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ObjectiveThe aim of this study was to characterize utilization and benefit of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP).MethodsFrom August 2012 to February 2015, 301 children with ARP or CP were enrolled in the INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) study. Physicians reported utilization and benefit of therapeutic ERCP at enrollment. Differences were analyzed using appropriate statistical methods.ResultsOne hundred seventeen children (38.9%) underwent at least 1 therapeutic ERCP. The procedure was more commonly performed in children with CP compared with those with ARP (65.8% vs 13.5%, P < 0.0001). Utility of therapeutic ERCP was reported to be similar between ARP and CP (53% vs 56%, P = 0.81) and was found to be helpful for at least 1 indication in both groups (53/99 patients [53.5%]). Predictors for undergoing therapeutic ERCP were presence of obstructive factors in ARP and CP, Hispanic ethnicity, or white race in CP.ConclusionsTherapeutic ERCP is frequently utilized in children with ARP or CP and may offer benefit in selected cases, specifically if ductal obstruction is present. Longitudinal studies are needed to clarify the efficacy of therapeutic ERCP and to explore subgroups that might have increased benefit from such intervention.

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).New knowledge of human islet biology and issues surrounding the engraftment process offer opportunities for innovative approaches toward optimizing islet cell transplantation.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).

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.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.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.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.

Introduction Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response. Methods This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10–18) with ARP/CP and their parents from twenty-one INSPPIRE ( IN ternational S tudy Group of P ediatric P ancreatitis: I n search for a cu RE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization. Conclusions This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431.

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis (CP). The session was held on July 23, 2014, and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, gastrointestinal complications in this population, and unique features of children with CP considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of CP and total pancreatectomy outcomes as well as postsurgical diabetes outcomes was repeatedly emphasized.

Children with severe chronic pancreatitis may undergo total pancreatectomy with islet autotransplantation (TPIAT) to relieve pain while minimizing the risk of postsurgical diabetes. Because overstimulation of transplanted islets by hyperglycemia can result in β-cell loss, we developed a specialized intravenous insulin infusion protocol (IIP) for pediatric TPIAT recipients to maintain euglycemia or near-euglycemia posttransplant.Our objective was to review glucose control using an IIP specific for TPIAT recipients at a single institution. We reviewed postoperative blood glucose (BG) levels for 32 children 4-18 years old with chronic pancreatitis who underwent TPIAT between July 2011 and June 2013. We analyzed the proportion of BG values in the range of 70-140 mg/dL, mean glucose, glucose variability, and occurrence of hypoglycemia during the IIP; we also evaluated the transition to subcutaneous therapy (first 72 h with multiple daily injections [MDI]).During IIP, the mean patient BG level was 116±27 mg/dL, with 83.1% of all values in the range of 70-140 mg/dL. Hypoglycemia was rare, with only 2.5% of values70 mg/dL. The more recent era (n=16) had a lower mean BG and less variability than the early era (first 16 patients) (P≤0.004). Mean glucose level (116 vs. 128 mg/dL) and glucose variability were significantly lower during the IIP compared with MDI therapy (P0.0001).Tight glycemic control without excessive severe hypoglycemia was achieved in children undergoing TPIAT using an IIP specifically designed for this population; the ability to maintain BG in target range improved with experience with the protocol.

We used intravenous arginine with measurements of insulin, C-peptide, and glucagon to examine β-cell and α-cell survival and function in a group of 10 chronic pancreatitis recipients 1–8 years after total pancreatectomy and autoislet transplantation. Insulin and C-peptide responses correlated robustly with the number of islets transplanted (correlation coefficients range 0.81–0.91; P < 0.01–0.001). Since a wide range of islets were transplanted, we normalized the insulin and C-peptide responses to the number of islets transplanted in each recipient for comparison with responses in normal subjects. No significant differences were observed in terms of magnitude and timing of hormone release in the two groups. Three recipients had a portion of the autoislets placed within their peritoneal cavities, which appeared to be functioning normally up to 7 years posttransplant. Glucagon responses to arginine were normally timed and normally suppressed by intravenous glucose infusion. These findings indicate that arginine stimulation testing may be a means of assessing the numbers of native islets available in autologous islet transplant candidates and is a means of following posttransplant α- and β-cell function and survival.

Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from nondiabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus nonhepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 ± 6, pg/mL, mean ± SE, n = 9, p = ns; symptom score = 1 ± 1, p = ns). When islets were transplanted in both intrahepatic + nonhepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H + NH: glucagon increment = 54 ± 14, n = 5; symptom score = 7 ± 3; control glucagon increment = 67 ± 15, n = 5; symptom score = 8 ± 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 ± 8, n = 7). Transplantation of a portion of the islets into a nonhepatic site should be seriously considered in TP/IAT to avoid posttransplant abnormalities in glucagon and symptom responses to hypoglycemia.

Describe the surgical technique, complications, and long-term outcomes of total pancreatectomy and islet autotransplantation (TP-IAT) in a large series of pediatric patients.Surgical management of childhood pancreatitis is not clear; partial resection or drainage procedures often provide transient pain relief, but long-term recurrence is common due to the diffuse involvement of the pancreas. Total pancreatectomy (TP) removes the source of the pain, whereas islet autotransplantation (IAT) potentially can prevent or minimize TP-related diabetes.Retrospective review of 75 children undergoing TP-IAT for chronic pancreatitis who had failed medical, endoscopic, or surgical treatment between 1989 and 2012.Pancreatitis pain and the severity of pain statistically improved in 90% of patients after TP-IAT (P0.001). The relief from narcotics was sustained. Of the 75 patients undergoing TP-IAT, 31 (41.3%) achieved insulin independence. Younger age (P = 0.032), lack of prior Puestow procedure (P = 0.018), lower body surface area (P = 0.048), higher islet equivalents (IEQ) per kilogram body weight (P = 0.001), and total IEQ (100,000) (P = 0.004) were associated with insulin independence. By multivariate analysis, 3 factors were associated with insulin independence after TP-IAT: (1) male sex, (2) lower body surface area, and (3) higher total IEQ per kilogram body weight. Total IEQ (100,000) was the single factor most strongly associated with insulin independence (odds ratio = 2.62; P0.001).Total pancreatectomy and islet autotransplantation provides sustained pain relief and improved quality of life. The β-cell function is dependent on islet yield. Total pancreatectomy and islet autotransplantation is an effective therapy for children with painful pancreatitis that failed medical and/or endoscopic management.

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how obesity contributes to pancreatic cancer development is not well understood. Moreover, whether and at what point weight loss or other obesity-related interventions may impact PDAC progression remains largely unexplored, with significant implications for prevention and treatment. Leveraging an autochthonous genetically engineered model of PDAC, we demonstrate that obesity plays a stage-specific causal and reversible role in early PDAC progression. Molecular and histologic analyses reveal prominent microenvironmental alterations in tumors from obese mice, including increased inflammation and fibrosis and evidence for marked pancreatic islet cell adaptation. In particular, we identify aberrant expression of the peptide hormone cholecystokinin (CCK) in pancreatic islets in tumors as an adaptive response to obesity and show that islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Together, these studies link obesity, changes in the local microenvironment, and tumorigenesis and implicate islet-derived hormones beyond insulin in PDAC development. Furthermore, the reversible nature of these adaptations supports the potential of antiobesity strategies to intercept PDAC early during progression. Citation Format: Katherine Minjee Chung, Jaffarguribal Singh, Lauren Lawres, Kimberly Judith Dorans, Rebecca Robbins, Arjun Bhutkar, Ana Babic, Sara A. Vayrynen, Andressa D. Costa, Jonathan A. Nowak, Daniel T. Chang, Richard F. Dunne, Aram F. Hezel, Albert C. Koong, Joshua J. Wilhelm, Melena D. Bellin, Vibe Nylander, Anna L. Gloyn, Mark I. McCarthy, Brian M. Wolpin, Tyler Jacks, Charles S. Fuchs, Mandar Deepak Muzumdar. Microenvironmental adaptations drive obesity-associated pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A35.

In a retrospective multicentre study of patients with type 1 diabetes mellitus, islet transplantation was associated with sustained HbA1c levels of

Description Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure used to treat severe complications of chronic pancreatitis or very high risk of pancreatic cancer while reducing the risk of severe diabetes mellitus. However, clear guidance on indications, contraindications, evaluation, timing, and follow-up are lacking. Methods A working group reviewed the medical, psychological, and surgical options and supporting literature related to TPIAT for a consensus meeting during PancreasFest . Results Five major areas requiring clinical evaluation and management were addressed: These included: 1) indications for TPIAT; 2) contraindications for TPIAT; 3) optimal timing of the procedure; 4) need for a multi-disciplinary team and the roles of the members; 5) life-long management issues following TPIAP including diabetes monitoring and nutrition evaluation. Conclusions TPIAT is an effective method of managing the disabling complications of chronic pancreatitis and risk of pancreatic cancer in very high risk patients. Careful evaluation and long-term management of candidate patients by qualified multidisciplinary teams is required. Multiple recommendations for further research were also identified.

In patients with type 1 diabetes mellitus (T1DM) complicated by severe hypoglycemic episodes, fear of hypoglycemia can significantly impact daily life. We evaluated whether restoration of glycemic awareness and prevention of hypoglycemia by islet allotransplant could reduce fear and improve health status. We conducted a comprehensive evaluation of patient-based outcomes in 48 T1DM subjects screened for allogeneic islet transplant alone (ITA) and 27 subjects who received an ITA. A battery of generic health status and diabetes-specific measures were used to assess ITA at evaluation, six months, and then annually after ITA. Allogeneic islet transplant was associated with a reduction in behaviors adopted in avoiding hypoglycemia (p Value < 0.001) and attenuation in concerns about hypoglycemic episodes (p Value < 0.001). Changes in hypoglycemia fear tracked most closely with insulin use. While there was a trend toward global improvement in health as measured by the EQ-5D (p Value = 0.002) and in depression symptoms as measured by the Beck (p Value = 0.003), physical health remained unchanged following ITA. Our findings support the socioemotional benefits of ITA during the five years after ITA, which to some extent remains dependent on preservation of islet graft function.

Islet autotransplant (IAT) may ameliorate postsurgical diabetes following total pancreatectomy (TP), but outcomes are dependent upon islet mass, which is unknown prior to pancreatectomy. We evaluated whether preoperative metabolic testing could predict islet isolation outcomes and thus improve assessment of TPIAT candidates. We examined the relationship between measures from frequent sample IV glucose tolerance tests (FSIVGTT) and mixed meal tolerance tests (MMTT) and islet mass in 60 adult patients, with multivariate logistic regression modeling to identify predictors of islet mass ≥2500 IEQ/kg. The acute C-peptide response to glucose (ACRglu) and disposition index from FSIVGTT correlated modestly with the islet equivalents per kilogram body weight (IEQ/kg). Fasting and MMTT glucose levels and HbA1c correlated inversely with IEQ/kg (r values -0.33 to -0.40, p ≤ 0.05). In multivariate logistic regression modeling, normal fasting glucose (

Cystic fibrosis related diabetes (CFRD) is characterized by progressive insulin insufficiency. It is extraordinarily prevalent in the cystic fibrosis (CF) population, occurring in 15–20% of adolescents and, eventually, more than half of adults (1). Few of the remaining patients have completely normal glucose metabolism; even those with normal fasting and 2-hour oral glucose tolerance test (OGTT) glucose levels typically have mid-OGTT glucose elevation and have defective acute insulin secretion in response to intravenous glucose (2). While CFRD does not usually develop before puberty, it has its roots in childhood and glucose intolerance is common in 6–9 year old children with CF (3). It has not been studied in younger children, but ferret models of CF demonstrate insulin secretory abnormalities in the newborn period (4), suggesting that there may be an intrinsic defect in beta-cell function in CF. CF is caused by abnormalities in the CF transmembrane conductance regulator (CFTR), an ATP-binding cassette transporter-class ion channel involved in chloride, sodium and water transport and absorption across cell membranes. CFTR defects lead to thick, viscous secretions with well-known chronic complications including obstructive lung disease associated with infection and inflammation, sinusitis, intestinal obstruction, liver disease and infertility. Pancreatic exocrine insufficiency develops as plugged ductules prevent digestive enzymes from reaching the gut; autodigestion of the pancreas by these trapped enzymes leads to fibrosis. It has long been debated whether insulin insufficiency in CF is merely a physical, “by-stander” consequence of this fibrotic destruction of the pancreatic architecture, or if CFTR defects per se impact insulin secretion (5). CFTR is expressed in human and mouse pancreatic alpha- and beta-cells (6; 7), but it is not known whether it is involved in hormone secretion. There has previously been no way to directly test this in a human model. Ivacaftor (VX-770, Kalydeco™, Vertex Pharmaceuticals, Cambridge, MA) is the first of a group of “potentiator” molecules being developed to correct the CFTR defect. CFTR is made in the endoplasmic reticulum, processed in the Golgi apparatus, and secreted in vesicles which chaperone proteins carry to the cell membrane, where it must be inserted and then must function normally. Defects leading to CF may occur at any of these steps. In patients with the G551D mutation (about 4% of the CF population), CFTR is found in the cell membrane but is dysfunctional. Ivacaftor corrects this defect by restoring channel gating, through an as-yet unidentified mechanism (8). In clinical Phase 2 and 3 trials, ivacaftor produced dramatic improvements in skin sweat chloride levels and in lung function within just 3 weeks (9; 10), and the drug has recently been approved by the FDA in children down to age 6. The initiation of ivacaftor therapy offers a unique opportunity to test the role of CFTR in human insulin secretion, potentially opening the way for novel diabetes therapies and for prevention or at least amelioration of diabetes in CF.

Objective To examine whether insulin requirements and diabetes control differ between adolescents and adults with cystic fibrosis related diabetes (CFRD). Methods All CFRD patients on insulin therapy seen at the University of Minnesota outpatient clinic from 1 January 2011 to 1 June 2012 were identified. Hemoglobin A1c (HbA1c) levels obtained during this period were averaged for each patient, and the most recent outpatient insulin dose was obtained. In addition, retrospective chart review was performed in order to obtain longitudinal data on insulin requirements during the transition from adolescence to adulthood. Results Eighteen youth aged 14–19 yr and 137 adults aged 20–67 yr were identified to be currently on insulin therapy. The average insulin dose was 0.38 ± 0.29 units/kg/d for adolescents and 0.46 ± 0.30 units/kg/d for adults (p = 0.20). In adults, insulin doses were significantly higher in transplant recipients: Tx = 0.58 ± 0.29, no Tx = 0.43 ± 0.30 (p = 0.005). Average HbA1c was 6.9 ± 2.1% in youth and 6.9 ± 1.5% in adults (p = 0.35). There were no changes in the insulin dosage when adolescents transitioned to adulthood with diabetes were not on higher doses of insulin compared to when they were adolescents with diabetes. Conclusion Modest insulin requirements suggest the persistence of endogenous insulin secretion in both youth and adults with CFRD. In adolescents, residual endogenous insulin secretion likely compensates for the insulin resistance during puberty, keeping insulin requirements low.

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology; (2) exocrine complications; (3) endocrine complications; and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator (CFTR) potentiators as possible treatments for CP were discussed. Importantly, the need for chronic pancreatitis endpoints and intermediate targets for future drug trials was emphasized.

Total pancreatectomy with islet autotransplantation (TPIAT) is increasingly performed with remote islet cell processing and preparation, i.e., with islet cell isolation performed remotely from the primary surgical site at an appropriately equipped islet isolation facility. We aimed to determine whether TPIAT using remote islet isolation results in comparable long-term glycemic outcomes compared with TPIAT performed with standard local isolation.We performed a retrospective cohort study of adult patients who underwent TPIAT at three tertiary care centers from 2010 to 2013. Two centers performed remote isolation and one performed local isolation. Explanted pancreata in the remote cohort were transported ∼130 miles to and from islet isolation facilities. The primary outcome was insulin independence 1 year following transplant.Baseline characteristics were similar between groups except the remote cohort had higher preoperative hemoglobin A1c (HbA1c; 5.43 vs. 5.25, P=0.02) and there were more females in the local cohort (58% vs. 76%, P=0.049). At 1 year, 27% of remote and 32% of local patients were insulin independent (P=0.48). Remote patients experienced a greater drop in fasting c-peptide (-1.66 vs. -0.64, P=0.006) and a greater rise in HbA1c (1.65 vs. 0.99, P=0.014) at 1-year follow-up. A preoperative c-peptide2.7 (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6-14.3) and3,000 islet equivalents/kg (OR 11.0, 95% CI 3.2-37.3) were associated with one-year insulin independence in the local group.At 1 year after TPIAT, patients undergoing remote surgery have equivalent rates of long-term insulin independence compared with patients undergoing TPIAT locally, but metabolic control is superior with local isolation.

OBJECTIVES Approximately two thirds of patients will remain on insulin therapy after total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We investigated the relationship between measured pancreas volume on computerized tomography or magnetic resonance imaging and features of chronic pancreatitis on imaging, with subsequent islet isolation and diabetes outcomes. METHODS Computerized tomography or magnetic resonance imaging was reviewed for pancreas volume (Vitrea software) and presence or absence of calcifications, atrophy, and dilated pancreatic duct in 97 patients undergoing TPIAT. Relationship between these features and (1) islet mass isolated and (2) diabetes status at 1-year post-TPIAT were evaluated. RESULTS Pancreas volume correlated with islet mass measured as total islet equivalents (r = 0.50, P < 0.0001). Mean islet equivalents were reduced by more than half if any one of calcifications, atrophy, or ductal dilatation were observed. Pancreatic calcifications increased the odds of insulin dependence 4.0 fold (1.1, 15). Collectively, the pancreas volume and 3 imaging features strongly associated with 1-year insulin use (P = 0.07), islet graft failure (P = 0.003), hemoglobin A1c (P = 0.0004), fasting glucose (P = 0.027), and fasting C-peptide level (P = 0.008). CONCLUSIONS Measures of pancreatic parenchymal destruction on imaging, including smaller pancreas volume and calcifications, associate strongly with impaired islet mass and 1-year diabetes outcomes.

Summary Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

Total pancreatectomy with islet autotransplantation (TPIAT) is being used increasingly as a definitive treatment for chronic pancreatitis. Patients with chronic pancreatitis have an elevated risk of pancreatic cancer, which can also masquerade as acute or chronic pancreatitis, making the diagnosis challenging. We describe here the first case of pancreatic ductal adenocarcinoma developing in the liver of a patient after TPIAT for presumed benign chronic pancreatitis. Retrospective analysis of the patient's preoperative serum revealed normal carbohydrate antigen 19-9 and carcinoembryonic antigen levels but elevated levels of microRNAs -10b, -30c, and -106b compared with controls. Screening guidelines are important to reduce the risk of transplantation of malignant tissue. More sensitive screening tools, including the potential use of microRNAs, are needed to detect early preclinical disease, given the highly malignant nature of pancreatic cancer.

ImportancePediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood.ObjectiveTo characterize and identify risk factors associated with ARP and CP in childhood.Design, setting, and participantsA multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test.Main outcomes and measuresDemographic characteristics, risk factors, abdominal pain, and disease burden.ResultsA total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P

Among postsurgical and critically ill patients, malglycemia is associated with increased complications. Continuous glucose monitoring (CGM) in the inpatient population may enhance glycemic control. CGM reliability may be compromised by postsurgical complications such as edema or vascular changes. We utilized Clarke Error Grid (CEG) and Surveillance Error Grid (SEG) analysis to evaluate CGM performance after total pancreatectomy with islet autotransplantation.This subanalysis evaluated Medtronic Enlite 2 CGM values against YSI serum glucose in seven post-transplant patients (86% female; 38.6 ± 9.4 years) on artificial pancreas for 72 h at transition from intravenous to subcutaneous insulin. Sensor recalibration occurred for absolute relative difference (ARD) ≥20% x2, ≥30% x1, or by investigator discretion based on trend.Sensor analysis showed mean absolute relative difference (MARD) of 11.0% ± 11.5%. The sensors were recalibrated 8.3 times/day; active sensor was switched 1.4 times/day. Calibration factor was 7.692 ± 3.786 mg/nA·dL (target = 1.5-20 mg/nA·dL). CEG analysis showed 86.1% of pairs in Zone A (clinically accurate zone) and 99.4% of pairs in Zones A + B (low risk of error). SEG analysis of hypoglycemia/hyperglycemia risk showed 92.22% of pairs in the "no risk" zone, 5.96% of pairs in the "slight lower" risk zone, 1.01% of pairs in the "slight higher" risk zone, and only 0.81% of pairs in the "moderate lower" risk zone.Overall performance of the Medtronic Enlite 2 CGM in the post-transplant population was reasonably good with "no risk" or "slight lower" risk by SEG analysis and high CGM-YSI agreement by CEG analysis; however, frequent recalibrations were required in this intensive care population.

Objective To estimate selected direct medical care costs of children with chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). Methods We performed a cross-sectional study of data from International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE), a multinational registry of children with ARP or CP. We determined health care utilization and estimated costs of hospitalizations, surgical and endoscopic procedures, and medications in our study population. Health care utilization data were obtained from all subjects enrolled in the study, and costs were calculated using national United States costs. Results We included 224 subjects (median age 12.7 years), 42% of whom had CP. Mean number of hospitalizations, including for surgery and endoscopic retrograde cholangiopancreatography, was 2.3 per person per year, costing an estimated average $38,755 per person per year. Including outpatient medications, estimated total mean cost was $40,589 per person per year. Subjects using surgical procedures or endoscopic retrograde cholangiopancreatography incurred mean annual costs of $42,951 per person and $12,035 per person, respectively. Estimated annual costs of pancreatic enzyme replacement therapy, diabetic medications, and pain medications were $4114, $1761, and $614 per person, respectively. In an exploratory analysis, patients with the following characteristics appear to accrue higher costs than those without them: more frequent ARP attacks per year, reported constant or episodic pain, family history of pancreatic cancer, and use of pain medication. Conclusions ARP and CP are uncommon childhood conditions. The severe burden of disease associated with these conditions and their chronicity results in high health care utilization and costs. Interventions that reduce the need for hospitalization could lower costs for these children and their families.

Diabetes mellitus is a frequent consequence of chronic pancreatitis (CP). Little is known about pancreatic endocrine function before the development of diabetes mellitus in CP, particularly in females, or those without calcific and/or alcoholic pancreatitis.Twenty-five nondiabetic adult patients with CP (19 female; mean [SE] age, 34.2 [2.4] years) were compared with 25 healthy controls matched for age, sex, and body mass index. Subjects underwent frequent sample intravenous glucose tolerance testing (FSIVGTT) and mixed meal tolerance testing (MMTT).Mean (SE) fasting glucose was higher in patients with CP (89.5 [2.3] mg/dL) than in controls (84.4 [1.2] mg/dL, P = 0.04). On MMTT, patients with CP had a higher area under the curve (AUC) glucose and AUC glucagon compared with controls (P ≤ 0.01). The AUC C-peptide was equivalent (P = 0.6) but stimulated C-peptide at 30 minutes was lower in patients with CP (P = 0.04). Mean insulin sensitivity index calculated from the FSIVGTT was lower in CP group, indicating reduced insulin sensitivity (P ≤ 0.01). Disposition index (insulin secretion adjusted for insulin sensitivity on FSIVGTT) was lower in patients with CP (P = 0.01).Patients with CP had higher fasting and MMTT glucose levels, without a compensatory increase in insulin secretion suggesting subtle early islet dysfunction. Our cohort had relative hyperglucagonemia and was less insulin sensitive than controls.

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.

BACKGROUND The optimal enzyme blend that maximizes human islet yield for transplantation remains to be determined. In this study, we evaluated eight different enzyme combinations (ECs) in an attempt to improve islet yield. The ECs consisted of purified, intact or truncated class 1 (C1) and class 2 (C2) collagenases from Clostridium histolyticum (Ch), and neutral protease (NP) from Bacillus thermoproteolyticus rokko (thermolysin) or Ch (ChNP). METHODS We report the results of 249 human islet isolations, including 99 deceased donors (research n=57, clinical n=42) and 150 chronic pancreatitis pancreases. We prepared a new enzyme mixture (NEM) composed of intact C1 and C2 collagenases and ChNP in place of thermolysin. The NEM was first tested in split pancreas (n=5) experiments and then used for islet autologous (n=21) and allogeneic transplantation (n=10). Islet isolation outcomes from eight different ECs were statistically compared using multivariate analysis. RESULTS The NEM consistently achieved higher islet yields from pancreatitis (P

Total pancreatectomy (TP) and islet autotransplant (IAT) have been used to treat patients with painful chronic pancreatitis. Initial studies indicated that most patients experienced significant pain relief, but there were few validated measures of quality of life. We investigated whether health-related quality of life improved among pediatric patients undergoing TP/IAT.Nineteen consecutive children (aged 5-18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Insulin requirements were recorded.Before TP/IAT, patients had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores improved to 50 and 46, respectively (global effect, PCS P.001, MCS P = .06). Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had lower yields of islets (P = .01) and greater incidence of insulin dependence (P = .04).Quality of life (physical and emotional components) significantly improve after TP/IAT in subsets of pediatric patients with severe chronic pancreatitis. Minimal or no insulin was required for most patients, although islet yield was reduced in patients with previous surgical drainage operations.

Islet autotransplantation (IAT) is performed at the time of total pancreatectomy (TP) to prevent or minimize post-surgical diabetes. Corticosteroids induce insulin resistance and present a risk to islet autografts, through glucotoxicity and increased metabolic demand on a marginal islet mass. We present four IAT recipients treated with oral or injected corticosteroids after transplant for medical conditions unrelated to chronic pancreatitis or TPIAT. Hyperglycemia or insulin resistance was evident in all four patients, including reversion to long-term insulin therapy in two patients. One patient receiving corticosteroid injections had a transient increase in hemoglobin A1c (+0.6% above baseline), and one patient given a one time dose of oral dexamethasone exhibited hyperglycemia despite high insulin (>200 mU/L) and C-peptide (15.3 ng/mL) production on an oral glucose tolerance test. IAT recipients have insufficient islet mass to compensate for the insulin resistance induced by corticosteroids. Caution should be given to using these agents in IAT recipients. When corticosteroids are medically necessary, insulin therapy should be administered temporarily to compensate for the increased metabolic demand and minimize long-term risks on the islet graft.

X-linked adrenoleukodystrophy is characterized by elevated levels of very long chain fatty acids in the serum, brain, and adrenal glands that can lead to neurodevelopmental impairment and decreased adrenal function. We report here the case of a pediatric patient with pericarditis who was found to have adrenoleukodystrophy. More common causes of pericarditis (such as infectious, autoimmune, and metabolic) were excluded. On the basis of the examination finding of cutaneous hyperpigmentation, hypocortisolism was discovered. Further evaluation revealed elevated serum levels of very long chain fatty acids and a partial deletion of the ABCD1 gene, consistent with the diagnosis of X-linked adrenoleukodystrophy. Two of the index patient's brothers were subsequently found to have the same disease. Although pericarditis has been reported previously in association with autoimmune diseases that affect the adrenal glands, this is the first reported case (to our knowledge) of pericarditis in association with hypocortisolism from a nonautoimmune cause. Therefore, we suggest that hypocortisolism itself may lead to pericarditis in some patients.

The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen-1 antibody efalizumab which permits long-term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single-islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long-term follow-up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid-free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long-term islet allograft survival.

OBJECTIVES: The probability of insulin independence after intraportal islet autotransplantation (IAT) for chronic pancreatitis (CP) treated by total pancreatectomy (TP) relates to the number of islets isolated from the excised pancreas. Our goal was to correlate the islet yield with the histopathologic findings and the clinical parameters in pediatric (age

Bellin MD, Blondet JJ, Beilman GJ, Dunn TyB, Balamurugan AN, Thomas W, Sutherland DER, Moran A. Predicting islet yield in pediatric patients undergoing pancreatectomy and autoislet transplantation for chronic pancreatitis. Background/Objective: Chronic pancreatitis (CP) in children is associated with significant morbidity and can lead to narcotic dependence. Total pancreatectomy (TP) may be indicated in refractory CP to relieve pain; simultaneous islet autotransplant (IAT) may prevent postsurgical diabetes. About half of pediatric patients are insulin independent 1 yr after IAT. Insulin independence correlates best with the number of islets available for transplantation (islet yield). Currently there is no known method to predict islet yield in a given patient. We assessed the ability of preoperative metabolic tests to predict islet yields in 10 children undergoing TP/IAT. Design/Methods: Hemoglobin A1c (HbA1c) and mixed meal tolerance tests (MMTT) were obtained prior to surgery in 10 patients age ≤ 18 yr. Fasting glucose, C-peptide, and creatinine were used to calculate the C-peptide to glucose* creatinine ratio (CPGCR). C-peptide peak and area under the curve (AUC) were determined from 2 h MMTT. Linear regressions were performed to predict islet yield from baseline test results. Results: Islet yield ranged from 7000 to 434 000 islet equivalents (IE) (mean 222 452 ± 148 697 IE). Islet yield was well predicted from body weight and fasting plasma glucose (R 2 = 57%, adjusted for overfitting by bootstrap). Islet yield was positively associated with CPGCR, peak C-peptide, and AUC C-peptide and negatively associated with HbA1c. Conclusions: Pilot data from 10 pediatric patients suggest that simple preoperative measurement of fasting plasma glucose may give a useful prediction of islet yield. Islet yield correlates with HbA1c and C-peptide levels. This information allows individual candidates to weigh the specific risk of becoming diabetic against the benefit of pain relief should they undergo TP-IAT.

Pancreatitis in children can result from metabolic and toxic risk factors, but the evidence linking these factors is sparse. We review the evidence for association or causality of these risk factors in pancreatitis, discuss management strategies, and their rationale. We conducted a review of the pediatric pancreatitis literature with respect to the following risk factors: hyperlipidemia, hypercalcemia, chronic renal failure, smoking exposure, alcohol, and medications. Areas of additional research were identified. Hypertriglyceridemia of 1000 mg/dL or greater poses an absolute risk for pancreatitis; persistent elevations of calcium are predisposing. Further research is necessary to determine whether end-stage renal disease leads to increased pancreatitis in children similar to adults. It is unknown whether cigarette smoking exposure, which clearly increases risk in adults, also increases risk in children. The role of alcohol in pediatric pancreatitis, whether direct or modifying, needs to be elucidated. The evidence supporting most cases of medication-induced pancreatitis is poor. Drug structure, improper handling of drug by host, and bystander status may be implicated. Other pancreatitis risk factors must be sought in all cases. The quality of evidence supporting causative role of various toxic and metabolic factors in pediatric pancreatitis is variable. Careful phenotyping is essential, including search for other etiologic risk factors. Directed therapy includes correction/removal of any agent identified, and general supportive measures. Further research is necessary to improve our understanding of these pancreatitis risk factors in children.

This article provides a summary of the current outcomes of β-cell replacement strategies, an algorithm for choosing a specific modality while highlighting associated advantages and disadvantages, and outlines remaining challenges and areas of active investigation in β-cell replacement therapy.The most recent reports of islet cell allotransplantation have shown improvements over previous eras and now rival some outcomes of pancreas alone transplantation. Active areas of investigation are focused on improving techniques for islet isolation, graft monitoring, and managing challenges posed by the innate and alloimmune systems.Patients with insulin-dependent diabetes who continue to experience life threatening hypoglycemia despite maximal medical management can benefit from β-cell replacement. Emerging nontransplant technologies have not provided a physiologic euglycemic state to the extent offered by transplantation. Islet transplantation eliminates hypoglycemic episodes/unawareness, facilitates normalization of hemoglobin A1c (HbA1c), decreases microvascular disease progression, and improves quality of life for patients with problematic diabetes. Mid- and long-term outcomes of islet transplantation performed at expert centers approximate those of registry reports of solitary pancreas transplant, whereas the complication profile is quite favorable.

Our objective was to analyze factors predicting outcomes after a total pancreatectomy and islet autotransplantation (TP-IAT).Chronic pancreatitis (CP) is increasingly treated by a TP-IAT. Postoperative outcomes are generally favorable, but a minority of patients fare poorly.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.In our patients, the duration (mean ± SD) of CP before their TP-IAT was 7.1 ± 0.3 years and narcotic usage of 3.3 ± 0.2 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 index30, 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.This article represents the largest study of factors predicting outcomes after a TP-IAT. Preoperatively, the patient subgroups we identified warrant further attention.

Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seeing increasing numbers of Somali children with diabetes.To assess the immune basis of diabetes in Somali children in the Twin Cities, Minnesota.A total of 31 Somali children ≤19 yr were treated for type 1 diabetes (T1D) at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota underwent analysis of human leukocyte antigen (HLA) alleles (n = 30) and diabetes autoantibodies [glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (ZnT8); n = 31]. HLA alleles were analyzed in 49 Somalis without diabetes (controls). Anti-transglutaminase autoantibodies (TGA) for celiac disease were also measured.In Somali children with T1D aged 13.5 ± 5 yr (35% female, disease duration 6.5 ± 3.6 yr), the most common HLA allele was DRB1*03:01 (93%, compared with 45% of Somali controls), followed by DRB1*13:02 (27%). There was a relatively low frequency of DR4 (13%). Controls showed a similar pattern. All 31 participants were positive for at least one diabetes autoantibody. Insulin antibodies were positive in 84% (all were on insulin). Excluding insulin antibodies, 23 (74%) subjects tested positive for at least one other diabetes autoantibody; 32% had 1 autoantibody, 32% had 2 autoantibodies, and 10% had 3 autoantibodies. GAD65 autoantibodies were found in 56% of subjects, IA-2 in 29%, and ZnT8 in 26%. Four (13%) were TGA positive.The autoantibody and HLA profiles of Somali children with diabetes are consistent with autoimmune diabetes. Their HLA profile is unique with an exceptionally high prevalence of DRB1*03:01 allele and relative paucity of DR4 alleles compared with African Americans with T1D.

A total pancreatectomy and islet autotransplant (TPIAT) offers substantial pain relief and improved quality of life for children who are severely affected by chronic or recurrent acute pancreatitis and for whom the usual medical and endoscopic therapies have failed. The pancreas is entirely resected, and the pancreatic islets are isolated from the pancreas and infused back into the patient’s liver. Because this is an autologous transplant, no immunosuppression is required. Over several months, the islets engraft in the liver; the patient is then slowly weaned off insulin therapy. Slightly more than 40 % of patients become and remain insulin independent, yet even among patients who remain on insulin, most have some islet function, permitting easier diabetes control. The majority of patients experience pain relief, with significant improvements in health-related quality of life. A TPIAT should be considered for children who are significantly disabled by chronic pancreatitis.