DYNAMICS OF PANCREATIC BETA CELLS: Evidence for Beta Cell Turnover and Attempted Regeneration in Diabetes from Sources of Beta Cells other than Beta Cell Replication in Rats, Monkeys, and Humans
Year: 2010
Type: dissertation
Abstract: Since the fundamental defect in both type 1 (T1DM) and type 2 diabetes (T2DM) is beta cell failure, there is increasing interest in the capacity, if any, for beta cell regeneration. In this context quantitative analysis of beta cell turnover becomes essential to permit investigation of the mechanisms that regulate it. For example, how does beta cell mass adapt to obesity? How is beta cell mass preserved during aging? How does beta cell mass expand during childhood? In collaboration with the Larry Hillblom Islet Research at David Geffen School of Medicine, University of California Los Angeles, we developed a dynamic model to estimate beta cell turnover. Assuming homogeneity of beta cells, the model describes beta cell mass as the balance between beta cell formation and loss. Beta cells are added either by replication of existing beta cells or by other sources of beta cells (OSB), and they are mainly lost through beta cell apoptosis. Since all the model parameters can be quantified with the exception of OSB, it was possible to solve for this unknown. The resulting components of beta cell turnover, i.e. new beta cell formation (replication of existing beta cells plus other sources of beta cells rather than beta cell replication) and beta cell death (apoptosis), were used to develop a population model to assess the mean age of a beta cell as well as the mean beta cell lifetime. The resulting model is a variation of the classical McKendrick-von Foerster equation and describes beta cells as a variegate population of cells that differ each other by their own age. The novel insights that emerge by applying the model to different species, i.e. rats, monkeys, and humans are: 1) there is ongoing beta cell turnover in non diabetic rats, monkeys, and humans through adult life; 2) formation and maintenance of the population of adult beta cells largely depend on OSB in non diabetic rats, monkeys, and humans; 3) the formation of new beta cells from other sources of beta cells increases substantially in the face of the increased beta cell apoptosis in the HIP rat model of type 2 diabetes, delaying the decline in beta cell mass. In contrast, beta cell turnover is low in the streptozotocin (STZ) monkey model of T1DM, compared to non diabetic controls. The extent that beta cells are formed in the STZ monkey is again primarily from OSB. 4) Beta cell replication is the primary mechanism subserving the postnatal expansion of beta cell mass in childhood, while in adulthood OSB is the principal mechanism for maintaining beta cell mass in face of an increased beta cell apoptosis; 5) beta cell mass and beta cell turnover increase in response to obesity in humans; 6) the estimated mean age of a beta cell (1-2 months in rats, 2-5 months in monkeys, and 6 months- 2 years in humans) and the mean beta cell lifetime (1-3 months in rats, 2-5 months in monkeys, and 6 months-2 years in humans) potentially permit endogenous regeneration of beta cell mass in diabetes if beta cell turnover could be altered therapeutically. The presented models provide, for the first time, information about sources of beta cells other than those derived from beta cell replication and estimates of the mean age of a beta cell and the mean beta cell lifetime in rats, monkeys, and humans. The results have an impact from a clinical point of view considering that: a) the origin of beta cells is actively debated, i.e. some propose duplication of existing beta cells, and others suggest formation of new beta cells from a variety of sources; b) restoration of glycemic control in type 1 and type 2 diabetes through endogenous regeneration could be a potential alternative strategy to pancreas transplantation given the insufficient number of pancreases available for transplantation and the risks of prolonged immunosuppression; c) the unique experimental approach to identify other sources of beta cells is the cell-lineage tracing that is not available in humans. Furthermore, the results encourage: a) future studies on beta cell turnover in patients with diabetes; b) the development of ad hoc experiments that identify the possible other sources of beta cells rather than beta cell replication; c) to plan both experiments and mathematical models to establish the forms and the time required for endogenous regeneration of beta cell mass.
Author: Erica Manesso
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W164362894