OR10-03 Tumor necrosis factor alpha induces incretin hormone resistance and defective first phase insulin release in beta-cells via non-canonical incretin receptor internalization in mouse and human beta-cells
Year: 2024
Type: article
Abstract: M.A. Hussain: None. U. Song: None. W. Cheng: None. D. Lee: None. A. Prabhu: None. Loss of first phase insulin release (FPIR) is among the earliest detectable parameters of β-cell dysfunction and a strong predictor of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). The molecular mechanism and potential Examining the potential role of cytokines in inducing FPIR loss, we find that TNFα at low concentrations - but not IL1β or IFNγ - impairs FPIR in mouse and human islets - coinciding with TNFα-induced internalization of GLP-1R and GIPR in a ligand-independent manner, thereby also rendering β-cells less responsive to GLP-1R and GIPR agonists. Using NanoBiT technology we find that in GLP-1R couples through predominantly with Gαs and less with Gαq, while GIPR couples with Gαs only. Using HiBiT-based receptor internalization assay we find that TNFα induces GLP-1R and GIPR internalization away from the cell surface, resulting in reduced receptor-mediated signaling. We also find that TNFα significantly reduces GIPR coupling to Gαs and GLP-1R coupling to both Gαs and Gαq, albeit GLP-1 induced IP3 production appears less suppressed than cAMP production following TNFα. Mechanstically, TNFα signals through TNF receptor 1/p55 -TRAF2 to activate β-Arrestin2-induced GLP-1R and GIPR internalization. Accordingly, mice lacking Tnrf1/p55 or TRAF2 selectively in β-cells are protected from high fat diet-induced dysglycemia; and their islets remain protected from TNFα-induced FPIR loss and do not show TNFα-induced internalization of GLP1R or GIPR. Furthermore, our findings indicate that cholinergic signaling through the α7 nicotinic receptor (Chrna7) on ß-cells counteracts TNFα-induced FPIR loss and GLP-1R internalization. Mouse islets lacking Chrna7 selectively in β-cells exhibit diminished GSIS potentiation upon GLP-1R agonism; and pharmacologic Chrna7 activation via ERK signaling also protects wild-type islets from TNFα-induced FPIR reduction. Importantly, human islets also show reduced FPIR and incretin hormone resistance after TNFα treatment; and human pseudo-islets – reaggregated dispersed human islet cells - also exhibit TNFα-induced GLP-1R and GIPR internalization, which is also inhibited by Chrna7 agonism. Thus, our findings indicate that TNFα signaling in β-cells underlies reduced FPIR in diabetes mellitus; and that TNFα signals in non-canonical manner to increase GLP-1R internalization, thereby reducing β-cells response to incretin action – as is found in T2DM. Pharmacologic cholinergic signaling via the nicotinic receptor Chrna7 – a target for drug development for Alzheimer’s disease- protects β-cells from TNFα-induced β-cell dysfunction. Monday, June 3, 2024
Source: Journal of the Endocrine Society
Authors: M A Hussain, U Song, W Cheng, D Lee, A Prabhu
Institutions: University of California, Irvine, University of Michigan
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,418
OpenAlex ID: W4409920134