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At least 19 recordsLinked to original sources
PubMed2026

Overcoming Immunological Barriers in MSC-Derived Insulin-Producing Cells through CRISPR-Based Hypoimmunogenic Engineering and Translational Perspectives for Type 1 Diabetes.

Mesenchymal stromal cell (MSC)-derived insulin-producing cells (IPCs) represent an emerging strategy for β-cell replacement in type 1 diabetes mellitus (T1DM) owing to their differentiation potential, intrinsic immunomodulatory properties, and lower tumorigenic risk compared with pluripotent stem cell-derived platforms. However, accumulating evidence indicates that differentiation-associated immunogenicity, context-dependent immune recognition, and recurrent autoimmune responses may substantially limit long-term graft survival and therapeutic durability following transplantation. This review critically examines the immunological barriers associated with MSC-derived IPCs, including altered MHC expression, susceptibility to alloimmune and autoimmune-mediated rejection, and potential reactivation of autoreactive immune memory. We discuss the application of CRISPR-based hypoimmunogenic engineering strategies targeting antigen presentation pathways, NK-cell activation, and immune checkpoint modulation to generate more immune-evasive MSC-derived IPCs while preserving β-cell functionality. By integrating insights from T1DM immunopathogenesis, MSC biology, genome editing, and translational immunology, we propose a framework linking immune engineering with controlled differentiation, functional maturation, and long-term safety evaluation. In parallel, we comparatively position MSC-derived IPCs alongside clinically advancing iPSC-derived β-cell platforms to highlight their distinct translational niche, including potential advantages related to safety, immunomodulatory capacity, manufacturing accessibility, and scalability, while acknowledging the superior functional maturity and clinical progression currently demonstrated by iPSC-derived systems. Finally, we discuss key translational challenges, including genomic stability, immune-evasion durability, GMP-compliant manufacturing, and the need for rigorous functional and immunological benchmarking prior to clinical application of hypoimmunogenic MSC-derived IPC therapies in T1DM.

Humans↗
PubMed1977

The identification of the F-cell in the dog pancreas as the pancreatic polypeptide producing cell.

The endocrine cells of the processus uncinatus in the dog pancreas were investigated with special reference to the formerly known F-cell. The F-cell was detected frequently in the periphery of pancreatic islets as well as among exocrine tissue. In both localizations the F-cell shows similar ultrastructural features. Membrane-bound irregularly shaped secretory granules of variable electron density were seen. The cell possesses all features of an endocrine polypeptide secreting cell. Using the immunofluorescence and immunoperoxidase technique in the uncinate processus of the dog, we could reveal that the anti-sera against bovine pancreatic polypeptide (BPP) reacts with the cell which is localized at the same sites as the F-cell. We therefore conclude that the pancreatic F-cell is identical to the pancreatic polypeptide-producing cell. The other endocrine cell types of the dog pancreas are glucagon-producing A-cells, insulin-producing B-cells, and somatostatin-producing D-cells, as well as serotonin-producing EC-cells which are regularly present in the dog pancreatic islets and also scattered among exocrine tissue and the duct epithelial cells.

Animals↗
PubMed1975

Functional subdivision of islets of Langerhans and possible role of D cells.

Immunocytochemical examination of the islets of Langerhans in various animal species, including man, indicates that insulin-producing cells (B cells), glucagon-producing cells (A cells), and cells producing somatostatin or a somatostatin-like peptide (D cells) are not randomly arranged within the islet. Whenever A cells are found in the islet--i.e., mostly in its peripheral part--they are accompanied by D cells. However, most B cells, which occupy a central position, are in contact only with other B cells. In view of the inhibitory effect of somatostatin on both insulin and glucagon secretion, it is suggested that the arrangement of A, B and D cells is important to the normal and pathological functioning of the islet.

Animals↗
PubMed1976

[Evidence of pseudoisocyanine--positive endocrine cells in the gastric mucosa of the dog].

The tunica mucosa of the stomach and the other parts of the intestine (duodenum, jejunum, ileum colon) of the dog has been investigated in order t to demonstrate insulin producing cells. By means of thepseudoisocyanine-reaction it was possible to visualize in the lamina epithelialis of the stomach singular cells containing metachromatically reacting granules. It was possible to distinguish these cells from mast cells localised outside of the lamina epithelialis of the tunica mucosa. The value of this observation is given by the fact that until now hormone producing cells could be demonstrated in the laimina epithelialis of stomach and intestine of mammalia with exception of insulin-producing cells.

Animals↗
PubMed1976

Onto- and phylogenetical aspects on insulin-producing islet-cell tumors.

When onto- and phylogenetical aspects are taken into account when studying insulin-producing islet-cell tumors, it becomes clear that the recently discovered "type IV" islet parenchymal cells (or "delta 1" -cells) may play an important role in various states of hypoglycemia, both of neoplastic and non-neoplastic origin. Moreover, it becomes obvious that increased attention to this kind of islet cell through intensified light-microscopical, histochemical, ultrastructural and experimental investigations covering a wide range of animals, may help to clarify several unsolved problems in the cytological composition of the islets of Langerhans. The occurrence of islet-cell tumors (or hamartomas) in the most primitive vertebrate islet parenchyma known, viz. that of the hagfish, Myxine glutinosa, is reported, as well as an additional case of mixed carcinoid-islet-cell tumor in a human pancreas.

Adenoma, Islet Cell↗
PubMed2026

International consensus guidance for general population screening for islet autoantibodies to diagnose early-stage type 1 diabetes: a nominal group technique process.

Type 1 diabetes is an autoimmune disease that targets and destroys insulin-producing beta cells in the pancreatic islets. The incidence of type 1 diabetes is rising globally. At the clinical diagnosis of type 1 diabetes, between 20% and 67% of children and adolescents present with diabetic ketoacidosis (DKA) requiring hospitalisation, and one-third of these require intensive care. Type 1 diabetes can be detected in early stages, prior to the insulin-requiring clinical diagnosis, through screening for islet autoantibodies (IAbs). Identifying individuals with early-stage type 1 diabetes, combined with monitoring of and education on disease progression, prevents DKA and results in a milder clinical onset. This allows for timely insulin initiation in outpatient settings and improved long-term glucose management. Early diagnosis also enables access to novel disease-modifying therapies that can delay the clinical onset of diabetes. In this international consensus, we provide guidance on the principles and practice of implementing general population screening for IAbs to diagnose early-stage type 1 diabetes. We also outline the minimum requirements for establishing effective population screening programmes to diagnose early-stage type 1 diabetes through IAb detection. This consensus statement has been endorsed by the following professional associations: Advanced Technologies & Treatments for Diabetes (ATTD); Association of Diabetes Care and Education Specialists (ADCES); Association Belge Du Diabète; Associazione Medici Diabetologi (AMD); Australian Diabetes Society (ADS); Belgian Diabetes Liga; Breakthrough T1D; Czech Diabetes Society (ČDS); EASD; Finnish Diabetes Association (FDS); Fondazione Italiana Diabete (FID); International Diabetes Federation (IDF)-Europe; International Society of Paediatric and Adolescent Diabetes (ISPAD); Paediatric Endocrinology Nursing Society (PENS); Polish Diabetes Society; Portuguese Diabetes Association (APDP); Sociedade Portuguesa de Diabetologia (SPD); Società Italiana di Diabetologia (SID); Société Francophone du Diabète (SFD) and Type 1 Diabetes Exchange (T1D Exchange).

Consensus report↗
PubMed1975

Regulation of in vitro insulin release from a transplantable Syrian hamster insulinoma.

An insulin-producing islet cell tumor of the Syrian hamster has been studied in vitro for its capacity to respond to known stimuli of insulin release. Insulin secretion during short term incubation and perifusion of fragments of tumor was detected by radioimmunoassay. Insulin release was increased 2-4 fold by 40 mM potassium in the presence of calcium, glucose (22 mM), glucagon (0.3-3.0 muM), N6,02'-dibutyryl adenosine 3',5'-monophosphate (cAMP; 6mM), and theophylline (10 mM). Concentrations of glucagon that induced insulin release were also effective in activating adenylate cyclase in the membranes of tumor cells. Thus, this tumor appears to possess a cAMP-mediated mechanism for insulin release. Somatostatin (0.8-25 mum) inhibited glucagon-induced insulin release without altering basal or glucagon stimulated adenylate cyclase activity. It would appear that inhibition of glucagon induced insulin release by somatostatin is not mediated by adenylate cyclase. We propose that insulin release by this tumor is sufficiently similar to that found in normal islets so as to make it a suitable model for biochemical studies that require large quantities of homogeneous tissue.

Adenoma, Islet Cell↗
PubMed1977

Subselective angiography in localizing insulinomas of the pancreas.

Preoperative angiography was performed on 10 patients who had insulin-producing islet cell adenomas. Eight of the 10 islet cell tumors were localized. Seven of the eight adenomas were demonstrated only on subselective injections into the small intrapancreatic arteries, and one was demonstrated by a selective injection into a large artery. Failure to localize two islet cell adenomas was probably caused by the inability to subselect the small intrapancreatic arteries supplying the tumor. One tumor was seen only with subtraction techniques, which were used in all cases. Localization was not related to vascularity, size of tumor, or location within the pancreas. Vasoconstrictive pharmacoangiography was not helpful; magnification was helpful but not essential. The most important factor in localizing islet cell tumors is demonstrating the complete pancreatic blood supply with subselective injections into the small intrapancreatic arteries supplying the tumor (inferior and superior pancreaticoduodenal and dorsal arteries).

Adenoma↗
PubMed1977

Microchemical assays of glutathione, zinc, cobalt and manganese in micro-dissected areas of the endocrine pancreas in the hagfish, Myxine glutinosa.

In hagfish islet parenchyma, consisting practically only of insulin-producing B-cells and agranular B-cell precursors, the contents of glutathione (GSH) and total protein-free thiols (NPSH) were determined on micro-dissected islet lobules. GSH was found to be of the same order of magnitude (22-25 mg/100 g wet weight) as in the islet parenchyma of a previously studied teleost fish and of some mammals, including man. However, the NPSH was found to be considerably higher in the islet lobules of the hagfish than in the teleostean islet parachyma. As in both teleost fish and mammals, GSH made up most of the NPSH in the hagfish erythrocytes, myocardium, and skeletal musculature. This discrepancy between hagfish islet parenchyma and other tissues indicates that the non-GSH portion of NPSH may be of particular significance for the insulin-producing B-cells. By means of flameless atomic absorption spectrophotometry the contents of zinc, cobalt, and manganese were determined in micro-dissected hagfish islet lobules. Neither zinc, nor cobalt, occurred in significantly higher concentrations in the islet parenchyma than in the liver or the skeletal musculature. Only manganese was found in somewhat higher amounts in the islet lobules than in the other tissues, but the contents were still low. The results indicate that none of the three heavy metals play any important role in the synthesis, storage, or release of insulin in the hagfish. The significance of this in relation to the prevailing hypotheses regarding the pathogenesis of alloxan diabetes is discussed.

Animals↗
PubMed1976

Characterization of the protein kinases in a transplantable islet cell tumor of the Syrian hamster.

The protein kinase activities of a transplantable, insulin-producing hamster islet cell tumor were characterized using gel filtration, sucrose density gradient centrifugation and acrylamide gel electrophoresis. The post-microsomal supernatant fluid contains 70-80% of the protein kinase activity present in crude homogenates. A cAMP-dependent protein kinase, PK I (Mr 170,000), represents 25% of the soluble protein kinase activity assayed with protamine as substrate. It dissociates in the presence of cAMP into a cAMP-binding protein, R2 (Mr 90,000) and a catalytic subunit C (Mr 33,000). The dissociation induced by cAMP seems to be facilitated by the addition of Mg2+ and ATP. The regulatory subunit, R2, changes its gel filtration pattern in the presence of 0.5 M NaCl suggesting dissociation into a smaller subunit, R1 (Mr 44,000). By analogy with purified beef heart protein kinase (Erlichman et al., 1973) and skeletal muscle protein kinase, PK I. The presence in crude homogenates of a free cAMP-binding protein indistinguishable from the R2 derived by dissociation of PK I, suggests that PK I is partially dissociated in vivo. A cAMP-independent (casein) kinase (Mr 210,000) elutes with PK I on columns of Sepharose 6B. Another cAMP-independent protein kinase, PK II (Mr 88,000), is the predominatn form of soluble protein kinase accounting for approximately 75% of the soluble protein kinase activity detected using protaimine as substrate. This cAMP-independent protein kinase changes its gel filtration pattern in the presence of 0.5 M NaCl giving rise to a form which appears to have the same Mr (33,000) as the catalytic subunit of PK I. Studies comparing the catalytic subunit C of PK I with PK II and its salt-induced smaller molecular form demonstrate facile association of C with the cAMP-binding protein of purified bovine heart protein kinase to yield a hybrid holoenzyme, whereas PK II and its smaller form fail to recombine in this fashion. The 33,000 dalton forms derived from PK I (by cAMP) and PK II (by salt) also show different substrate specificities. It would appear, therefore, that pK II is a cAMP-independent protein kinase unrelated to PK I.

Adenoma, Islet Cell↗
PubMed1978

[Malignant insuloma. Evaluation of the response to treatment with streptozotocin, using selective arteriography of the celiac axis].

A patients with metastatic insulin-producing islet-cell carcinoma has been treated with Streptozotocin intravenously and studied by selective celiac angiography during treatment. A 50% decrease of the tumor's size has been demonstrated by this technique after a total dose of 19 grams of the drug together with return to normal of the serum-insulin and blood-glucose values. The usefulness of angiography in evaluating the tumor response to Streptozotocin and in managing chemotherapy is discussed.

Adenoma, Islet Cell↗
PubMed1975

The ultrastructure of focal islet cell adenomatosis in the newborn with hypoglycemia and hyperinsulinism.

In a newborn severe persistent hypoglycemia due to an insulin-producing tumorous proliferation of pancreatic islet cells (insulinoma) was observed. The insulinoma showed the histologic pattern of focal adenomatosis of islet cells. According to the present literature the focal proliferation of islet cell complexes seems to be a frequent and particular feature of insulinomas in the newborn. Differential islet cell staining identified 80%-90% of the proliferated islet cells as B cells. 10%-20% of the cells were found to be A or D cells. Ultrastructurally the majority of the proliferated islet cells were well differentiated B cells. The remaining cells represented either A or D cells or a fourth islet cell type with small spheric granules. Electronmicrscopic evidence of transitions between differentiated islet cells, particularly B cells, and the fourth islet cell type suggests that the fourth islet cell type might represent a precursor cell within the APUD-cell system.

Adenoma, Islet Cell↗
PubMed1978

Localization of insulinomas and islet cell hyperplasias by pancreatic vein catheterization and insulin assay.

Percutaneous transhepatic portal vein catheterization and transfemoral portal and caval catheterizations were performed under local anesthesia in five patients with symptoms of organic hypoglycemia. During the investigation, results of pancreatic phlebography revealed the pancreatic venous anatomy. Blood obtained from the celiac artery, caval branches and pancreatic veins was assayed for insulin by two different radioimmunoassay methods. Pathologically high, pancreatic arteriovenous insulin differences in two patients with insulinomas and in two patients with islet cell hyperplasia. In one of the patients with an insulinoma, one of the assays failed to detect the tumor insulin. This inconsistency still remains unexplained. Angiography revealed a pancreatic abnormality in only two patients. During operation, two of the tumors were found upon palpation and inspection. Pancreatic resections were performed according to the findings of pathologic hormone differences in all five patients. Immunocytochemistry revealed that three of the patients had insulin-producing tumors and two had local islet cell hyperplasia. Catheterizations performed two months postoperatively confirmed the radicality of the operation in all patients, with the possible exception of one patient. In one patient, a recurrance was detected by catheterization ten months postoperatively.

Adenoma, Islet Cell↗
PubMed1975

Failure of somatostatin to inhibit tolbutamide-induced insulin secretion in patients with insulinomas: a possible diagnostic tool.

The effects of somatostatin on tolbutamide-stimulated insulin release were studied in 4 patients with insulin-producing tumors of the pancreas and in 6 normal subjects. In contrast to its effective inhibition of insulin release in normal subjects, somatostatin, without exception, failed to inhibit tolbutamide-induced insulin release in the patients with pancreatic beta-cell tumors. This differential effect of somatostatin may prove useful in the diagnosis of insulin-producing tumors of the pancreas.

Adenoma, Islet Cell↗
PubMed1976

Insulinoma in a pregnant woman.

The case of a 37-year-old primigravida suffering from severe hypoglycemia due to insulinoma is reported. Diagnosis was established on clinical grounds by assessment of inappropriate insulin release. Laparotomy was performed by the 12th gestational week. A wide distal pancreatectomy was carried out, and histopathologic study proved the existence of multiple islet cell adenomatosis. Glycemic levels and insulin secretion returned to normal immediately after surgery. The course of pregnancy was unhampered, judged by clinical criteria and by serial estimations of human chorionic somatomammotropin levels before and after removal of the insulin-producing tumor. A normal female infant was delivered at term, and no histopatholgic changes were detected in the placenta. After 1 year, clinical and analytical evaluation of both mother and child was normal.

Adenoma, Islet Cell↗