The IGF-II values correlated with GFR and HbA_1c (r=0.63,r=0.70 respectively). There were linear correlations between RPV and GFR, RPV and ERPF, HbA_1c and GFR, and ERPF and RPV. Decreased NA concentrations and increased IGF-II values appear to be factors contributing to renal hyperfunction in these patients.     

The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation

Total pancreatectomy with islet autotransplantation is a promising treatment for refractory chronic pancreatitis. We analyzed postoperative complications in 83 TPIAT patients and their impact on islet graft function. We examined patient demographics, preoperative risk factors, intraoperative variables, and 30- and 90-day postoperative morbidity and mortality. Daily insulin requirement, HbA1c, C-peptide levels, and narcotic requirements were analyzed before and after surgery. Adverse events were recorded, with postoperative complications graded according to the Clavien-Dindo classification. There was no mortality in this patient group. Postoperative complications occurred in 38 patients (45.7%). Patients with postoperative complications were readmitted significantly more often within 30 days (p = 0.01) and 90 days posttransplant (p < 0.0003) and had a significantly longer hospital stay (p = 0.004) and intensive care unit stay (p = 0.001). Insulin dependence and graft function assessed by HbA1c, C-Peptide and insulin requirements did not differ significantly by these complications. Postoperative complications after TPIAT are associated with longer hospital and intensive care unit stay and with readmission; however, the surgical complications do not affect islet graft function.