The epidemiology and burden of childhood chronic pancreatitis in South Australia

Available online 3 December 2021OBJECTIVE: To assess longitudinal, population-based data regarding the prevalence and impact of chronic pancreatitis on children. STUDY DESIGN: Administrative data linkage was used to ascertain an index cohort consisting of all individuals who had an initial diagnosis of chronic pancreatitis before the age of 19 years in the South Australian public hospital system between June 2000 and June 2019. Age- and sex-matched controls were drawn from the general population of South Australia, children with type 1 diabetes, and children with type 2 diabetes Main outcomes and measures included: hospital visits, days in hospital, emergency department visits, ICU admissions, education comparators, incidence, and prevalence estimates. RESULTS: A total of 73 incident cases were identified. Crude prevalence and incidence of paediatric chronic pancreatitis were estimated at 6·8/100,000 and 0·98/100,000 per annum respectively. Of the index cohort, 24 (32.8%) cases of paediatric chronic pancreatitis identified as Aboriginal and/or Torres Strait Islander people. Children with chronic pancreatitis averaged 11-fold more hospital visits, 5-fold more emergency department visits, 9-fold more ICU admissions, spent 10-fold more days in hospital, and had 2-fold higher rates of absence from school than matched general population controls (all P <0.001). Children with chronic pancreatitis similarly utilized substantially more health resources than children with type 1 or 2 diabetes. CONCLUSIONS: Paediatric patients with chronic pancreatitis consume a high volume of public health services and are significantly impacted in their ability to engage in education.Tristan J.Bampton, Richard Couper, Sanjeev Khurana, David Moore, Alex Brown, Chris Drogemuller ... et al

Development of a coaxial 3D printing platform for biofabrication of implantable islet-containing constructs

Over the last two decades, pancreatic islet transplantations have become a promising treatment for Type I diabetes. However, although providing a consistent and sustained exogenous insulin supply, there are a number of limitations hindering the widespread application of this approach. These include the lack of sufficient vasculature and allogeneic immune attacks after transplantation, which both contribute to poor cell survival rates. Here, these issues are addressed using a biofabrication approach. An alginate/gelatin-based bioink formulation is optimized for islet and islet-related cell encapsulation and 3D printing. In addition, a custom-designed coaxial printer is developed for 3D printing of multicellular islet-containing constructs. In this work, the ability to fabricate 3D constructs with precise control over the distribution of multiple cell types is demonstrated. In addition, it is shown that the viability of pancreatic islets is well maintained after the 3D printing process. Taken together, these results represent the first step toward an improved vehicle for islet transplantation and a potential novel strategy to treat Type I diabetes.Xiao Liu, Sarah-Sophia D. Carter, Max Jurie Renes ... Darling Macarena Rojas-Canales, Daniella Penko ... Christopher John Drogemulle ... et al

Desmoglein-2 is important for islet function and β-cell survival

Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic β-cells. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions that support pancreatic function is still lacking. To characterize the pancreatic endocrine compartment, we studied pancreata from healthy adult donors and investigated a single cell surface adhesion molecule, desmoglein-2 (DSG2). Genetically-modified mice lacking Dsg2 were examined for islet cell mass, insulin production, responses to glucose, susceptibility to a streptozotocin-induced mouse model of hyperglycaemia, and ability to cure diabetes in a syngeneic transplantation model. Herein, we have identified DSG2 as a previously unrecognized adhesion molecule that supports β-cells. Furthermore, we reveal that DSG2 is within the top 10 percent of all genes expressed by human pancreatic islets and is expressed by the insulin-producing β-cells but not the somatostatin-producing δ-cells. In a Dsg2 loss-of-function mice (Dsg2lo/lo), we observed a significant reduction in the number of pancreatic islets and islet size, and consequently, there was less total insulin content per islet cluster. Dsg2lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocininduced diabetes, and islets isolated from Dsg2lo/lo mice were more susceptible to cytokine-induced β-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2lo/lo mice were less effective than their wildtype counterparts at curing diabetes. In vitro assays using the Beta-TC-6 murine β-cell line suggest that DSG2 supports the actin cytoskeleton as well as the release of cytokines and chemokines. Taken together, our study suggests that DSG2 is an under-appreciated regulator of β-cell function in pancreatic islets and that a better understanding of this adhesion molecule may provide new opportunities to combat type 1 diabetes.Kay K. Myo Min, Darling Rojas-Canales, Daniella Penko, Mark DeNichilo, Michaelia P. Cockshell, Charlie B. Ffrench, Emma J. Thompson, Olof Asplund, Christopher J. Drogemuller, Rashmi B. Prasad, Leif Groop, Shane T. Grey, Helen E. Thomas, Thomas Loudovaris, Thomas W. Kay, My G. Mahoney, Claire F. Jessup, P. Toby Coates, and Claudine S. Bonde

Australian experience with total pancreatectomy with islet autotransplantation to treat chronic pancreatitis

First published: 06 May 2021BACKGROUND: This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. METHODS: Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. RESULTS: Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P < 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. CONCLUSION: The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.Tristan J. Bampton, D. Jane Holmes-Walker, Chris J. Drogemuller, Toni Radford, Patricia Anderson, C. Etherton, C. H. Russell, S. Khurana, David J. Torpy, J. J. Couper, R. L. T. Couper, Pamela Macintyre, E. L. Neo, Paul Benitez-Aguirre, G. Thomas, T. Loudovaris, H. E. Thomas, Lyle J. Palmer, Denghao Wu, Natasha M. Rogers, L. Williams, W. J. Hawthorne, P. J. O, Connell, Tom W. Kay, Henry Pleass, John W. Chen, and P. Toby Coates, Australian Islet Consortiu