Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

Progress in individualizing autologous islet isolation techniques for pediatric islet autotransplantation after total pancreatectomy in children for chronic pancreatitis.

Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (<2000 IEQ/g or IEQ/kg) have decreased substantially over time, 6.8% and 9.1%, respectively, in the most recent tertile of time compared to 19.2% and 23.4% in the middle and 34.1% and 36.4% in the oldest tertile. IEQ/g and IEQ/kg adjusted for patient and disease factors improved in consistency and yield in the modern era. Minimal mechanical disruption during digestion, warm enzymatic digestion using enzyme collagenase:NP activity ratio < 10:1, coupled with extended distension and trimming time during islet isolation of younger and fibrotic pediatric pancreases, gave increased islet yield with improved patient outcomes.

Regulatory considerations of delayed autologous islet infusion in a 4-year-old child undergoing total pancreatectomy for chronic pancreatitis.

In patients undergoing total pancreatectomy for chronic pancreatitis, isolation, and infusion of autologous islets must comply with Good Manufacturing Practices standards established by the Food and Drug Administration (FDA) but does not standardly require an Investigational New Drug (IND) status. We report a case of a 4-year-old child with severe hereditary pancreatitis who developed clinical sepsis during total pancreatectomy (TP) surgery; subsequent pancreas, islet, and blood cultures were positive for Enterococcus. Because of clinical deterioration, planned islet infusion was aborted and islets were kept viable in a culture period while the patient was stabilized. Two days later, 38 000 islet equivalents (IEQ, 2808 IEQ/kg) were infused in a second procedure. Because maintaining the islets in culture met the FDA standard for "more than minimal" tissue manipulation, an emergency IND was obtained from the FDA to permit delayed infusion. The patient tolerated islet infusion well, and subsequently has partial islet graft function with normal glucoses and minimal insulin needs. This case highlights the possibility to delay islet infusion in an emergency, the potential for success with few islets in a young child, and the need to consider regulatory complexities of islet transplant in this situation.

Combination of pancreas volume and HbA1c level predicts islet yield in patients undergoing total pancreatectomy and islet autotransplantation.

Islet yield is an important predictor of acceptable glucose control after total pancreatectomy with islet autotransplantation (TP-IAT). We assessed if pancreas volume calculated with preoperative MRI could assess islet yield and postoperative outcomes. We reviewed dynamic MRI studies from 154 adult TP-IAT patients (2009-2016), and associations between calculated volumes and digest islet equivalents (IEQs) were tested. In multivariate regression analysis, pancreas volume (P < .001) and preoperative HbA1c levels (P = .009) were independently associated with digest IEQs. The IEQ prediction formula was calculated according to each preoperative HbA1c level, (a) pancreas volume × 5800 for HbA1c ≥ 6.5, (b) pancreas volume × 10 000 for HbA1c ≥5.7/<6.5 and (iii) pancreas volume × 11 400 for HbA1c < 5.7. The formula was internally validated with 28 TP-IAT patients between 2017 and 2018 (r2  = .657 and r2  = .710 when restricted to 24 patients without prior pancreatectomy). An estimated IEQs/Body Weight (kg) ≥3700 predicted HbA1c ≤6.5 and insulin independence at 1 year after TP-IAT with 77% and 88% sensitivity and 55% and 43% specificity, respectively. The combination of pancreas volume and preoperative HbA1c levels may be useful to estimate islet yield. Estimated IEQs were reasonably sensitive to predict acceptable glucose control at 1 year.

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.

The impact of using an intraoperative goal directed fluid therapy protocol on clinical outcomes in patients undergoing total pancreatectomy and islet cell autotransplantation.

BACKGROUND: Patients undergoing total pancreatectomy and islet cell autotransplant (TPIAT) for treatment of pancreatitis are at risk for complications of over and under resuscitation. We hypothesized that using a goal directed fluid therapy (GDFT) protocol might impact clinical outcomes. MATERIALS AND METHODS: A consecutive series of adult patients undergoing TPIAT were managed intraoperatively using either standard fluid therapy (SFT, n = 44) or GDFT (n = 23) as part of a pilot study between January 2013 and May 2015. Patient characteristics, intraoperative, and postoperative data were recorded prospectively, then retrospectively analyzed for differences between the groups. RESULTS: The GDFT group had lower total fluid resuscitation (3,240 cc vs 5,173 cc, p < 0.0001) and transfusion requirements (1.0 cc/kg vs 3.3 cc/kg, p = 0.050) compared to the SFT group. The pre to postop nadir hemoglobin change was significantly less for GDFT (4.2 vs 5.1 gm/dl, p = 0.021) despite less transfusion. CONCLUSIONS: Compared to SFT, using an intraoperative GDFT protocol in TPIAT patients was associated with significantly decreased intraoperative fluid resuscitation, blood transfusion and less postoperative dilutional anemia, without any difference in complications of underresuscitation. This pilot study suggests that GDFT is likely safe and further investigation is warranted.

Total Pancreatectomy With Islet Autotransplantation Resolves Pain in Young Children With Severe Chronic Pancreatitis.

OBJECTIVES: Fear of diabetes and major surgery may prohibit referral of young children severely affected by pancreatitis for total pancreatectomy with islet autotransplant (TPIAT). We evaluated outcomes in our youngest TPIAT recipients, 3 to 8 years of age at surgery. METHODS: Medical records were reviewed for 17 children (9 girls) ages 8 years or younger undergoing TPIAT from 2000 to 2014. Most (14/17) had genetic risk factors for pancreatitis. Since 2006, TPIAT recipients were followed prospectively with health questionnaires including assessments of pain and narcotic use, and scheduled hemoglobin A1c (HbA1c) and mixed-meal tolerance tests (6 mL/kg Boost HP) before surgery, and at regular intervals after. Patients are 1 to 11 years post-TPIAT (median 2.2 years). Data are reported as median (25th, 75th percentile). RESULTS: All had relief of pain, with all 17 patients off narcotics at most recent follow-up. Hospitalization rates decreased from 5.0 hospitalization episodes per person-year of follow-up before TPIAT, to 0.35 episodes per person-year of follow-up after TPIAT. Fourteen (82%) discontinued insulin, higher than the observed insulin independence rate of 41% in 399 patients older than 8 years of age undergoing TPIAT over the same interval (P = 0.004). Median post-TPIAT HbA1c was 5.9% (5.6%, 6.3%), and within patient post-TPIAT mean HbA1c was ≤6.5% for all but 2 patients. CONCLUSIONS: Young children with severe refractory chronic pancreatitis may be good candidates for TPIAT, with high rates of pain relief and insulin independence, and excellent glycemic control in the majority.

Autologous islet transplantation: challenges and lessons.

PURPOSE OF REVIEW: Human islet isolation and autotransplantation [autologous islet transplant (AUTX)] is performed to prevent or ameliorate brittle diabetes after total pancreatectomy performed for benign disease. The success or failure of the transplant can be associated with a profound impact on the individual's quality of life and even survival. AUTX offers unique insights into the effects of pancreas quality, islet number, isolation technique and alternate site engraftment on transplant efficacy. Herein, we review islet isolation with a focus on potential pathways to further optimize the endocrine outcome of AUTX, and compare and contrast differences in islet processing for AUTX and allotransplantation (allogeneic islet transplant). RECENT FINDINGS: New knowledge of human islet biology and issues surrounding the engraftment process offer opportunities for innovative approaches toward optimizing islet cell transplantation. SUMMARY: Improving the rate and durability of insulin independence in the often-times marginal dose model of AUTX may provide new insight toward improving the efficiency and durability of single donor islet (allogeneic islet transplant).

Microbial contamination of transplant solutions during pancreatic islet autotransplants is not associated with clinical infection in a pediatric population.

BACKGROUND/OBJECTIVES: Total pancreatectomy and islet autotransplant (TP-IAT) is a potential treatment for children with severe refractory chronic pancreatitis. Cultures from the resected pancreas and final islet preparation are frequently positive for microbes. It is unknown whether positive cultures are associated with adverse outcomes in pediatric patients. METHODS: We reviewed the medical records of children (n = 86) who underwent TP-IAT from May 2006-March 2015 with emphasis on demographics, previous pancreatic interventions, culture results, islet yield, hospital days, posttransplant islet function, and posttransplant infections. We compared outcomes in patients with positive (n = 57) and negative (n = 29) cultures. RESULTS: Patients with positive cultures had higher rates of previous pancreas surgery (P = 0.007) and endoscopic retrograde cholangiopancreatography (P < 0.0001). Positive cultures were not associated with posttransplant infections (P = 1.00) or prolonged hospital length of stay (P = 0.29). Patients with positive final islet preparation culture showed increased rates of graft failure at 2 years posttransplant (P = 0.041), but not when adjusted for islet mass transplanted (P = 0.39). CONCLUSIONS: Positive cultures during pediatric TP-IATs do not increase the risk of posttransplant infections or prolong hospital length of stay. Endocrine function depends on islet mass transplanted.

Factors Predicting Outcomes After a Total Pancreatectomy and Islet Autotransplantation Lessons Learned From Over 500 Cases.

OBJECTIVE: Our objective was to analyze factors predicting outcomes after a total pancreatectomy and islet autotransplantation (TP-IAT). BACKGROUND: Chronic pancreatitis (CP) is increasingly treated by a TP-IAT. Postoperative outcomes are generally favorable, but a minority of patients fare poorly. METHODS: In our single-centered study, we analyzed the records of 581 patients with CP who underwent a TP-IAT. Endpoints included persistent postoperative "pancreatic pain" similar to preoperative levels, narcotic use for any reason, and islet graft failure at 1 year. RESULTS: In our patients, the duration (mean ±â€ŠSD) of CP before their TP-IAT was 7.1 ±â€Š0.3 years and narcotic usage of 3.3 ±â€Š0.2 years. Pediatric patients had better postoperative outcomes. Among adult patients, the odds of narcotic use at 1 year were increased by previous endoscopic retrograde cholangiopancreatography (ERCP) and stent placement, and a high number of previous stents (>3). Independent risk factors for pancreatic pain at 1 year were pancreas divisum, previous body mass index >30, and a high number of previous stents (>3). The strongest independent risk factor for islet graft failure was a low islet yield-in islet equivalents (IEQ)-per kilogram of body weight. We noted a strong dose-response relationship between the lowest-yield category (<2000 IEQ) and the highest (≥5000 IEQ or more). Islet graft failure was 25-fold more likely in the lowest-yield category. CONCLUSIONS: This article represents the largest study of factors predicting outcomes after a TP-IAT. Preoperatively, the patient subgroups we identified warrant further attention.

Pancreatic Cancer-Related Mutational Burden Is Not Increased in a Patient Cohort With Clinically Severe Chronic Pancreatitis.

INTRODUCTION: Chronic pancreatitis is associated with an increased risk of developing pancreatic cancer, and patients with inherited forms of pancreatitis are at greatest risk. We investigated whether clinical severity of pancreatitis could also be an indicator of cancer risk independent of etiology by performing targeted DNA sequencing to assess the mutational burden in 55 cancer-associated genes. METHODS: Using picodroplet digital polymerase chain reaction and next-generation sequencing, we reported the genomic profiles of pancreases from severe clinical cases of chronic pancreatitis that necessitated palliative total pancreatectomy with islet autotransplantation. RESULTS: We assessed 57 tissue samples from 39 patients with genetic and idiopathic etiologies and found that despite the clinical severity of disease, there was no corresponding increase in mutational burden. The average allele frequency of somatic variants was 1.19% (range 1.00%-5.97%), and distinct regions from the same patient displayed genomic heterogeneity, suggesting that these variants are subclonal. Few oncogenic KRAS mutations were discovered (7% of all samples), although we detected evidence of frequent cancer-related variants in other genes such as TP53, CDKN2A, and SMAD4. Of note, tissue samples with oncogenic KRAS mutations and samples from patients with PRSS1 mutations harbored an increased total number of somatic variants, suggesting that these patients may have increased genomic instability and could be at an increased risk of developing pancreatic cancer. DISCUSSION: Overall, we showed that even in those patients with chronic pancreatitis severe enough to warrant total pancreatectomy with islet autotransplantation, pancreatic cancer-related mutational burden is not appreciably increased.

Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.

Pre-operative Sarcopenia Predicts Low Islet Cell Yield Following Total Pancreatectomy with Islet Autotransplantation for Chronic Pancreatitis.

BACKGROUND AND AIM: Sarcopenia defined as degenerative loss of skeletal muscle mass associated with aging, represents an objective parameter to measure frailty and to estimate patient's physiologic reserves. It is a robust predictor of post-operative complications in transplantation and major oncologic surgeries. There is no data regarding the prevalence of sarcopenia in chronic pancreatitis or its impact on the outcome of patients undergoing TPIAT for CP. We sought to estimate the prevalence of sarcopenia, its impact on post-operative morbidity and prediction of islet yield and metabolic outcomes in patients undergoing TPIAT. METHODS: Adult patients undergoing TPIAT between 2008 and 2018 were identified from our prospectively maintained database and were included if they had CT within 6 months before TPIAT. Skeletal muscle index (SMI) was evaluated by pre-operative CT at the level of L3 vertebra. Sarcopenia was defined as SMI < 52.4 in males and < 38.5 in females. Post-operative morbidity occurring within 90 days after TPIAT was graded as per the validated Clavien-Dindo score. Major post-surgical morbidity was defined as Clavien-Dindo score of IIIa or more. The yield of islets was quantified as islet equivalents (IEQ) and IEQ/kg recipient body weight was calculated. RESULTS: One hundred and thirty-eight patients underwent TPIAT, with 46 (one-third) being classified as having pre-operative sarcopenia based on CT. No significant differences were observed in the incidence of any major surgical complications, length of hospital stay (median (range in days) 111-8 vs. 122-9; p = 0.6) and 30-day readmission rate (7 (15.2%) vs, 2 (2.2%); p = 0.5) between sarcopenic and non-sarcopenic patients. More patients with sarcopenia needed to be discharged to residential rehabilitation facility compared with non-sarcopenic patients (7 (15.2%) vs. 2 (2.2%), p = 0.007). Sarcopenia (OR 7.4 (95% CI 1.32-41.24); p = 0.023) and presence of calcification (OR 5.5 (95% CI 0.94-32.19); p = 0.05) were independent predictors of low islet yield (< 2500 IEQ/kg) on multivariate analysis. CONCLUSION: Sarcopenia is frequent in CP patients undergoing TPIAT, but not readily recognized by standard anthropometric measurement. Sarcopenia was associated with increased chance of discharge to a residential rehabilitation facility and with a poor islet yield during TPIAT. It is therefore critical to optimize nutrition prior to TPIAT surgery in CP patients.

Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death: A Multi-laboratory Assay Comparison.

CONTEXT: There is an unmet need for biomarkers of pancreatic beta-cell death to improve early diagnosis of type 1 diabetes, enroll subjects into clinical trials, and assess treatment response. To address this need, several groups developed assays measuring insulin deoxyribonucleic acid (DNA) with unmethylated CpG sites in cell-free DNA. Unmethylated insulin DNA should be derived predominantly from beta-cells and indicate ongoing beta-cell death. OBJECTIVE: To assess the performance of three unmethylated insulin DNA assays. DESIGN AND PARTICIPANTS: Plasma or serum samples from 13 subjects undergoing total pancreatectomy and islet autotransplantation were coded and provided to investigators to measure unmethylated insulin DNA. Samples included a negative control taken post-pancreatectomy but pretransplant, and a positive control taken immediately following islet infusion. We assessed technical reproducibility, linearity, and persistence of detection of unmethylated insulin DNA for each assay. RESULTS: All assays discriminated between the negative sample and samples taken directly from the islet transplant bag; 2 of 3 discriminated negative samples from those taken immediately after islet infusion. When high levels of unmethylated insulin DNA were present, technical reproducibility was generally good for all assays. CONCLUSIONS: The measurement of beta cell cell-free DNA, including insulin, is a promising approach, warranting further testing and development in those with or at-risk for type 1 diabetes, as well as in other settings where understanding the frequency or kinetics of beta cell death could be useful.

Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels.

Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non-glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by ß-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak-mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid-stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.

Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes.

Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation.

Incidental Neuroendocrine Tumor Discovered After Total Pancreatectomy Intended for Islet Autotransplantation: Important Considerations for Surgical Decision-Making.

Total pancreatectomy (TP) is a treatment option for patients experiencing chronic pancreatitis (CP) refractory to medical management. Patients who are candidates for TP benefit from islet autotransplantation (IAT), which preserves available ß-cell mass and thereby reduces the risk of brittle diabetes. Malignancy is an absolute contraindication for IAT to prevent the transplantation of occult malignant cells. We present the case of a patient with CP who was approved to undergo TP with IAT (TPIAT) but was intraoperatively discovered to have a pancreatic neuroendocrine tumor. The case illustrates a number of important surgical decision-making considerations for patients undergoing TPIAT and should help guide surgeons should they be presented with this clinical scenario. We stress the importance of vigilance for possible malignancy and to consider an intraoperative biopsy to further investigate unexpected findings that might represent an occult pancreatic malignancy in patients with CP undergoing TPIAT.

Effect of intrapancreatic fat on diabetes outcomes after total pancreatectomy with islet autotransplantation.

BACKGROUND: Pancreatic fat may adversely affect ß-cell mass and function, possibly via local release of non-esterified fatty acids, and proinflammatory and vasoactive factors released by adipose tissue. However, the effects of intrapancreatic fat in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplantation (TPIAT) have not been studied. This study investigated whether pancreatic fatty infiltration has a negative effect on metabolic outcomes following TPIAT. METHODS: The association between pancreatic fatty infiltration and diabetes outcomes was studied in 79 patients with low or high pancreatic fat content (LPF [n = 53] and HPF [n = 26], respectively) undergoing TPIAT. Pancreatic fatty infiltration was stratified using gross examinations during isolation and validated with histomorphometry of archived histology samples. RESULTS: Fat area percentage in histology samples differed significantly between the LPF and HPF groups (2.1% ± 4.3% vs 10.6% ± 8.9%, respectively; P = 0.0009). Insulin dependence was more common in the HPF group, whereas more patients in the LPF group were insulin independent or on partial insulin supplementation at 1 year (P = 0.022). Furthermore, 1- and 2-h glucose concentrations during mixed-meal tolerance tests were significantly higher in the HPF group (P = 0.032 and 0.027, respectively) and ß-scores (a composite measure of islet function and metabolic control) were significantly greater in the LPF than HPF group (6.1 ± 1.7 vs 4.6 ± 2.0; P = 0.034). CONCLUSIONS: Patients with HPF were more likely to be insulin dependent, with higher postprandial glucose excursion, suggesting that intrapancreatic fat may lead to ß-cell dysfunction with detrimental effects on diabetes outcomes after TPIAT.

Age and Disease Duration Impact Outcomes of Total Pancreatectomy and Islet Autotransplant for PRSS1 Hereditary Pancreatitis.

OBJECTIVES: We investigated the impact of patient age and disease duration on islet isolation results, diabetes outcomes, and pain outcomes after total pancreatectomy with islet autotransplant (TPIAT) performed in 64 patients with hereditary pancreatitis due to PRSS1 gene mutation. METHODS: We evaluated the association of patient age and disease duration on islet isolation results and opioid use at 1 year using logistic regression and on graft function using 1-way analysis of variance. RESULTS: Islet mass was negatively associated with increasing age and longer disease duration, with a 13% reduction (95% confidence interval [CI], 3%-22%) and 22% (95% CI, 14%-29%) reduction in islet equivalents per kilogram body weight (IEQ/kg) for each 5 years of age and disease duration, respectively. Full graft function was associated with younger age and shorter duration of disease (P < 0.01). Persistent opioid use (15% of patients at 1 year) increased with age (P = 0.05) and disease duration (P = 0.04). CONCLUSIONS: The TPIAT outcomes were adversely impacted by older age and prolonged disease. In particular, islet mass is lower and risk of diabetes high in older patients with prolonged disease. This should be considered when counseling this subgroup of TPIAT recipients on expected outcomes.