GO:0010255 glucose mediated signaling pathway: Nutrient Sensing, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0010255 (glucose mediated signaling pathway) describes how changes in glucose levels trigger gene expression programs that control metabolic and developmental processes.
• Glucose signaling is not passive fuel sensing; it is an active allosteric and post-translational signaling system, exemplified by glucose-phosphate-mediated allosteric control of glycogen metabolism in the brain.
• Core effectors include insulin/IGF signaling components such as FoxO and PEPCK, which couple glucose availability to gluconeogenic gene transcription.
• High glucose can directly engage growth and autophagy pathways, including Notch3-mTOR signaling in kidney epithelial cells.
• Glucose metabolism is integrated with innate immune signaling through MAVS, linking nutrient status to RIG-I-like receptor antiviral responses.
• CRISPR knockout, point-mutation, knock-in and overexpression models are the standard tools for causally testing glucose signaling genes in metabolic and developmental contexts [3,4,5].
Description
Glucose is both a metabolic substrate and a signaling molecule. GO:0010255, glucose mediated signaling pathway, captures the process in which a change in the level of mono- and disaccharide glucose triggers the expression of genes controlling metabolic and developmental processes. This distinguishes glucose signaling from simple energy supply: the cell reads glucose concentration and converts that information into transcriptional outputs. A well-studied example is the allosteric signaling role of glucose phosphates, which can sustain brain function by coordinating glycogen metabolism with neuronal demand. In parallel, glucose availability is relayed through insulin signaling to transcription factors such as FoxO, which regulate PEPCK and gluconeogenesis in Drosophila and mammalian liver models. Because glucose signaling intersects with growth, autophagy and immunity, it is a central node in metabolic disease, cancer and infection research [4,5]. Understanding GO:0010255 therefore requires both biochemical knowledge of glucose flux and genetic tools to test which downstream genes are causally regulated.
glucose mediated signaling pathway At A Glance
| GO ID | GO:0010255 |
|---|---|
| GO term | glucose mediated signaling pathway |
| Ontology | biological_process |
| Synonym | glucose mediated signalling |
| Definition | The process in which a change in the level of mono- and disaccharide glucose trigger the expression of genes controlling metabolic and developmental processes. |
| Major function | Coupling glucose availability to transcriptional programs that control metabolism, growth and development [2,3]. |
| Representative effectors | Insulin/FoxO/PEPCK axis, Notch3-mTOR, MAVS, SIK1-CRTC2, SGLT1-Akt/mTOR/p70S6K [3,4,5,6,7]. |
| Cellular contexts | Liver, kidney epithelium, brain, sperm, perivascular preadipocytes and immune cells [2,4,5,7,8]. |
| Research relevance | Target for diabetes, metabolic syndrome, cancer metabolism, neuroprotection and antiviral immunity studies [3,4,5]. |
What Is GO:0010255?
GO:0010255 is the biological process in which a change in the level of glucose, a mono- and disaccharide, triggers the expression of genes that control metabolic and developmental processes. In practice, this means glucose acts less like a passive fuel and more like a signal: its concentration is sensed, transmitted through intracellular pathways, and converted into changes in gene transcription. The term is narrower than general carbohydrate metabolism because it emphasizes signal transduction leading to gene expression, and broader than a single pathway because it includes insulin-dependent and insulin-independent branches [3,4].
Why Is glucose mediated signaling pathway Important in Cell Biology?
Glucose mediated signaling is important because it converts a ubiquitous nutrient into precise transcriptional instructions. When this process is dysregulated, cells lose the ability to match gene expression to energy availability, contributing to metabolic disease, cancer progression, neurodegeneration and impaired immune responses [2,3,4,5]. Because glucose signaling intersects with insulin, mTOR, autophagy and innate immunity, it is a high-value target for both mechanistic studies and therapeutic development.
• Controls gluconeogenic gene expression through the insulin-FoxO-PEPCK axis, directly affecting blood glucose homeostasis.
• Links high glucose to autophagy regulation via Notch3-mTOR signaling in kidney epithelial cells, relevant to diabetic nephropathy.
• Integrates glucose metabolism with RIG-I-like receptor antiviral signaling through MAVS, connecting nutrition to innate immunity.
• Regulates CRTC2-mediated gluconeogenesis via SIK1 in human and mouse liver cells, a key node in hepatic glucose output.
• Mediates glucose uptake-dependent biofunctions in perivascular preadipocytes through SGLT1 and Akt/mTOR/p70S6K signaling.
• Supports brain function through glucose-phosphate allosteric signaling that sustains glycogen metabolism.
• Controls developmental processes such as the acrosome reaction in chicken sperm via membrane raft-mediated glucose signaling.
• Provides mechanistic entry points for diabetes, obesity, cancer metabolism and neuroprotection research [3,4,5].
• Enables CRISPR-based causal testing of candidate glucose-sensing genes in metabolic and developmental models [3,4,5].
What Happens During glucose mediated signaling pathway?
Glucose sensing and signal initiation
In simple terms: The cell first notices that glucose levels have changed.
Glucose mediated signaling begins when a change in glucose concentration is detected at the cell surface or within the cytosol. In the brain, glucose phosphates generated from glycogen breakdown can act as allosteric signals that sustain function during periods of demand. In kidney epithelial cells, high glucose itself acts as the initiating signal that engages Notch3 and downstream mTOR signaling. In perivascular preadipocytes, glucose uptake through sodium-glucose cotransporter 1 initiates Akt/mTOR/p70S6K signaling. These examples show that the initiating event can be extracellular glucose, intracellular glucose phosphates, or transporter-mediated flux [2,4,7].
Transmission through kinase cascades
In simple terms: The glucose signal is passed along a chain of molecular messengers.
Once initiated, the glucose signal is transmitted through kinase cascades. Insulin signaling relays glucose status to FoxO transcription factors, which in turn regulate PEPCK and gluconeogenesis. SIK1 controls CRTC2-mediated gluconeogenesis in human and mouse liver cells, providing a second kinase relay that converts glucose signals into transcriptional output. In kidney cells, Notch3-mediated mTOR signaling is engaged by high glucose and regulates autophagy. In perivascular preadipocytes, Akt/mTOR/p70S6K signaling is activated downstream of SGLT1. These cascades allow a single glucose change to be amplified into multiple downstream effects [3,4,6,7].
Transcriptional reprogramming
In simple terms: The signal reaches the nucleus and switches genes on or off.
The defining output of GO:0010255 is gene expression change. FoxO-PEPCK regulation directly controls gluconeogenic gene transcription in response to glucose and insulin status. CRTC2 is a transcriptional coactivator regulated by SIK1 that drives gluconeogenic gene expression in liver cells. High glucose-induced Notch3-mTOR signaling alters the expression of autophagy-related genes in bovine kidney epithelial cells. These examples illustrate that glucose signaling converges on transcription factors and coactivators to reshape metabolic and developmental gene programs [3,4,6].
Integration with immune and stress signaling
In simple terms: Glucose signals also talk to the immune system.
Glucose metabolism is integrated with innate immune signaling through MAVS, which links glucose metabolism to RIG-I-like receptor signaling. This integration means that changes in glucose availability can modulate antiviral responses, and conversely that immune activation can reshape glucose handling. Such crosstalk expands the physiological scope of GO:0010255 beyond classical metabolism into host defense and inflammation.
Tissue-specific developmental outputs
In simple terms: In some tissues, glucose signals control specialized developmental events.
Glucose signaling can drive developmental processes in a tissue-specific manner. In chicken sperm, membrane raft-mediated glucose signaling leads to the acrosome reaction, a specialized developmental event required for fertilization. In the brain, glucose-phosphate allosteric signaling sustains glycogen metabolism and neuronal function. These examples show that GO:0010255 is not limited to metabolic gene regulation but extends to developmental and specialized cellular functions [2,8].
Key Genes Involved in GO:0010255 glucose mediated signaling pathway
The following genes and proteins are experimentally implicated in glucose mediated signaling pathway (GO:0010255) based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| FOXO | Transcription factor downstream of insulin signaling regulating PEPCK and glucose homeostasis | Target for diabetes and metabolic studies in Drosophila and mammalian models |
| PEPCK (PCK1/PCK2) | Rate-limiting gluconeogenic enzyme transcriptionally regulated by FoxO | Readout of hepatic glucose output and insulin sensitivity |
| NOTCH3 | Receptor mediating high glucose-induced mTOR signaling and autophagy | Model for diabetic kidney disease and autophagy regulation |
| MTOR | Central kinase integrating glucose signals to growth and autophagy [4,7] | Target for metabolic and cancer signaling studies [4,7] |
| MAVS | Mitochondrial antiviral signaling adaptor integrating glucose metabolism with RIG-I-like receptor signaling | Links nutrition to innate immunity and antiviral defense |
| SIK1 | Kinase regulating CRTC2-mediated gluconeogenesis | Hepatic glucose output and metabolic disease target |
| CRTC2 | Transcriptional coactivator driving gluconeogenic gene expression | Readout of cAMP/calcium-regulated glucose signaling |
| SGLT1 (SLC5A1) | Sodium-glucose cotransporter initiating Akt/mTOR/p70S6K signaling | Target in perivascular adipose tissue and glucose uptake studies |
| AKT | Kinase downstream of SGLT1 mediating glucose-dependent biofunctions | Central node in insulin and growth signaling |
| P70S6K (RPS6KB1) | Effector of mTOR signaling downstream of glucose uptake | Marker of translational activation in metabolic models |
| NRF2 (NFE2L2) | Transcription factor in antioxidant and ferroptosis-related signaling | Context for glucose-related oxidative stress studies |
| HO-1 (HMOX1) | Antioxidant enzyme downstream of NRF2 | Readout of stress-responsive signaling in metabolic injury models |
| RIG-I (DDX58) | Cytosolic RNA sensor in antiviral signaling integrated with MAVS | Connects glucose metabolism to innate immunity |
| Glycogen phosphorylase | Enzyme generating glucose phosphates for allosteric signaling | Brain energy metabolism and neuroprotection studies |
| Membrane raft proteins | Platform for glucose signaling leading to acrosome reaction | Reproductive biology and sperm function studies |
How Is glucose mediated signaling pathway Regulated?
Glucose mediated signaling is regulated at multiple levels. Insulin signaling controls FoxO activity and thereby PEPCK transcription, providing endocrine feedback on glucose availability. SIK1 regulates CRTC2-mediated gluconeogenesis, linking cellular energy status to transcriptional coactivation in liver. mTOR integrates glucose signals with growth and autophagy, as shown in high glucose-treated kidney epithelial cells and in SGLT1-dependent perivascular preadipocyte signaling. MAVS provides a regulatory interface between glucose metabolism and innate immune signaling. In the brain, glucose phosphates act as allosteric regulators of glycogen metabolism, adding a metabolite-level control layer. Together, these mechanisms ensure that glucose signaling is tuned to tissue-specific demands and systemic metabolic state [2,3,4,5,6,7].
glucose mediated signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FOXO / PEPCK | Diabetes and hepatic gluconeogenesis | Liver cell lines with FOXO or PEPCK knockout and glucose challenge |
| NOTCH3 / MTOR | Diabetic kidney disease and autophagy | Kidney epithelial cells with NOTCH3 knockout under high glucose |
| SIK1 / CRTC2 | Metabolic disease and hepatic glucose output | Human and mouse liver cells with SIK1 or CRTC2 perturbation |
| SGLT1 / AKT / MTOR | Metabolic syndrome and adipose dysfunction | Perivascular preadipocytes with SGLT1 knockout or overexpression |
| MAVS | Antiviral immunity and metabolic stress | Immune or epithelial cells with MAVS knockout and glucose modulation |
Diabetes and metabolic disease
Dysregulated glucose signaling is central to diabetes and metabolic syndrome. The insulin-FoxO-PEPCK axis controls gluconeogenic gene expression, and its misregulation contributes to excessive hepatic glucose output. SIK1-CRTC2 signaling in human and mouse liver cells further regulates gluconeogenesis, making it a candidate target for glycemic control. SGLT1-dependent Akt/mTOR/p70S6K signaling in perivascular preadipocytes links glucose uptake to adipose tissue biology relevant to metabolic disease.
Diabetic kidney disease and autophagy
High glucose induces Notch3-mediated mTOR signaling and autophagy in bovine kidney epithelial cells, providing a mechanistic link between glucose signaling and kidney cell stress responses. This pathway is relevant to diabetic nephropathy, where glucose-driven autophagy dysregulation contributes to epithelial injury.
Neuroprotection and brain metabolism
In the brain, glucose-phosphate-mediated allosteric signaling sustains glycogen metabolism and neuronal function. Polysaccharides that modulate NRF2/HO-1 signaling and ferroptosis-related neuroinflammation have been studied in cerebral ischemia-reperfusion injury, highlighting the intersection of glucose-related metabolic signaling with neuroprotective strategies.
Infection and innate immunity
MAVS integrates glucose metabolism with RIG-I-like receptor signaling, meaning that glucose signaling status can influence antiviral responses. This crosstalk has implications for infections in metabolically stressed hosts and for understanding how nutrient availability shapes immunity.
From glucose mediated signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is FOXO required for glucose-dependent PEPCK transcription? | FOXO knockout in liver cells followed by glucose and insulin challenge |
| Does NOTCH3 mediate high glucose-induced autophagy? | NOTCH3 knockout kidney epithelial cells under high glucose |
| Does SIK1 control CRTC2-dependent gluconeogenesis? | SIK1 knockout or point-mutant liver cells with gluconeogenic assays |
| Is SGLT1 required for Akt/mTOR/p70S6K activation? | SGLT1 knockout or overexpression in perivascular preadipocytes |
| Does MAVS integrate glucose metabolism with antiviral signaling? | MAVS knockout cells with glucose modulation and RIG-I stimulation |
| Does membrane raft glucose signaling drive acrosome reaction? | Sperm models with raft disruption or tagged knock-in of signaling components |
How to Study the glucose mediated signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptional changes in response to glucose | Identifying glucose-responsive gene programs [3,6] |
| Phospho-Western blot | Activation of Akt, mTOR, p70S6K, SIK1, Notch3 | Validating signaling cascades downstream of glucose [4,6,7] |
| Metabolite profiling | Glucose phosphates, glycogen and flux intermediates | Biochemical evidence of glucose signaling |
| CRISPR knockout screening | Causal contribution of candidate genes | Discovering glucose signaling regulators [3,4,5] |
| Live-cell imaging | Localization and dynamics of signaling proteins | Membrane raft and compartmentalized signaling studies |
| Co-immunoprecipitation | Protein-protein interactions in glucose signaling complexes | Mapping MAVS and mTOR complex interactions [5,7] |
| Reporter assays | Transcriptional activity of FoxO, CRTC2 or NF-kB | Quantifying glucose-dependent promoter activity [3,6] |
Transcriptomic profiling of glucose-responsive genes
RNA-seq after controlled glucose shifts identifies the gene expression programs downstream of GO:0010255. This approach has been used to define FoxO-PEPCK-dependent gluconeogenic transcription and CRTC2-mediated gluconeogenic programs. Comparing wild-type and CRISPR knockout cells under high versus low glucose reveals which genes are causally regulated by specific glucose signaling nodes [3,6].
Kinase and signaling pathway assays
Western blotting and phospho-specific antibodies measure activation of Akt, mTOR, p70S6K, SIK1 and Notch3 in response to glucose changes [4,6,7]. These assays establish the signaling relay between glucose sensing and transcriptional output, and are essential for validating CRISPR phenotypes [4,6,7].
Metabolic flux and metabolite measurement
Measuring glucose phosphates, glycogen and gluconeogenic flux provides biochemical evidence of glucose signaling activity. In brain and liver models, such measurements connect allosteric glucose signaling to functional outcomes [2,3].
Imaging and membrane raft analysis
Membrane raft integrity and localization of signaling components can be assessed by imaging and biochemical fractionation, as applied to glucose signaling leading to the acrosome reaction in sperm. This method is useful for studying compartmentalized glucose signaling events.
How CRISPR Can Be Used to Study GO:0010255 glucose mediated signaling pathway
Knockout
CRISPR knockout of glucose signaling genes such as FOXO, NOTCH3, SIK1, SGLT1 or MAVS allows researchers to test whether a candidate gene is required for glucose-dependent transcriptional and phenotypic outputs [3,4,5,6,7]. Knockout models are particularly useful for distinguishing causal signaling nodes from correlative changes in gene expression [3,4,5].
Point Mutation
Point mutations can be introduced to dissect specific phosphorylation sites or catalytic residues in kinases such as SIK1, AKT or mTOR, revealing which molecular features are required for glucose signaling [6,7]. This approach provides mechanistic resolution beyond simple loss-of-function [6,7].
Knock-in
Knock-in of tagged or reporter alleles enables tracking of glucose signaling proteins in their endogenous context, for example to monitor FoxO localization or CRTC2 recruitment to gluconeogenic promoters [3,6]. Tagged knock-in lines also facilitate interaction and imaging studies [3,6].
Overexpression
Overexpression of glucose signaling components such as SGLT1, MAVS or constitutively active Akt can test sufficiency and amplify pathway output in metabolic and immune models [5,7]. Overexpression is often combined with knockout to establish bidirectional causality [5,7].
How EDITGENE Supports glucose mediated signaling pathway Research
Researchers studying glucose mediated signaling pathway-related genes often need to determine whether a candidate gene is causally involved in glucose sensing, signal transmission or transcriptional reprogramming, rather than merely correlating with glucose levels. Establishing causality requires precise genetic models in which the candidate gene is removed, mutated, tagged or overexpressed in a controlled cellular background. EDITGENE provides these models together with screening and bioinformatics support to accelerate mechanistic discovery in glucose signaling research.
Contact EDITGENE today to design your custom CRISPR model for glucose mediated signaling pathway research.
Frequently Asked Questions About glucose mediated signaling pathway
What is glucose mediated signaling pathway (GO:0010255)?
GO:0010255 is the biological process in which a change in glucose level triggers the expression of genes controlling metabolic and developmental processes.
What genes are involved in glucose mediated signaling pathway?
Key genes include FOXO, PEPCK, NOTCH3, MTOR, MAVS, SIK1, CRTC2, SGLT1, AKT and P70S6K, based on published mechanistic studies [3,4,5,6,7].
How does glucose regulate gene expression?
Glucose signals are transmitted through kinase cascades such as insulin-FoxO, SIK1-CRTC2 and Notch3-mTOR, which converge on transcription factors and coactivators to change gene expression [3,4,6].
Is glucose mediated signaling the same as glycolysis?
No. Glycolysis is glucose breakdown for energy, whereas GO:0010255 specifically describes glucose-triggered signaling that leads to gene expression changes.
What is the role of mTOR in glucose signaling?
mTOR integrates glucose signals with growth and autophagy, as shown in high glucose-induced Notch3-mTOR signaling and SGLT1-dependent Akt/mTOR/p70S6K activation [4,7].
How is glucose signaling linked to the immune system?
MAVS integrates glucose metabolism with RIG-I-like receptor signaling, connecting nutrient status to antiviral innate immunity.
Can CRISPR be used to study glucose mediated signaling pathway?
Yes. CRISPR knockout, point mutation, knock-in and overexpression models are used to test causal roles of glucose signaling genes in metabolic and developmental processes [3,4,5,6,7].
What diseases are associated with dysregulated glucose signaling?
Diabetes, diabetic kidney disease, metabolic syndrome, neuroinflammatory conditions and impaired antiviral immunity have been linked to glucose signaling dysregulation [1,3,4,5,6,7].
What experimental models are used for glucose signaling research?
Common models include liver cells, kidney epithelial cells, perivascular preadipocytes, brain metabolic preparations and sperm models, often combined with CRISPR perturbation [2,3,4,6,7,8].
How do I choose between knockout and overexpression for glucose signaling studies?
Knockout tests necessity, while overexpression tests sufficiency; combining both provides bidirectional causal evidence for a candidate gene in GO:0010255 [3,5,7].
Conclusion
GO:0010255, glucose mediated signaling pathway, defines how glucose levels are translated into gene expression programs that control metabolism and development. The verified literature shows that this process operates through insulin-FoxO-PEPCK, SIK1-CRTC2, Notch3-mTOR, SGLT1-Akt/mTOR/p70S6K and MAVS-dependent immune signaling, with additional roles in brain glycogen metabolism and sperm developmental biology [2,3,4,5,6,7,8]. Because dysregulation of these pathways contributes to diabetes, kidney disease, metabolic syndrome and immune dysfunction, glucose signaling remains a high-priority research area [1,3,4,5,6,7]. CRISPR-based knockout, point-mutation, knock-in and overexpression models, combined with transcriptomic and biochemical readouts, provide the causal evidence needed to move from correlation to mechanism in this field [3,4,5,6,7].
References
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- 2. DiNuzzo M. 2019. How glycogen sustains brain function: A plausible allosteric signaling pathway mediated by glucose phosphates.. J Cereb Blood Flow Metab 39(8):1452-1459 PMID: 31208240
- 3. Zang S et al.. 2024. Insulin Signaling Pathway Mediates FoxO-Pepck Axis Regulation of Glucose Homeostasis in Drosophila suzukii.. Int J Mol Sci 25(19) PMID: 39408770
- 4. Cui Y et al.. 2022. Notch3-Mediated mTOR Signaling Pathway Is Involved in High Glucose-Induced Autophagy in Bovine Kidney Epithelial Cells.. Molecules 27(10) PMID: 35630598
- 5. He QQ et al.. 2023. MAVS integrates glucose metabolism and RIG-I-like receptor signaling.. Nat Commun 14(1):5343 PMID: 37660168
- 6. Wang C et al.. 2020. SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells.. Front Endocrinol (Lausanne) 11:580 PMID: 33013689
- 7. Liu Z et al.. 2024. Sodium-glucose cotransporter 1 promotes the biofunctions of perivascular preadipocytes mediated by Akt/mTOR/p70S6K signaling pathway.. Am J Physiol Cell Physiol 326(6):C1611-C1624 PMID: 38646789
- 8. Ushiyama A et al.. 2019. Membrane raft-mediated regulation of glucose signaling pathway leading to acrosome reaction in chicken sperm†.. Biol Reprod 100(6):1482-1491 PMID: 30721935
