Contribution of metabolism-independent glucose sensing to metabolic homeostasis

Abstract

Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independently of their roles in transporting glucose. Moreover, we review the emerging roles of G-protein coupled receptors (GPCRs) in sensing glucose and consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlight the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.

Glucose sensing and metabolism are not always coupled

Sensing and cellular responses to fluctuating levels of glucose in the body are fundamental to the metabolic machinery in order to maintain a homeostatic environment, whose dysregulation leads to a plethora of metabolic disorders. The molecular basis of glucose sensing and metabolism (see Glossary) is not limited to one organ or cell type; rather, it is an integrated and coordinated mechanism involving peripheral organs (e.g., liver, pancreas, kidney), nervous system (e.g., autonomic nervous system, hypothalamic neurons, neurons in hindbrain) and the flux of glucose and its generating substrates between these organs.

The classical molecular machinery involving K⁺-ATP channel, which is known for elucidating glucose sensing and its homeostasis does not sufficiently address the spatial and temporal regulation of glucose signaling versus metabolism [1]. For example, multiple non-dogmatic glucose signaling pathways have been recognized that do not involve K⁺-ATP channel for the secretion of insulin by β-cells [2-4].

In mice, both glucose-excitatory (GE) and glucose-inhibitory (GI) neurons have been found to sense glucose independently of its metabolic pathway [5]. In rats, sodium-glucose co-transporter 2 (SGLT2) expressed by mesangial cells was found to act as glucose sensor independently of its transport function [6]. In addition, taste receptors (in β-cells, neurons and astrocytes) [4,7] and adhesion G-protein-coupled receptors (aGPCRs) (in ventromedial hypothalamus) [8] are reported to contribute to glucose sensing mechanisms independently of glucose metabolism. Overall, these emerging developments in the field implicate that (i) glucose sensing may not be confined to pancreatic β-cells or neurons in the brain; rather, other tissues also contribute substantially to the glucose sensing and transport mechanisms [9-11]; (ii) glucose transporters may demonstrate a dual function both as a transporter and a sensor [12,13]; (iii) glucose sensing and metabolism may exist as independent mechanisms and need not to be coupled for monitoring the energy status and maintaining glucose homeostasis [5,14,15] (Figure 1). This area of research is expected to develop further because the molecular details of such metabolism-independent glucose sensing mechanisms in regulating glucose and energy homeostasis still remain in its infancy and are debatable. Here, we discuss how glucose transporters may be involved in sensing glucose in addition to their role in glucose uptake and release. We then review new findings that demonstrate the contribution of GPCRs to glucose sensing. Finally, we discuss outstanding research questions in the field, challenges in designing futures studies and interpreting their outcomes to establish the phenomenon of glucose sensing and subsequent signaling pathways independently of glucose metabolism.

Figure 1: Metabolism-dependent versus metabolism-independent glucose sensing mechanisms.

In metabolism-dependent mechanism, glucose enters the cell via glucose transporters such as GLUT1 or GLUT2 and is metabolized to cause changes in cellular energy status, insulin/glucagon secretion and expression of glucose responsive biomolecules. In metabolism-independent mechanisms, glucose binds to the transporter or receptor and induces conformational changes that trigger intracellular signaling cascade to regulate expression of glucose responsive biomolecules. Figure created using BioRender.

Recognizing the contribution of glucose transporters to glucose sensing

Glucose levels are tightly regulated across intra and extracellular compartments through the presence of transporters in plasma membranes. In eukaryotes, transporters mainly known to distribute glucose across different tissues and organelles include glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs). GLUTs belong to the Major Facilitator Superfamily (MFS) of membrane transporters and are encoded by SLC2A genes. GLUTs have been classified into three classes (I-III) consisting of 14 different isoforms differing with respect to their varying amino acid sequences, cellular localization and substrate affinities [16] (Table 1).

Table 1:

Tissue-Specific Roles of GLUTs and SGLTs in Glucose Transport and Sensing

Transporter	Km (mM)	Affinity for glucose	Function as a transporter	Role as a sensor	References
GLUT1	~1-2	High	High affinity glucose transport in brain	May contribute to low glucose sensing in CNS	[16,19]
GLUT2	~17	Low	High-capacity glucose transporter in liver, kidney, intestines, pancreatic β-cells and CNS	May function as a sensor in pancreatic β-cells, liver, and hypothalamus	[16-19,34,36]
GLUT3	~1.4	High	Basal role in glucose uptake in skeletal muscle	Possibly involved in neuronal glucose sensing	[16,43,44]
GLUT4	~5	Moderate	Transporter in the muscle, adipose tissue, brain and heart	May play a role in neuronal glucose sensing	[16,19,37,39]
SGLT1	~0.4	High	Na+ dependent high affinity low-capacity transporter in kidney	May play a role in glucose sensing in VMH and in neuropod cells of the duodenum	[45,46,52,53]
SGLT2	~2	Moderate to low	High-capacity glucose transport in kidney	Possible role as a sensor in mesangial cells of kidney	[6,46]

CNS, central nervous system; GLUT1, glucose transporter 1; GLUT2, glucose transporter 2; GLUT3, glucose transporter 3; GLUT4, glucose transporter 4; Km, Michaelis-Menten constant; SGLT1, sodium–glucose co-transporter 1; SGLT2, sodium–glucose co-transporter 2; VMH, ventromedial hypothalamus

Glucose transporter 2 (GLUT2) and glucose transporter 4 (GLUT4) are considered major contributors to the maintenance of whole-body glycemic levels. GLUT2 is a low affinity glucose transporter with a high Km of around ~17 mmol/L [17-19]. This biochemical property enables this transporter to sense fluctuations in glucose even at low concentrations rather than being merely a transporter and getting saturated at low glucose concentrations like other high affinity glucose transporters including glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). Expression studies have revealed GLUT2 as a main glucose transporter in pancreatic islets of rodents, whereas human pancreatic islets and β-cells predominantly express GLUT1 and GLUT3 [17]. Expression of GLUT1 in β-cells has been found to compensate for the deficiency of GLUT2 and reverse the defects observed in global Glut2 knockout mice [20,21]. Corroborating this observation, it was observed that normal β-cell Glut2 gene expression is not required for maintaining systemic glucose and regulation of glucose stimulated insulin secretion [22]. Therefore, β-cell GLUT2 may not be a significant contributor to systemic glucose homeostasis. However, GLUT2 in other tissues may be essential for cell-specific glucose sensing; therefore, changes in Glut2 expression in such tissues affect whole-body glucose and energy balance. Knockout of renal Glut2 causes massive loss of glucose in urine, reverses hyperglycemia and normalizes body weight in mouse models of diabetes and obesity. Interestingly, renal Sglt2 gene expression was also found to be almost abolished three weeks after inducing renal Glut2 deficiency, implicating a probable molecular crosstalk between the two transporters [23]. Moreover, renal GLUT2 is an effector for the hypothalamic melanocortin system [24] and neurohormonal pathways [25,26] in regulating blood glucose levels. These findings demonstrate the function of local GLUT2 in regulating systemic glucose homeostasis.

Transgenic mice with deletion or mutation in large intracellular loop of GLUT2 exhibit disrupted glucose-stimulated gene expression and hormonal responses without any alteration in glucose transport, implying that this loop functions as a signaling domain independently of the transport function [27]. Moreover, non-metabolizable glucose analogs like 3-O-methylglucose activate GLUT2-dependent signaling in the liver and β-cells, indicating that metabolism may not always be coupled with glucose sensing [28] (Figure 2).

Figure 2: Function of GLUT2 as a glucose transporter (metabolism-dependent pathway) and as a glucose sensor (metabolism-independent pathway).

GLUT2 mediates glucose transport into the cell, enabling glucose metabolism and interaction with intracellular proteins to trigger signaling pathways. This signaling leads to activation of transcription factors (TFs) such as ChREBP, modulating the expression of glucose-responsive biomolecules. Deletion of the large intracellular loop of GLUT2 preserves glucose transport function and metabolism but disrupts signaling, resulting in dysregulated glucose homeostasis. Non-metabolizable glucose analogs (e.g., 3-O-methylglucose) are transported by GLUT2 without contributing to metabolism but still can initiate signaling through interacting proteins, leading to induction of gene expression. Figure created using BioRender.

In the brain, GLUT2 is involved in feeding and thermal regulation as well as sympathetic and parasympathetic functions [29-31]. Tanycytes, specialized glial cells present in hypothalamic region of brain express both GLUT1 and GLUT2. Glucose is presumed to be transported through GLUT2 and converted to glucose-6-phopshate by glucokinase followed by increased levels of ATP. Tanycytes have also been found to respond to non-metabolizable glucose analogs such as 2-deoxyglucose and methyl glucopyranoside, suggesting metabolism-independent glucose sensing through GLUT2 [32]. Additionally, rodent studies demonstrate that tanycytes may sense glucose through the taste receptors, TAS1R2 and TAS1R3 [33]. Despite these and other studies [34-36], there is a need for more direct and unequivocal evidence to explicitly demonstrate the role of GLUT2 as an independent glucose sensor apart from its transport capacity.

GLUT4 is a key transporter for insulin-stimulated glucose absorption in the heart, adipose tissue, and skeletal muscle [37]. It has reportedly a Km value of ~5 mmol/L for glucose [19,37] and is mainly expressed on trans-Golgi membrane endosomes and vesicular structures (GSVs). Insulin stimulation causes mobilization of these GLUT4 from vesicles to plasma membrane and subsequently cause rapid uptake of glucose from blood. GLUT4 plays a rate limiting role in glucose metabolism with respect to muscle and hence its overexpression leads to enhanced glycogen storage under insulin stimulation. However, under reduced insulin-stimulated glucose uptake in muscle-specific Glut4 knockout mice, muscle glycogen levels remained normal or increased under conditions of fasting, implying that there is a compensatory mechanism for the import of glucose [37]. Although it is not the primary transporter in the brain that facilitates the uptake of glucose, GLUT4 is expressed in 57% of glucose-activated and 63% of glucose-inhibited neurons [38]. Brain-specific Glut4 knockout mice show impaired counterregulatory responses to hypoglycemia [39]. These observations suggest its role as a glucose sensor in maintaining energy homeostasis in neurons.

GLUT1 exhibits a low Km (~1-2 mmol/L) for glucose [19], and is suggested to mediate glucose transport in glial cells [40], astrocytes [41] as well as other regions of brain [13]. Although astrocytic GLUT1 is known to be involved in regulating glucose homeostasis [41] and there is some evidence to support the astrocyte-to-neuron lactate shuttle hypothesis for elucidating brain energy metabolism [42], the role of GLUT1 in direct glucose sensing is unclear. GLUT3, on the other hand, plays a basal role in glucose uptake in skeletal muscle [43] and is mainly expressed in the brain and testis [16]. It has a high affinity for glucose (Km is about 1.4 mmol/L) and its expression in the glucose responsive neurons support a role in glucose sensing and signaling even under low glucose concentration [16,44].

SGLTs are another class of glucose transporter involved in symport of Na⁺ ions and glucose into the cell. There are six SGLTs (1-6), of which sodium-glucose co-transporter 1 (SGLT1) and SGLT2 have been thoroughly investigated in humans. SGLT1 is the primary apical transporter known to be mainly involved in absorption of glucose in small intestines with a km of ~ 0.4-2 mmol/L [45] whereas SGLT2 is a low affinity glucose transporter with Km of ~2 mmol/L mediating reabsorption of glucose in the kidneys [46]. Though expression of both these SGLTs has been found in the brain [47-49], their precise role in the brain remains to be fully explored.

In case of diabetic condition, expression of SGLT1 is upregulated, promoting glucose absorption in the small intestines immediately followed by postprandial hyperglycemic condition [50,51]. In the midbrain, SGLT1 contributes to 80% of glucose absorption occurring through SGLTs [47]. In primary rat hypothalamic neuronal culture, a non-metabolizable substrate of SGLT1 was found to activate 67% of glucose-excited hypothalamic neurons and trigger similar excitation as that of high levels of glucose. The effect was observed to be reversed by an SGLT inhibitor or removal of Na⁺ [49]. Further, knocking down the expression of Sglt1 gene in the ventromedial hypothalamus (VMH) region showed improved counterregulatory response to hypoglycemia through increased glucose production in the liver [52]. These findings suggest a role for VMH-SGLT1 in regulating glucose homeostasis and perhaps as a potential glucose sensor. Interestingly, a study recently showed how neuropod cells present in the duodenum establish synaptic connections with vagal neurons, express SGLT1 and increase intracellular levels of Ca²⁺ in response to glucose [53]. These studies provide rationale to further explore whether SGLT1 may function as a glucose sensor in addition to its established role in glucose transport and metabolism.

Although SGLT2 is known for its role in glucose reabsorption, it is also expressed in the human and rodent brain [54] [47]. SGLT2 is reported to sense glucose and regulate contractile responses in rat mesangial cells [6]. SGLT2 inhibitors lower blood glucose levels by inhibiting the reabsorption of glucose in kidneys and thereby causing glycosuria [55]. However, this beneficial effect is offset by a simultaneous increase in endogenous glucose production [55-58]. Mechanisms responsible for causing this increase in endogenous production of glucose are reportedly independent of changes in plasma insulin and glucagon levels [59,60]. Expression of renal SGLT2 is upregulated by an increase in sympathetic nervous system activity (SNA) [61] and in contrast, SGLT2 inhibition suppresses the activity of rostral ventrolateral medulla neurons [62] that regulate the SNA. These findings may explain the beneficial effects of SGLT2 inhibitors on the brain function independently of their influence on glucose reabsorption [63,64].

In summary, lack of SGLT2 and GLUT2 cause profound glycosuria even in the absence of hyperglycemia [23,65-68]. Despite this massive loss of glucose in urine, rodents and humans maintain normal fasting blood glucose levels, indicating a compensatory increase in endogenous glucose production [55,58,69]. This compensatory glucose production demonstrates the presence of glucose sensing mechanisms that involve SGLT2 and GLUT2 coupled with other interacting biomolecules that help restore normal blood glucose levels to maintain glucose homeostasis. In contrast, the same compensatory mechanisms compromise the efficiency of SGLT2 inhibitors in treating diabetes mellitus [55,58] where an increase in glucose production may not be desired and rather offset the beneficial effects of SGLT2 inhibition. These observations suggest that GLUT2 and SGLT2 may be involved in glucose sensing independently of their contribution to the transport and metabolism of glucose. How these glucose transporters monitor glucose levels and then convey that information to their interacting biomolecules is unclear. Future studies in this domain are expected to address the interactions between glucose sensing, its metabolism and transport.

G-Protein-coupled receptors (GPCRs) in glucose sensing and signaling

With more than 800 human genes included in the GPCR database, GPCRs are one of the largest cell membrane protein receptor families in humans. These receptors, mostly activated by hormones, metabolites, and neurotransmitters, are druggable targets due to their established roles in many physiological processes including metabolism, cancer and neurological functions [70]. Drugs targeting GPCRs for treating diabetes and obesity alone constitute around 10% of the total drug molecules under clinical trials at present [71] reflecting the unexploited potential of GPCRs to serve as effective therapeutic targets for treatment of diabetes and associated complications.

GPCRs traditionally couple with heterotrimeric G proteins and activate downstream molecules such as adenylate cyclase (AC), phospholipase C (PLC), protein kinase C (PKC), which further lead to production of second messengers such as cyclic adenosine monophosphate (cAMP), diacylglycerol (DAG), inositol triphosphates (IP3) and calcium ions that are critical for mediating the downstream effects of specific stimuli. The resultant biological effects vary across different tissues even with targeting the same GPCR because of different downstream coupling and signaling mechanism [72].

Contribution of sweet taste receptors to glucose sensing

Mechanisms sensing sweet taste in the oral cavity have been known for quite some time now and the lingual taste receptors involved are members of class C of the GPCR superfamily [73,74]. These receptors consist of an intracellular domain, a transmembrane domain, a cysteine-rich domain, and a N-terminal venus fly trap domain, and belong to receptor type 1 (T1R) subfamily with members forming a functional heterodimer in different tissues [75]. One such example is heterodimer TIR2-TIR3 that has been identified and functions as a glucose sensor in duodenal neuropod cells [74,76]. Glucose binding to T1R2-T1R3 heterodimer activates the GPCR mediated signaling and transduces the glucose sensing signal from the gut to the brain through afferent neurons. Recent research has also revealed the presence of sweet taste receptors in neurons and astrocytes, suggesting that these receptors may serve as glucose sensors in the cerebellum [7] (Figure 3A). The taste receptors in other parts of the brain such as the hypothalamus are involved in regulating feeding responses and energy homeostasis, indicating an important role of these receptors in glucose sensing, homeostasis and metabolism [7]. For example, the hypothalamic sweet taste receptors T1R2-T1R3 [77] facilitate the activation of non-proopiomelanocortin leptin and glucose responding neurons. In addition, high glucose downregulates the taste receptor gene Tas1r2 independently of changes in metabolism in the mouse hypothalamic cells [78]. Animal studies have reported that defects in hypothalamic T1R2+T1R3 signaling impair secretion of insulin leading to glucose metabolism disorders [77-79]. Recently, a study identified TAS1R2, a sugar sensing GPCR as the mediator linking regulation of peripheral glucose sensing to modulation of nicotinamide adenine dinucleotide (NAD) in muscles [80]. Another study on streptozotocin induced diabetes (STZ) showed that a glucagon-like peptide −1 (GLP-1) receptor agonist dampened the T1R2-TIR3 mediated signaling and reduces glucose absorption in duodenum. [81]. Taste receptors have also been found to be involved in cephalic phase responses [82], suggesting the possibility of a molecular crosstalk between taste receptors and downstream glucose signaling pathways as observed in gastrointestinal tract [83]. Cells displaying sweet taste receptors also selectively co-express glucose transporters or sensors such as SGLT1 and subunits sulfonylurea receptor 1 (SUR1) and potassium inwardly rectifying channel (Kir 6.1) of the KATP channel [84]. Expression of Sglt1 gene was found to be increased in enterocytes through glucagon-like peptide-2 (GLP-2) secreted by enteroendocrine K cells in response to glucose sensing by T1R2-T1R3 [75]. Activation of these sweet taste receptors through no-calorie sweeteners stimulate glucose transport as well as metabolism [85] and defects in T1R3 receptor impairs this glucose transport [86]. Disordered glucose metabolism has been attributed to downregulation of α-gustducin, phospholipase C-β2 (PLCβ2) and transient receptor potential cation channel subfamily M member 5 (TRPM5), which serve as key components of sweet taste receptor signaling cascade leading to a decrease in intracellular levels of calcium ions [87]. Collectively, these studies present compelling evidences to support that taste receptors play a role in glucose sensing and regulate uptake of glucose by modulating the expression of transporters SGLT1 and GLUT2 present at the apical membrane of gastrointestinal tract.

Figure 3: Glucose sensing and signaling through G protein-coupled receptors.

A. Glucose sensing in neurons, astrocytes, or tanycytes, through taste receptors. Glucose binding to the T1R2-T1R3 heterodimer leads to dissociation of α-gustducin subunit from βγ subunit and triggers downstream signaling cascades. α-gustducin affect intracellular cAMP levels through regulation of adenylate cyclase and phosphodiesterase (PDE) activity. βγ subunit activates phospholipase C-β (PLC-β) pathway leading to formation of 1,4,5-inositol triphosphate (IP3) and subsequent release of Ca²⁺ from intracellular stores. These events lead to activation of calcium-dependent kinases and transcriptional regulation, altering the expression of other glucose transporters (GLUTs) and receptors/channels. B. ADGRL1 is a glucose binding receptor involved in regulating glucose and energy homeostasis. ADGRL1 mediates its downstream signaling through Gαi and regulates insulin secretion. Downstream signaling through ADGRL1 can vary based on different cell systems. Figure created using BioRender.

Adhesion GPCRs (aGPCRs) in glucose sensing

AGPCRs are one of the five main subfamilies (GRAFS classification) in the GPCR superfamily. This sub-family of GPCRs is composed of three domains – extracellular domain (ECD), seven transmembrane domain (7TM) and an intracellular C-terminal tail (ICD). Another atypical characteristic of this family is presence of a highly conserved auto proteolytic cleavage site in the GAIN domain in ECD region. This autoproteolysis results in cleaving the aGPCR into N-terminal fragment (NTF) and C-terminal fragment (CTF) exposing a tethered ligand, Stachel, responsible for activating the aGPCR signaling. The NTF domain is structurally similar in all three ADGRLs (1-3) and consists of a cysteine rich region homologous to a lectin (carbohydrate binding proteins) domain. Elucidation of aGPCR structure, ligand binding motifs and signaling has provided an impetus to drug discovery for targeting these aGPCRs in condition like diabetes and obesity [88].

Adhesion G protein-coupled receptor L1 (ADGRL1), a member of the latrophilin family was recently identified as a glucose binding receptor that controls energy and glucose homeostasis. Glucose-ADGRL1 binding was validated in CHO-K1 cell line stably expressing human ADGRL1. The interaction exhibited a K_D value of 3.44× 10⁻¹⁴ mmol/l or 4.86 ×10⁻⁹ mmol/l depending on the experimental conditions. Glucose-ADGRL1 binding was observed to activate Gαi signaling as glucose decreased cAMP concentration in a dose dependent manner [8,89,90]. Adgrl1 is highly expressed in VMH region of the mouse brain (Figure 3B). VMH-specific male Adgrl1 knockout mice display fasting hyperinsulinemia and increased glucose-stimulated insulin secretion, including insulin resistance, overall showing altered feeding responses to glucose and fasting. The role of ADGRL1 in regulating energy balance was recently validated in humans [91]; however, whether ADGRL1 is a glucose sensor and an activator of downstream glucose signaling pathways need to be studied further.

ADGRL1 is also expressed in the pancreatic islets and is involved in exocytosis-mediated insulin secretion [92]. Similarly, ADGRL3 - another member of the latrophilin family - was recently shown to be involved in modulating insulin secretion through G_i-mediated signaling pathway and subsequent decrease in intracellular cAMP levels in pancreatic islets [93]. These findings implicate potential roles of ADGRL1 and ADGRL3 in mediating glucose induced insulin secretion. Further research is warranted to establish their precise role as glucose sensors.

Altogether, some GPCRs – especially with the lectin domains such as ADGRL1 - may be involved in sensing glucose and triggering glucose signaling pathways independently of glucose metabolism. Targeting these GPCRs may open new avenues for cell-specific precise treatment of diabetes and associated metabolic complications without unintended effects on blood glucose levels.

Concluding remarks and future perspectives

Although our understanding of the mechanisms governing glucose homeostasis has advanced significantly, fundamental aspects involved in direct glucose sensing remain unclear. It is a common assumption that glucose sensing is tied to its metabolism to activate its downstream signaling pathways for the regulation of glucose and energy homeostasis. However, glucose transporters and glucose binding receptors identified in the brain, airways, adipose tissue, gut and urothelium have revealed new insights into direct glucose sensing. These new findings provide opportunities to address outstanding questions in the field (see Outstanding Questions). How do the transporters, receptors and neurocircuits operate as glucose sensors? How does glucose sensing activate its downstream signaling pathways to impact systemic energy status and metabolism? To address these research questions, it would be necessary to identify the extracellular receptor domains that are specifically involved in activating glucose signaling pathways even before it is transported across the plasma membrane. For example, determining the structural and sequence differences between glucose binding pockets in the same transporter may help elucidate the motifs that are responsible for either glucose transport or its sensing. Researchers would likely observe that a portion of the extracellular domain is involved in glucose sensing and another region in the vicinity may be required for its transport. The potential challenges in designing such studies would include the precision by which researchers can detect specific glucose signals without the interference from its downstream metabolites. In addition, it is likely that low, normal, and high glucose levels would differentially modulate multiple GPCR signaling pathways, which would require an interdisciplinary science integrating the GPCR and glycobiology fields. Despite the challenges, these future studies are expected to identify important molecular cues that facilitate fine-tuning of glucose levels to accomplish its homeostasis. Altogether, delineating the molecular machinery responsible for metabolism-independent glucose sensing would lead to a better understanding of the pathogenesis of glucose dysregulation in diabetes, obesity, and their complications. This information would then be applied to invent precise therapeutics for treating these disorders by targeting cell-specific glucose signaling pathways, which would be a major improvement compared to the current approach of targeting blood glucose levels.

Outstanding questions.

1. What are the metabolism-independent mechanisms that activate glucose signaling pathways?

2. What motifs in the glucose transporters are responsible for their function as a glucose sensor?

3. How do GLUTs and SGLTs integrate information about blood glucose levels to regulate glucose homeostasis under physiological or pathological conditions?

4. How does metabolism-independent glucose sensing influence energy balance, feeding behavior, satiety, neurotransmitter activity and cognition processes?

5. Which GPCRs or other plasma membrane receptors sense glucose to regulate systemic metabolic homeostasis?

Highlights.

• Metabolism-independent glucose sensing and signaling pathways significantly contribute to energy homeostasis.

• Glucose transporters including GLUT2 and SGLT2 may be involved in metabolism-independent glucose sensing. Glucose regulates the expression of these transporters through an inter-organ molecular crosstalk.

• G-protein-coupled receptors may be involved in glucose sensing. ADGRL1 is one such member of aGPCR family that was recently found to bind glucose through its lectin domain and regulate energy homeostasis.

• Targeting cell-specific and metabolism-independent glucose signaling pathways – instead of the current therapeutic approach of regulating blood glucose levels - will provide better precision for treating metabolic diseases like diabetes and obesity with minimal unintended effects.

Glossary

Cephalic phase responses

The conditioned anticipatory physiological response to food signals.

Counterregulatory responses

Responses generated to counter abnormally low blood glucose levels through secretion of hormones like glucagon, epinephrine, norepinephrine, cortisol and growth hormone to recover from the hypoglycemic state.

Glucose metabolism

Use of glucose in biochemical reactions for energy production and utilization.

Glucose sensing

Endogenous detection and monitoring of glucose per se.

Glucose signaling

Cellular and molecular pathways through which glucose initiates a cascade of downstream events that lead to specific biological responses.

Glycosuria

High glucose concentration in urine.

GRAFS Classification

Classification system according to which majority of human GPCRs are grouped into five major families: adhesion, frizzled/taste2, secretin, glutamate, and rhodopsin.

Tethered Ligand

Ligand (usually a peptide sequence within a protein) that is part of a receptor itself, which modulates the receptor under certain conditions without the need of a separate molecule.