Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis

Abstract

BackgroundPlasma insulin levels are predominantly the product of the morphological mass of insulin producing beta cells in the pancreatic islets of Langerhans and the functional status of each of these beta cells. Thus, deficiency in either beta cell mass or function, or both, can lead to insufficient levels of insulin, resulting in hyperglycemia and diabetes. Nonetheless, the precise contribution of beta cell mass and function to the pathogenesis of diabetes as well as the underlying mechanisms are still unclear. In the past, this was largely due to the restricted number of technologies suitable for studying the scarcely accessible human beta cells. However, in recent years, a number of new platforms have been established to expand the available techniques and to facilitate deeper insight into the role of human beta cell mass and function as cause for diabetes and as potential treatment targets.Scope of ReviewThis review discusses the current knowledge about contribution of human beta cell mass and function to different stages of type 1 and type 2 diabetes pathogenesis. Furthermore, it highlights standard and newly developed technological platforms for the study of human beta cell biology, which can be used to increase our understanding of beta cell mass and function in human glucose homeostasis.Major ConclusionsIn contrast to early disease models, recent studies suggest that in type 1 and type 2 diabetes impairment of beta cell function is an early feature of disease pathogenesis while a substantial decrease in beta cell mass occurs more closely to clinical manifestation. This suggests that, in addition to beta cell mass replacement for late stage therapies, the development of novel strategies for protection and recovery of beta cell function could be most promising for successful diabetes treatment and prevention. The use of today's developing and wide range of technologies and platforms for the study of human beta cells will allow for a more detailed investigation of the underlying mechanisms and will facilitate development of treatment approaches to specifically target human beta cell mass and function.

Islet macrophages drive islet vascular remodeling and compensatory hyperinsulinemia in the early stages of diabetes

“…Islet size in db/db mice was consistently approximately 3.5 fold larger compared to lean mice (Supplemental Figure 1D-E), corroborating an earlier observation (24). These results are similar to the metabolic adaptations seen in pre-diabetic humans (1,25,26) making the db/db mouse an ideal model for studying mechanisms of islet compensation in early T2D.…”

Delivery of shRNA via lentivirus in human pseudoislets provides a model to test dynamic regulation of insulin secretion and gene function in human islets

“…; Chen et al. ). As the three‐dimensional structure of pancreatic islets supports viability and function of beta cells through cell‐cell and cell‐matrix communications (Rutter and Hodson ; Arous and Wehrle‐Haller ; Reissaus and Piston ; Briant et al.…”

“…The loss of functional beta cell mass is the central pathology for both type 1 and type 2 diabetes (Kahn 2001;Atkinson et al 2014;Chen et al 2017). As the threedimensional structure of pancreatic islets supports viability and function of beta cells through cell-cell and cell-matrix communications (Rutter and Hodson 2015;Arous and Wehrle-Haller 2017;Reissaus and Piston 2017;Briant et al 2018), it is critical to address beta cell pathophysiology in pancreatic islets.…”

Cellular and Molecular Probing of Intact Transparent Human Organs

“…We demonstrate that the 3D distribution of pancreatic beta cells as single cell or groups of cells within the islet of Langerhans can be readily imaged and quantified by our new approach demonstrating the islet size heterogeneity. Regional differences of islet size and distribution (head vs. tail) in human pancreas are well known, and alterations in beta cell mass occur in diverse metabolic disorders [47]. For instance in disease conditions like type 2 diabetes, regional changes of islet distribution leading to preferentially large islets in the head region occur [48].…”