The role of Ang- (1-7) and its Mas and MrgD receptors in the proliferation / regeneration of pancreatic beta cells

• Applicants: Professor Dr. Uwe Lendeckel; Professor Dr. Niels Wessel, since 1/2024
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446519514

The absolute insulin deficiency characteristic of type I diabetes (T1DM) and the relative deficiency of T2DM have aroused great interest in understanding mechanisms/processes that control pancreatic beta cell mass. Recent data shows that beta cell mass is determined by the integration of various effects, including neogenesis of islets, proliferation and hyperplasia of existing beta cells, and a finely-regulated balance between beta cell maturation/differentiation and apoptosis. Beta cells can be divided into several subpopulations based on the expression of different marker genes or surface antigens.Angiotensin (Ang)-(1-7) is generated by ACE2 from AngII and often counteracts the negative AngII effects by interacting with its own two receptors, Mas and MrgD. In preliminary work we demonstrated a drastically reduced basal and stimulated insulin secretion of isolated islets of Mas-deficient mice, whereas Ang-(1-7) strongly increased insulin secretion. These data implicate a regulatory role of the Ang-(1-7)/Mas and/or MrgD axis for beta cell function. Importantly, we recently discovered that Ang-(1-7) not only reduced blood glucose levels in a T1DM model, but also significantly increased the pancreatic beta cell volume fraction (insulin-positive cell fraction).The experiments planned are intended to show that Ang-(1-7) and related agonists represent a new and promising strategy for the treatment of diabetes mellitus, by verifying that these compounds - in addition to improving peripheral insulin resistance - can restore beta cell function (adequate glucose-stimulated insulin secretion) by e.g. stimulating the regeneration of functional beta cells.For this purpose, the Ang-(1-7)-dependent effects on the number/size of islets or beta cells will be revealed in a preclinical model ("multi-low dose" STZ) and the mediating receptors identified. Mechanisms by which Ang-(1-7) affects distinct beta cell subpopulations ("beta cell heterogeneity") and the regulation of gene expression profiles in these subpopulations will be elucidated in vitro. The contribution of invading stem/progenitor cells to Ang-(1-7)-dependent changes in beta cell quantity and islet subpopulation profile will be explored. Finally, the importance of the identified mechanisms under physiological and pathophysiological conditions will be tested in a spontaneous preclinical model of the T1DM ("non-obese diabetic" [NOD] mouse).The proposal targets with various different experimental approaches the establishment of Ang-(1-7) and first non-peptidic small molecules stimulating specific Ang-(1-7) receptors as a new therapeutic option in DM. The experiments will identify the mechanisms underlying the proliferation of beta cells and the regeneration of pancreatic islets and bridge the gap to a translational approach that can be implemented quickly. Accordingly, a considerable benefit from the proposed project can be expected for the individual patient, but also for the health economic system.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Thomas Walther, Ph.D., until 1/2024