SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Pancreas

185

Pancreatic cystic lesions (PCLs) are increasingly frequent radiological incidentalomas, with a considerable proportion representing precursors of pancreatic cancer. Better diagnostic tools are required for patients to benefit from this development.

Concepts: Cancer, Pancreas, Pancreatic cancer

184

Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.

Concepts: Cell, Insulin, Glucose, Stem cell, Islets of Langerhans, Pancreas, Cellular differentiation, Embryonic stem cell

168

Loss of function mutations in EIF2AK3, encoding the Pancreatic Endoplasmic Reticulum (ER) Kinase, PERK, are associated with dysfunction of the endocrine pancreas and diabetes. However to date it has not been possible to uncouple the long term developmental effects of PERK deficiency from sensitization to physiological levels of ER unfolded protein stress upon interruption of PERK-modulation of protein synthesis rates. Here we report that a selective PERK inhibitor acutely deregulates protein synthesis in freshly isolated islets of Langerhans, across a range of glucose concentrations. Acute loss of the PERK-mediated strand of the unfolded protein response leads to rapid accumulation of misfolded pro-insulin in cultured beta cells and is associated with a kinetic defect in pro-insulin processing. These in vitro observations uncouple the latent role of PERK in beta cell development from the regulation of unfolded protein flux through the ER and attest to the importance of the latter in beta cell proteostasis.

Concepts: DNA, Protein, Enzyme, Insulin, Islets of Langerhans, Pancreas, Beta cell, Amylin

167

The generation of functional endodermal lineages, such as hepatocytes and pancreatic endocrine cells, from pluripotent stem cells (PSCs) remains a challenge. One strategy to enhance the purity, yield and maturity of endodermal derivatives is to expand endoderm committed stem or progenitor cell populations derived from PSCs before final differentiation. Recent studies have shown that this is in fact a viable option both for expanding pure populations of endodermal cells as well as for generating more mature derivative tissues, as highlighted in the case of pancreatic beta cells.

Concepts: Developmental biology, Stem cell, Stem cells, Cell biology, Pancreas, Progenitor cell, Multipotency, Pluripotency

167

VEGF-A expression in beta cells is critical for pancreatic development, formation of islet-specific vasculature and insulin secretion. However, two key questions remain. First, is VEGF-A release from beta cells coupled to VEGF-A production in beta cells? Second, how is the VEGF-A response by beta cells affected by metabolic signals? Here, we show that secretion of VEGF-A, but not VEGF-A gene transcription, in either cultured islets or purified pancreatic beta cells, was significantly reduced early on during low glucose conditions. In vivo, a sustained hypoglycemia in mice was induced with an insulin pellet, which resulted in a significant reduction in beta cell mass. This loss of beta cell mass could be significantly rescued with continuous delivery of exogenous VEGF-A, which had no effect on beta cell mass in normoglycemic mice. In addition, an increase in apoptotic endothelial cells during hypoglycemia preceded an increase in apoptotic beta cells. Both endothelial and beta cell apoptosis were prevented by exogenous VEGF-A, suggesting a possible causative relationship between reduced VEGF-A and the loss of islet vasculature and beta cells. Furthermore, in none of these experimental groups did beta cell proliferation and islet vessel density change, suggesting a tightly regulated balance between these two cellular compartments. The average islet size decreased in hypoglycemia, which was also prevented by exogenous VEGF-A. Taken together, our data suggest that VEGF-A release in beta cells is independent of VEGF-A synthesis. Beta cell mass can be regulated through modulated release of VEGF-A from beta cells based on physiological need.

Concepts: Protein, Gene, Enzyme, Insulin, Islets of Langerhans, Pancreas, Beta cell, Insulinoma

167

Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H(+)] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.

Concepts: Pancreas, Stomach, Receptor antagonist, Cannabinoid receptor, Digestion, Gastric acid, Somatostatin, HU-210

163

Activity-guided isolation of a methanolic extract of Galla Rhois using pancreatic lipase and 3T3-L1 adipocytes led to the isolation of seven phenolic compounds: protoaphin-fb (1), 2-O-digalloyl-1,3,4,6-tetra-O-galloyl-b-D-glucose (2), 1,2,3,4,6-penta-O-galloyl-b-D-glucose (3), 1,2,4,6-tetra-O-galloyl-b-D-glucose (4), 3-hydroxy-5-methoxy-phenol 1-O-b-D-glucoside (5), methylgallate (6), and gallic acid (7). Their structures were established on the basis of NMR and MS spectroscopic data interpretation. All isolates were evaluated for their inhibitory effects on pancreatic lipase, and compounds 1-5 exhibited potent inhibitory effects on this enzyme, with IC50 values ranging from 30.6 ± 2.4 to 3.5 ± 0.5 mM. In addition, the highly galloylated compound 2 was also found to induce potent inhibition of adipocyte differentiation in 3T3-L1 cells.

Concepts: Enzyme, Pancreas, Cytoplasm, Fat, Adipocyte, Lipase, Gallic acid, Pancreatic lipase

160

Zinc is essential for the activities of pancreatic beta-cells, especially insulin storage and secretion. Insulin secretion leads to co-release of zinc which contributes to the paracrine communication in the pancreatic islets. Zinc-transporting proteins (zinc-regulated transporter, iron-regulated transporter-like proteins [ZIPs] and zinc transporters [ZnTs]) and metal-buffering proteins (metallothioneins, MTs) tightly regulate intracellular zinc homeostasis. The present study investigated how modulation of cellular zinc availability affects beta-cell function using INS-1E cells.

Concepts: Enzyme, Insulin, Cell biology, Islets of Langerhans, Glucagon, Pancreas, Beta cell, Amylin

151

The purpose of this prospective study was to establish the ultrasonographic characteristics of the dimension of the right pancreatic lobe with that of the associated anatomic landmarks in healthy dogs. Ultrasonographic examinations were performed on 25 dogs. The thickness of the right pancreatic lobe was compared with that of mural thickness of duodenum, diameters of duodenum, pancreatic duct, abdominal aorta, portal vein, caudal vena cava, and length and width of the right kidney and right adrenal gland. The correlation between each pancreatic parameter and the dimensions of the anatomical landmarks were assessed using linear regression analysis and Pearson’s correlation coefficient ® test. Significant, but weak linear correlations were observed between thickness of right pancreatic lobe with that of duodenum mural thickness (r=0.605, R(2)=0.339, P=0.001); duodenum diameter (r=0.573, R(2)=0.299, P=0.003); and right adrenal gland length (r=0.508, R(2)=0.052, P=0.01). There was no significant dimensional relationship with other selected anatomic landmarks. The ratio between the thickness of right pancreatic lobe and the mural thickness of duodenum, diameter of duodenum and length of right adrenal gland were 2.88 ± 0.53, 1.27 ± 0.27, and 0.81 ± 0.15, respectively. Calculating the ratio of thickness of the right pancreatic lobe with the dimension of significantly correlated anatomic landmarks is a useful and simple method for evaluating the size of the right pancreatic lobe in dogs in clinical practice.

Concepts: Kidney, Pancreas, Spearman's rank correlation coefficient, Abdominal aorta, Correlation and dependence, Pearson product-moment correlation coefficient, Covariance and correlation, Adrenal gland

120

Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life-long need for often-toxic antirejection drugs. Coadministering islets with bone marrow-derived mesenchymal stem cells (MSCs) that exert robust immune-modulating, anti-inflammatory, anti-apoptotic, and angiogenic actions, improves intrahepatic islet survival and function. Encapsulation of insulin-producing cells to prevent immune destruction has shown both promise and failures. Recently, stem cell-derived insulin secreting β-like cells induced euglycemia in diabetic animals, although their clinical use would still require encapsulation or anti-rejection drugs. Instead of focusing on further improvements in islet transplantation, we demonstrate here that the intraperitoneal administration of islet-sized “Neo-Islets” (NIs), generated by in vitro coaggregation of allogeneic, culture-expanded islet cells with high numbers of immuno-protective and cyto-protective MSCs, resulted in their omental engraftment in immune-competent, spontaneously diabetic nonobese diabetic (NOD) mice. This achieved long-term glycemic control without immunosuppression and without hypoglycemia. In preparation for an Food and Drug Administration-approved clinical trial in dogs with T1DM, we show that treatment of streptozotocin-diabetic NOD/severe combined immunodeficiency mice with identically formed canine NIs produced durable euglycemia, exclusively mediated by dog-specific insulin. We conclude that this novel technology has significant translational relevance for canine and potentially clinical T1DM as it effectively addresses both the organ donor scarcity (>80 therapeutic NI doses/donor pancreas can be generated) and completely eliminates the need for immunosuppression. Stem Cells Translational Medicine 2017.

Concepts: Insulin, Diabetes mellitus, Diabetes mellitus type 1, Islets of Langerhans, Glucagon, Pancreas, Diabetes, Organ transplant