review of literature on clinical pancreatology - The Pancreapedia

have been employed to study the mechanisms <strong>of</strong> the process. Islet neogenesis, theregeneration <strong>of</strong> pancreatic islets from pancreatic stem cells, is arguably the least fraught withbarriers to widespread use as a therapy for diabetes. These animal models have led to thedescription <strong>of</strong> the reg family <strong>of</strong> proteins that appear to be related to islet regeneration. Isletneogenesis-associated protein (INGAP) is an initiator <strong>of</strong> islet neogenesis in animal modelsand a peptide sequence from INGAP carries the biological activity. INGAP peptide has beenshown to stimulate an increase in beta cell mass in mice, rats, hamsters and dogs. INGAP isalso found in the pancreas in human pathological states involving islet neogenesis. Thepeptide has been tested in human clinical trials, with success being reported. The evidencepoints to INGAP as a major factor in stimulating islet neogenesis, and, therefore, may play asignificant therapeutic role in diabetes [108].ConnexinsDiabetes and the related metabolic syndrome are multisystem disorders that result fromimproper interactions between various cell types. Even though the underlying mechanismremains to be fully understood, it is most likely that both the long and the short distancerange cell interactions, which normally ensure the physiologic functioning <strong>of</strong> the pancreas,and its relationships with the insulin-targeted organs, are altered. One <strong>review</strong> focused on theshort-range type <strong>of</strong> interactions that depend on the contact between adjacent cells and,specifically, on the interactions that are dependent on connexins. The widespread distribution<strong>of</strong> these membrane proteins, their multiple modes <strong>of</strong> action, and their interactions withconditions/molecules associated to both the pathogenesis and the treatment <strong>of</strong> the 2 mainforms <strong>of</strong> diabetes and the metabolic syndrome, make connexins an essential part <strong>of</strong> thechain <strong>of</strong> events that leads to metabolic diseases [109].Diphtheria toxin gene A chain (DTA)Cell lineage analysis is critical in understanding the relationship between progenitors anddifferentiated cells as well as the mechanism underlying the process <strong>of</strong> differentiation. Inorder to study the zebrafish endocrine pancreas cell lineage, transgenic expression <strong>of</strong>diphtheria toxin gene A chain (DTA) under two cell type-specific promoters derived from theinsulin (ins) and somatostatin2 (sst2) genes was used to ablate the two types <strong>of</strong> endocrinecells: insulin-producing beta-cells and somatostatin-producing delta-cells, respectively. It wasfound that ablation <strong>of</strong> beta-cells resulted in a reduction <strong>of</strong> not only beta-cells but alsoglucagon-producing alpha-cells; in contrast, delta-cells were largely unaffected. Ablation <strong>of</strong>delta-cells led to reduction <strong>of</strong> all three types <strong>of</strong> endocrine cells: alpha-, beta-, and delta.Interestingly, alpha-cells were more pr<strong>of</strong>oundly affected in both beta- and delta-cell ablationsand were frequently reduced together with beta- and delta-cells. Thus, the currentobservations indicated differential interdependence <strong>of</strong> these three cell lineages. Thedevelopment <strong>of</strong> zebrafish alpha-cells, but not delta-cells, is dependent on beta-cells, whilethe development <strong>of</strong> both alpha- and beta-cells is dependent on delta-cells. In contrast, thedevelopment <strong>of</strong> delta-cells is independent <strong>of</strong> beta-cells [110].Cell-surface markersIt was developed a novel panel <strong>of</strong> cell-surface markers for the isolation and study <strong>of</strong> all majorcell types <strong>of</strong> the human pancreas. Hybridomas were selected after subtractive immunization<strong>of</strong> Balb/C mice with intact or dissociated human islets and assessed for cell-type specificityand cell-surface reactivity by immunohistochemistry and flow cytometry. Antibodies wereidentified by specific binding <strong>of</strong> surface antigens on islet (panendocrine or alpha-specific) andnonislet pancreatic cell subsets (exocrine and duct). These antibodies were used individuallyor in combination to isolate populations <strong>of</strong> alpha, beta, exocrine, or duct cells from primaryhuman pancreas by FACS and to characterize the detailed cell composition <strong>of</strong> human islet