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.
Up to 9% of children with acute recurrent pancreatitis (ARP) or chronic pancreatitis have pancreatogenic diabetes mellitus (DM), and this risk likely increases as they age into adulthood. Risk ...factors for pancreatogenic DM in children vary depending on the clinical cohort but may include pancreatic atrophy, exocrine insufficiency, pancreatic calcifications, obesity/metabolic syndrome features, or autoimmune diseases. Knowledge regarding disease pathology is extrapolated nearly entirely from studies in adults. Insulin deficiency is the primary defect, resulting from islet loss associated with pancreatic fibrosis and cytokine-mediated β-cell dysfunction. Beta cell autoimmunity (type 1 diabetes) should also be considered as markers for this have been identified in a small subset of children with pancreatogenic DM. Hepatic insulin resistance, a deficient pancreatic polypeptide state, and dysfunctional incretin hormone response to a meal are all potential contributors in adults with pancreatogenic DM but their significance in pediatrics is yet unknown. Current guidelines recommend yearly screening for diabetes with fasting glucose and hemoglobin A1c (HbA1c). Insulin in the first-line pharmacologic therapy for treatment of pancreatogenic DM in children. Involvement of a multidisciplinary team including a pediatric endocrinologist, gastroenterologist, and dietitian are important, and nutritional health and exocrine insufficiency must also be addressed for optimal DM management.
Diabetes mellitus is characterized by the body's inability to control blood glucose levels within a physiological range due to loss and/or dysfunction of insulin producing beta cells. Progressive ...beta cell loss leads to hyperglycemia and if untreated can lead to severe complications and/or death. Treatments at this time are limited to pharmacologic therapies, including exogenous insulin or oral/injectable agents that improve insulin sensitivity or augment endogenous insulin secretion. Cell transplantation can restore physiologic endogenous insulin production and minimize hyper- and hypoglycemic excursions. Islet isolation procedures and management of transplant recipients have advanced over the last several decades; both tight glycemic control and insulin independence are achievable. Research has been conducted in isolating islets, monitoring islet function, and mitigating the immune response. However, this procedure is still only performed in a small minority of patients. One major barrier is the scarcity of human pancreatic islet donors, variation in donor pancreas quality, and variability in islet isolation success. Advances have been made in generation of glucose responsive human stem cell derived beta cells (sBCs) and islets from human pluripotent stem cells using directed differentiation. This is an emerging promising treatment for patients with diabetes because they could potentially serve as an unlimited source of functional, glucose-responsive beta cells. Challenges exist in their generation including long term survival of grafts, safety of transplantation, and protection from the immune response. This review focuses on the progress made in islet allo- and auto transplantation and how these advances may be extrapolated to the sBC context.
Objectives To assess whether the age of onset was associated with unique features or disease course in pediatric acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Study design ...Demographic and clinical information on children with ARP or CP was collected at INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) centers. The Cochran-Armitage trend test and Jonckheere-Terpstra test were used to examine for differences between pediatric age groups (<6, 6-11, and ≥12 years). Results Between September 2012 and March 2016, 342 children with ARP or CP were enrolled; 129 (38%) were <6 years of age at the time of first diagnosis of acute pancreatitis, 111 (32%) were 6-11 years of age, and 102 (30%) were ≥12 years of age. Early-onset disease was associated with mutations in cationic trypsinogen ( PRSS1 ) ( P < .01), chymotrypsin C ( CTRC ) ( P = .01), family history of acute pancreatitis ( P = .02), family history of CP ( P < .01), biliary cysts ( P = .04), or chronic renal failure ( P = .02). Later-onset disease was more commonly present with hypertriglyceridemia ( P = .04), ulcerative colitis ( P = .02), autoimmune diseases ( P < .0001), or medication use ( P < .01). Children with later-onset disease also were more likely to visit the emergency department ( P < .05) or have diabetes ( P < .01). Conclusions Early-onset pancreatitis is associated strongly with PRSS1 or CTRC mutations and family history of pancreatitis. Children with later-onset disease are more likely to have nongenetic risk factors. Future studies are needed to investigate whether the disease course, response to therapy, or clinical outcomes differ relative to the timing of disease onset.
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 β-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 K
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.
Total Pancreatectomy and Islet Autotransplantation (TPIAT) are a potential treatment for children with severe, refractory chronic pancreatitis. A laparoscopic-assisted approach provides a smaller ...incision and excellent visualization of the distal pancreas and spleen during resection. A minimally-invasive approach has proven advantageous for other pediatric procedures, but its value is unknown for this rare operation. This retrospective review compares outcomes between patients undergoing laparoscopic-assisted versus open TPIAT.
Children (n = 21) receiving laparoscopic-assisted TPIAT from 2013 to 2015 and children (n = 21) receiving open TPIAT from 2011 to 2015 were matched based on age, gender, symptom duration, previous interventions, and pancreatic fibrosis scores. Data reviewed included postoperative complications, operative time, estimated blood loss (EBL), intraoperative blood transfusions, number of islet equivalents (IEQ)/kg transplanted, hospital length-of-stay, graft function, narcotic use, and Patient Scar Assessment Questionnaire scores. Between-group differences were compared using Fisher's exact, Chi-square, and T-tests.
Surgical complications were similar between surgical groups (p = 0.35) and included wound complications (n = 11), chyle leak (n = 7), bowel obstruction (n = 5), bile leak (n = 3), gastrointestinal bleed (n = 2), and pneumonia (n = 1). There were no significant differences in operative time (p = 0.18), EBL (p = 0.96), blood transfusions (p = 0.34), IEQ/kg transplanted (p = 0.15), and hospital length-of-stay (p = 0.66). Insulin and opioid use was similar except for a slightly higher use of opioids (n = 4) at 2 years in the laparoscopic group. Patient surgical scar satisfaction was similar between groups (p = 0.26).
Outcomes for laparoscopic-assisted TPIAT appear comparable to open TPIAT. In children, a minimally-invasive approach does not compromise safety, effectiveness, or operative efficiency and may be used based on surgeon and patient preference.
For children with diminished quality of life and chronic pain caused by acute recurrent or chronic pancreatitis who are undergoing total pancreatectomy with islet autotransplantation, postoperative ...nutrition support has several unique characteristics. Surgical complications may lead to delays in nutrition support initiation or require modifications to the regimen. Early postoperative dysmotility requires the use of temporary enteral nutrition until this improves. The resultant complete exocrine pancreatic insufficiency necessitates lifelong pancreatic enzyme replacement therapy and fat‐soluble vitamin supplementation. A low‐oxalate diet is recommended to prevent kidney stones. Carbohydrate counting is needed for the provision of short‐term insulin dosing and possibly long‐term as well, depending on the transplanted islet yield. Children should have careful nutrition assessment and monitoring at several follow‐up visits during the first year, then annually, and at any time with concerns.
Purpose of review
In children, chronic pancreatitis is infrequent but may be associated with serious complications, including severe pain that limits activities, exocrine and endocrine pancreatic ...insufficiency and malnutrition. Investigation into pediatric chronic pancreatitis has transitioned from single center reports to multicenter, protocol-driven studies. As a result, we now have information on much larger numbers of children with chronic pancreatitis, allowing a more reliable understanding of the complications of chronic pancreatitis.
Recent findings
A high percentage of children with chronic pancreatitis use opioids frequently to control pain. About a quarter of children with chronic pancreatitis have exocrine pancreatic insufficiency, and about 6% have pancreatogenic diabetes. Mild malnutrition and low bone density are both common in children with chronic pancreatitis.
Summary
Large multicenter and single-center observational studies have allowed us to more accurately assess complications of chronic pancreatitis in children. These studies demonstrate the need for examination of therapies for these complications in children.
PURPOSE OF REVIEWWe reviewed the current state of total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis and recurrent acute pancreatitis (RAP).
RECENT FINDINGSAn ...increasing number of centers in the United States and internationally are performing TPIAT. In selected cases, TPIAT may be performed partially or entirely laparoscopically. Islet isolation is usually performed at the same center as the total pancreatectomy surgery, but new data suggest that diabetes outcomes may be nearly as good when a remote center is used for islet isolation. Ongoing clinical research is focused on patient and disease factors that predict success or failure to respond to TPIAT. Causes of persistent abdominal pain after TPIAT may include gastrointestinal dysmotility and central sensitization to pain. Several clinical trials are underway with anti-inflammatory or other islet protective strategies to better protect islets at the time of infusion and thereby improve the diabetes results of the procedure.
SUMMARYIn summary, there is an increasing body of literature emerging from multiple centers highlighting the benefits and persistent challenges of TPIAT for chronic pancreatitis and RAP. Ongoing study will be critical to optimizing the success of this procedure.
IMPORTANCE: Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood. OBJECTIVE: To characterize and identify risk factors associated with ARP and CP in ...childhood. DESIGN, SETTING, AND PARTICIPANTS: A 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 MEASURES: Demographic characteristics, risk factors, abdominal pain, and disease burden. RESULTS: A 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 < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions). CONCLUSIONS AND RELEVANCE: Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.
PDF
