Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome

Abstract

Individuals widely use non-nutritive sweeteners (NNS) in attempts to lower their overall daily caloric intake, lose weight, and sustain a healthy diet. There are insufficient scientific data that support the safety of consuming NNS. However, recent studies have suggested that NNS consumption can induce gut microbiota dysbiosis and promote glucose intolerance in healthy individuals that may result in the development of type 2 diabetes mellitus (T2DM). This sequence of events may result in changes in the gut microbiota composition through microRNA (miRNA)-mediated changes. The mechanism(s) by which miRNAs alter gene expression of different bacterial species provides a link between the consumption of NNS and the development of metabolic changes. Another potential mechanism that connects NNS to metabolic changes is the molecular crosstalk between the insulin receptor (IR) and G protein-coupled receptors (GPCRs). Here, we aim to highlight the role of NNS in obesity and discuss IR-GPCR crosstalk and miRNA-mediated changes, in the manipulation of the gut microbiota composition and T2DM pathogenesis.

Keywords: GPCR; gut microbiota; insulin receptor signaling; miRNAs; non-nutritive sweeteners; type 2 diabetes mellitus.

Figure 1

Proposed mechanisms of the underlying effects of non-nutritive sweeteners on the development of metabolic syndrome. NNS interact with the T1R family of sweet-taste receptors through associated G protein α-gustducin, which results in increased intracellular cAMP levels and increased neurotransmitter release. Through the associated GPCR signaling, this may explain how NNS can contribute to metabolic syndrome and insulin resistance. NNS also interfere with gut microbiota composition, with short-chain fatty acids (SCFAs) from dietary intake acting as ligands for GPCRs in the gastrointestinal tract, regulating NNS permeability and gut microbiota composition. Additionally, NNS are associated with insulin and other hormone secretion, which ultimately impact learned behavior and response to sweetness. Abbreviations: NNS, non-nutritive sweeteners; GPCR, G protein-coupled receptor; SCFA, short-chain fatty acid.

Figure 2

Gut microbiota dysbiosis and metabolic syndrome. Dysbiosis of the Firmicutes:Bacteroidetes ratio is associated with several conditions characteristic of metabolic syndrome, including weight gain/obesity, insulin resistance, high-fat diets, gut permeability, and inflammatory bowel disease (IBD). As a result, NNS consumption may contribute to the development of these conditions due to alterations in the Firmicutes:Bacteroidetes ratio. A bifidobacteria decrease combined with an enterobacteria increase leads to endotoxemia that causes a chronic low-grade inflammation associated with some pathological conditions such as insulin resistance and increased gut permeability. A right balance in the microbiota may be considered in gut homeostasis and maintaining the microbiota can be considered prebiotics and restore eubiosis in some pathological conditions. Abbreviations: IBD, inflammatory bowel disease; NNS, non-nutritive sweeteners.

Figure 3

Hypothetical G protein-coupled receptor (GPCR) heterodimeric T1R2/T1R3 taste receptors exist in a multimeric receptor complex with NMBR, IRβ, and Neu-1 in naïve IR expressing cells. Here, TIR2/TIR3 dimeric receptors are proposed to exist as a molecular link regulating the interaction and signaling mechanism(s) between these molecules on the cell surface. This molecular model uncovers a biased TIR2/TIR3 GPCR agonist-induced IRβ transactivation signaling axis, mediated by Neu-1 sialidase and modification of insulin receptor glycosylation. This novel biased GPCR-signaling platform potentiates neuraminidase-1 (Neu-1) and matrix metalloproteinase-9 (MMP-9) crosstalk on the cell surface that is essential for the activation of the insulin receptor β subunit (IRβ) tyrosine kinases. Notes: Insulin-binding receptor α subunits (IRα), as well as GPCR agonists, potentiate biased neuromedin B receptor (NMBR)-IRβ signaling and MMP-9 activation to induce Neu-1 sialidase. Activated MMP-9 is proposed here to remove the elastin-binding protein (EBP) as part of the molecular multienzymatic complex that contains β-galactosidase/Neu-1 and protective protein cathepsin A (PPCA). Activated Neu-1 hydrolyzes α-2,3 sialyl residues of IRβ at the ectodomain to remove steric hindrance to facilitate IRβ subunits association and tyrosine kinase activation. Activated phospho-IRβ subunits phosphorylate insulin receptor substrate-1 (pIRS1), which initiate intracellular insulin signaling via the Ras-MAPK and the PI3K-Akt pathway, among others. Abbreviations: PI3K, phosphatidylinositol 3-kinase; GTP, guanine triphosphate; IRS1, insulin receptor substrate-1; p, phosphorylation; Neu-1, neuraminidase-1. Taken in part from Cellular Signalling 43 (2018) 71–84. © 2018 Haxho et al., Published by Elsevier Inc., open-access under CC BY-NC-ND license. This is an open-access article which permits unrestricted noncommercial use, provided the original work is properly cited.