Islet Maintenance

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Even though fetal islet development in the context of pancreatic organogenesis has been studied extensively, maintenance of islet mass in the context of the adult organ is a relatively new area of interest. It has been observed that despite a relatively constant islet mass, the post-natal rodent pancreas undergoes significant islet neogenesis.96 A mathematical model developed to understand the processes involved explained this apparent incongruity on the basis of an apoptotic wave during a period of endocrine remodeling.50,96 Thus, it is likely that significant p-cell neogenesis, along with minimal levels of p-cell replication, effectively counter the apoptotic wave.96 These data are consistent with the notion that maintenance of p-cell mass in the post-natal period is indeed an active process in which cell proliferation, differentiation, and death are implicated as part of a delicate balance providing tightly integrated homeostatic control of p-cell mass, at least in neonates. Whether there is a similar dynamic regulation of p-cell mass with aging remains to be clarified.

Dynamic control of p-cell mass in the adult pancreas has been suggested by studies of pregnancy during which the mother's p-cell mass expands greatly as metabolic demands increase in response to the altered hormonal milieu.97,98 However, shortly after birth, when the hormonal environment reverts to the non-pregnant state, the expanded p-cell mass involutes, returning to normal levels through p-cell atrophy, increased p-cell apoptosis, and decreased p-cell replication.97 Similar cell mass regulation has also been reported for lacrimal glands and breast tissue.99-105 Thus, it appears that common control mechanisms in different tissues may serve to align cell mass with functional need, and it seems that such mechanisms are operative and particularly responsive not only in the neonatal, but in the adult pancreas as well.

Based on morphometric analyses of single p-cells and small p-cell clusters, Bouwens et al. suggested that islet neogenesis normally occurs in the adult human pancreas,106 presumably contributing to the ongoing maintenance of p-cell mass. However, evidence suggests neogenesis may be under regulatory control that provides for a continual basal rate, but also allows for response to various stimuli. Butler et al. have provided evidence for an increase in p-cell mass in the presence of obesity, without increased p-cell replication.18,107 This finding may suggest that neogenesis in the adult pancreas plays a physiologic role in response to certain critical stimuli or factors, including alterations in the local microenvironment. This notion seems highly likely in view of the recent observation that the development of type 2 diabetes may be correlated with a lack of a neogenic response in adult humans.18 The underlying mechanisms for regulating homeostatic control and feedback inhibition of islet neogenesis remain to be elucidated.

28.4.1 Animal Models of Neogenesis

Adult islet neogenesis leading to p-cell mass expansion can be induced by partial pancreatic duct obstruction initiated through cellophane wrapping of the hamster108,109 or monkey110 pancreas. The new p-cell mass displays normal glucose-responsiveness with a normal counter-regulatory mechanism.111 Moreover, the cellophane wrapping-induced neogenic islets are able to reverse hyperglycemia in streptozotocin (STZ)-treated hamsters.112,113 p-cell mass expansion in this model is mediated by islet neogenesis associated protein (INGAP), an acinar cell protein.113 It is noteworthy that some beneficial effects were observed using partial pancreatic ligation in children with type 1 diabetes over 70 years ago.114-117 It is significant that in vivo studies have not produced any evidence of hyperfunctioning (e.g., hypoglycemia) or unchecked cell growth (e.g., tumor formation), suggesting that the induction of p-cell mass expansion in the normal adult pancreas may be regulated by inherent homeostatic control mechanisms.118 Further studies have demonstrated that the administration of a biologically active 15 amino acid fragment of the native protein, termed INGAP peptide, is sufficient to induce the normalization of both p-cell mass and glycemia levels in STZ-treated mice.118 As such, INGAP peptide appears to be of interest as a mediator of islet neogenesis, and INGAP binding has been suggested as a potential marker of progenitor cells within the ducts and islets.119

Another model that exists to examine the response in p-cell mass dynamics to increased metabolic demand is that of chronic glucose infu-sion.120-125 In this model, animals receive a constant infusion of glucose via intravenous catheter. After 4 days of glucose infusion, the p-cell mass as much as doubles, accompanied by marked p-cell neogenesis. Furthermore, following glucose infusion, p-cell mass returns to basal values as a result of p-cell apoptosis and a decrease in p-cell replication, suggesting that homeostatic mechanisms exert dynamic control over the balance between neogenesis and apoptosis in the adult (rodent) pancreas.120

A third model of p-cell response to stimulation is the sucrose feeding model.126-129 Five weeks of high-sucrose feeding of adult hamsters leads to a neogenesis-associated doubling of p-cell mass. In a variant model, sucrose feeding of pregnant mothers,119 the offspring exhibit a significant decrease in p-cell apoptosis, together with a substantial increase in p-cell replication, islet neogenesis, and p-cell mass. INGAP is implicated in both cases,119 thus supporting a role for INGAP in p-cell mass expansion through a modulation of islet neogenesis. Thus, a homeostatic balance between p-cell neogenesis and apoptosis is important in regulation of p-cell mass in the adult pancreas.130

The incretin GLP-1 (and its long-acting homologue exendin-4) increases p-cell mass in animal models of diabetes,131,132 though the exact mechanism of p-cell mass expansion has not been fully clarified (i.e., anti-apoptotic effects of increased insulin secretion vs. effects of augmented insulin release on p-cell replication vs. effect on p-cell size). However, it has been suggested that GLP-1 expands p-cell mass directly by stimulating p-cell proliferation and inducing islet neogenesis in a PDX-1-dependent fashion in both young and old animals133-139 and by inhibiting apoptosis.140 These findings lend support to the view that the pancreas possesses control mechanisms to regulate p-cell mass throughout postnatal life. GLP-1 is an insulinotropic hormone secreted by enteroendocrine L-cells of the distal intestine in response to food ingestion,136 and also regulates blood glucose by stimulating glucose-dependent insulin secretion, insulin biosynthesis, and p-cell proliferation.

Finally, partial pancreatectomy has been proposed as a means of inducing islet neogenesis.141 In this model, in which 90% of the organ is excised, islet mass is restored to 45% of control at 8 weeks post-surgery.142-144 The islet neogenesis observed is thought to occur via the proliferation of small ductules from putative precursors in the ductal epithelium, followed by the differentiation of cells within these ductules into the various endocrine phenotypes. In this model, these changes occur over the course of 7 to 10 days and are associated with the expression of various genes associated with islet formation. The first of these is transforming growth factor-p (TGF-p), which appears to be involved in the arrest of ductal proliferation and marks the beginning of the differentiation stage. During the latter stage, hepatocyte growth factor (HGF) and insulin-like growth factor-I (IGF-I) are expressed in association with ductal epithelium.144 Furthermore, the Reg proteins (of which INGAP is a member) have been implicated in this instance of islet regeneration.145

There also exist other models of p-cell mass expansion, however the above were identified based on their ability to induce neogenesis, which is the novel formation of islets.

28.4.2 Stem/Progenitor Cells

Even though p-cell replication can account for a part of the novel islets required to maintain islet mass in the face of a certain amount of p-cell turnover, the aforementioned data strongly suggest that islet neogenesis plays a role in maintaining p-cell mass. As such, the persistence of a multipotent precursor cell throughout life, capable of replenishing the endocrine cell population, would be essential for the maintenance of islet homeostasis. However, although it seems certain that a stem cell or precursor for islet cells must exist at some point during the development of the organism146 and likely still exists in adulthood, there has been little success in finding this cell, or identifying a distinct marker.

Ultimately, the therapeutic potential of p-cell neogenesis may rest in the ability to reliably generate functional p-cell mass, either in vivo or in vitro for transplantation. This necessarily relies on the ability to identify, and possibly to isolate, maintain, and manipulate a precursor cell type. Despite these observations, the true presence of a stem cell population within the duct or islet has not been conclusively proven. Although several candidates have been identified, a reliable marker for such a cell type has not been defined. Candidates have included neuronal markers such as tyrosine hydroxylase,147 acid p-galactosidase,148 glucokinase,149 GLUT-2,150 and the ductal markers cytokeratin-19 (CK-19) and cytokeratin-20 (CK-20).151 Among more recently described markers, the intermediate filament protein nestin, thought to be expressed in neuronal stem cells,152 has been identified in islet cells as well.153,154 Other reports, however, question whether nestin expression may really represent intraislet fibroblasts.155 Any persistent stem cell population within the adult islet may in fact be rather innocuous and unremarkable, making their molecular identification much more difficult. Small, primitive cells fitting this description have been described in isolated islet preparations.3

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