Factors Controlling Pancreatic Islet Neogenesis

Abstract

We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of β-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be ‘cured’ at least half the time. There appears to be activation of growth factor(s) within the pancreas acting in an autocrine, paracrine or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning β-cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factory) which regulates islet cell proliferation and differentiation in our model may permit proto-undifferentiated cells and islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in vitro as well. Furthermore, islet cell growth factors could be used to provide ‘trophic support’ to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) has been isolated, purified, sequenced and cloned.

Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system

“…The role played by the DEC in our study is akin to the regulatory one it performs in the normal pancreas, where the relationship between the ductal and endocrine pancreatic components begins in embryonic development with the budding of the primordial ductal epithelium and the emergence of primitive islets [31,32]. The phenotypic maturation and differentiation of these cellular aggregates requires signals supplied by adjacent cells, which take the form of soluble, trophic factors released in a paracrine fashion [33,34]. This cellular inter-relationship is conserved in adulthood; maintenance of beta cell mass and remodelling occurs due to constant, yet limited, islet neogenesis [35], again under the influence of soluble factors derived from the ductal epithelium [34,36,37].…”

“…The phenotypic maturation and differentiation of these cellular aggregates requires signals supplied by adjacent cells, which take the form of soluble, trophic factors released in a paracrine fashion [33,34]. This cellular inter-relationship is conserved in adulthood; maintenance of beta cell mass and remodelling occurs due to constant, yet limited, islet neogenesis [35], again under the influence of soluble factors derived from the ductal epithelium [34,36,37]. Although, to date, most of the supporting evidence for this concept has been derived from animal (mainly rodent) studies, the results of the present investigation suggest that similar regulatory and/or trophic influences, exerted by the ductal epithelia, may be crucial for appropriate and sustained human beta cell function.…”

Measurements of Islet Function and Glucose Metabolism with the Dipeptidyl Peptidase 4 Inhibitor Vildagliptin in Patients with Type 2 Diabetes

“…Although a small early delay in gastric emptying has been observed after a single dose of vildagliptin (19), vildagliptin does not slow gastric emptying in a clinically meaningful manner after multiple dosing in patients with T2DM (20). Vildagliptin has been associated with attenuated insulin resistance during meals (12,21). It is not known, however, whether DPP-4 inhibition improves peripheral glucose utilization.…”

Hydrolysed Casein Diet Protects BB Rats from Developing Diabetes by Promoting Islet Neogenesis

“…Four mechanisms are reported to be involved in cell mass alteration: replication of pre-existing differentiated cells (cell proliferation), differentiation from precursor cells (neogenesis), programmed cell death (apoptosis), and change in individual cell volume [10][11][12][13]. O'Brien and colleagues found that -cell apoptosis precedes infiltration of inflammatory cells into the islets and it has been proposed that apoptosis is the mode of -cell death responsible for the development of spontaneous diabetes in non-obesediabetic (NOD) mice [14] and in the multiple low-dose streptozotocin diabetes in C57BL/6 mice [15].…”