Sucralose activates an ERK1/2–ribosomal protein S6 signaling axis

Abstract

The sweetener sucralose can signal through its GPCR receptor to induce insulin secretion from pancreatic β cells, but the downstream signaling pathways involved are not well‐understood. Here we measure responses to sucralose, glucagon‐like peptide 1, and amino acids in MIN6 β cells. Our data suggest a signaling axis, whereby sucralose induces calcium and cAMP, activation of ERK1/2, and site‐specific phosphorylation of ribosomal protein S6. Interestingly, sucralose acted independently of mTORC1 or ribosomal S6 kinase (RSK). These results suggest that sweeteners like sucralose can influence β‐cell responses to secretagogues like glucose through metabolic as well as GPCR‐mediated pathways. Future investigation of novel sweet taste receptor signaling pathways in β cells will have implications for diabetes and other emergent fields involving these receptors.

Mechanisms of the amplifying pathway of insulin secretion in the β cell

“…Glucose and amino acids themselves, signaling through receptors at the plasma membrane, may contribute to the amplification of GSIS. The taste receptor proteins T1R1, T1R2 and T1R3 have been the subject of recent investigation in the β cell and have been shown to impact pathways including mTOR activation and autophagy (Wauson, et al, 2015), cAMP and ATP concentrations Nakagawa, et al, 2014), and calcium influx (Guerra, et al, 2017). While sweeteners like sucralose have been used to investigate taste receptor signaling, ingestion of sucralose does not result in effective concentrations in plasma (Roberts, et al, 2000).…”

α2-Adrenergic Disruption of β Cell BDNF-TrkB Receptor Tyrosine Kinase Signaling

“…We also tested whether BDNF on its own can induce cAMP generation in MIN6 cells expressing a bioluminescence-resonance energy transfer-based cAMP reporter ( cAM P sensor using Y FP- E pac-RL u c or CAMYEL) ( Jiang et al, 2007 ; Guerra et al, 2017 ). While the known G s activator GLP-1 increased cAMP ( Holst, 2007 ), BDNF had no effect, either alone or in combination with glucose or GLP-1 ( Supplementary Figure 2C ).…”

α2-adrenergic signaling disrupts β cell BDNF-TrkB receptor tyrosine kinase signaling

“…We tested whether BDNF can induce cAMP generation in MIN6 cells expressing a bioluminescence-resonance energy transfer-based cAMP reporter (cAMP sensor using YFP-Epac-RLuc or CAMYEL) (50,51). While the known G s activator GLP-1 increased cAMP (52), BDNF had no effect on cAMP, either alone or in combination with glucose or GLP-1 ( Fig.…”

“…Epac-based bioluminescence resonance energy transfer (BRET) sensor for cAMP (CAMYEL) in MIN6 cells as previously described (50,51). Briefly, BRET assays were performed on the Synergy H1 microplate reader (BioTek).…”