Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

Abstract

N, Chessler SD. Extracellular CADM1 interactions influence insulin secretion by rat and human islet ␤-cells and promote clustering of syntaxin-1. Am J Physiol Endocrinol Metab 310: E874 -E885, 2016. First published April 12, 2016 doi:10.1152/ajpendo.00318.2015-Contact between ␤-cells is necessary for their normal function. Identification of the proteins mediating the effects of ␤-cell-to-␤-cell contact is a necessary step toward gaining a full understanding of the determinants of ␤-cell function and insulin secretion. The secretory machinery of the ␤-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the transcellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such transcellular interactions, important for both synaptic and ␤-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here, we tested the role of another synaptic cleft protein, CADM1, in insulinoma cells and in rat and human islet ␤-cells. We found that CADM1 is a predominant CADM isoform in ␤-cells. In INS-1 cells and primary ␤-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we found that CADM1 also influences insulin secretion in a transcellular manner. We asked whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on ␤-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing ␤-cell dysfunction in diabetes.cell adhesion molecule 1; SynCam; pancreatic islet; insulin secretion

Comparative quantitative proteomic analysis of disease stratified laser captured microdissected human islets identifies proteins and pathways potentially related to type 1 diabetes

“…In addition to insulin some of the other most significantly downregulated protein between T1D and the control cases is PFKB2 which is involved in glycolysis, hydroxyacyl-CoA dehydrogenase (HADH) which is involved in the beta-oxidation pathway and ATP2A3, magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium and STX1A, syntaxin 1A which is involved in peptide hormone metabolism and insulin secretion [ 50 ]. The others are SEC61B which is involved in the translocations of proteins to the ER, ASB9 which is involved in the ubiquitination pathway, PLCXD3 which has signal transducer and phosphoric diester hydrolase activity, UCHL1 which is a ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins and GSTM2 which is involved in the detoxification of electrophilic compounds and products of oxidative stress, by conjugation with glutathione.…”

Changes in pancreatic histology, insulin secretion and oxidative status in diabetic rats following treatment with Ficus deltoidea and vitexin

“…The levels of serum insulin were determined by Enzyme Linked Immunosorbent Assay kit specific for rat insulin (Cloud-Clone Corp., Houston, USA) as described by Zhang et al [ 24 ]. Serum was allowed to thaw and 50 μl serum was pipetted into duplicate wells followed by 50 μl of enzyme conjugate solution.…”

Exocytosis proteins as novel targets for diabetes prevention and/or remediation?

“…Although insulin granule exocytosis from ␤-cells requires actin depolymerization (39,47,82), whereas GLUT4 vesicle exocytosis requires F-actin polymerization (49,54,116), both are considered F-actin remodeling events that may coordinate the timing of STX4 activation with the arrival of incoming granules/vesicles. If true, the interaction of STX4 with the actin cytoskeleton may constitute an "excitosome," a localized site at the plasma membrane with concentrated SNARE complex proteins and accessory proteins that promote granule docking to the membrane (110,129). Overexpression of STX4 may provide the basis for more excitosomes, i.e., more docking sites for exocytosis in skeletal muscle and ␤-cells.…”