The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins) are widely used to treat type 2 diabetes and cardiovascular diseases. However, emerging evidence suggests that some gliflozin derivatives may also interact with the cardiac sodium channel Nav1.5, underscoring the need to understand the structural basis of target selectivity. In this study, we conducted a residue-level computational analysis of eight clinically relevant gliflozin inhibitors using molecular docking, all-atom molecular dynamics simulations (500 ns, two replicas), and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) binding free energy calculations in a membrane environment. The results show that SGLT2 binding is driven by a conserved hydrogen-bonding network involving key residues, including E99, S287, Q457 and F98, which stabilize the ligand and reduce structural flexibility. In contrast, negative control compounds exhibit weaker binding, greater solvent exposure, and increased residue mobility. Pharmacophore analysis of dapagliflozin reveals that hydroxyl groups within the glucose moiety are essential for binding, and their removal significantly reduces binding affinity. Structural comparison between SGLT2 and Nav1.5 further identifies a steric difference near the chloro-substituent region, where Nav1.5 can accommodate bulkier groups. These findings provide mechanistic insights into ligand binding and offer a structure-based framework for designing gliflozin derivatives with improved Nav1.5 selectivity and reduced SGLT2 activity.

Lactate is an important biomarker for assessing metabolic function, diagnosing lactic acidosis, and evaluating tissue hypoxia. It is also crucial for monitoring athletic performance in professional and high-level amateur athletes. This article presents a novel resonator-based wireless active sensing tag for lactate detection in saline solutions. The proposed system integrates a three-port split-ring resonator (SRR) sensor, a wideband amplifier, and an RF switch within a closed-loop oscillator architecture, generating two distinct oscillation frequencies corresponding to the first and second SRR resonance modes. This dual-mode operation allows the active sensing tag to provide sufficient information to determine the concentrations of individual components in a three-component mixture. A wideband antenna is employed for wireless signal transmission, and a microcontroller with a web-based interface enables remote control of the RF switch for frequency selection. Experimental results show that oscillation frequency shifts correlate reliably with the real permittivity of the material under test (MUT), enabling accurate estimation of lactate concentrations across various salt levels. For lactate concentrations ranging from 0 to 2000 mmol/L, polynomial regression yields a mean absolute error (MAE) of 4.567 mmol/L for lactate and 1.050 mmol/L for salt. For lower lactate concentrations ranging from 0 to 100 mmol/L, the model achieves an MAE of 0.752 mmol/L for lactate and 1.320 mmol/L for salt. The proposed sensing system offers noninvasive, wireless, and real-time detection of three-component mixtures, enabling reliable detection of lactate concentrations in complex saline environments.

The cardiac sodium channel (Nav1.5) serves as a crucial regulator of cardiac excitability and presents a potential therapeutic target. While the SGLT2 inhibitor dapagliflozin has exhibited cardioprotective effects, its structurally similar counterpart, ertugliflozin, which differs solely by an additional oxygen and methyl group, does not confer cardio-protection. To examine this discrepancy, a multiscale computational approach combining all-atom molecular dynamics (MD) and coarse-grained (CG) simulations was employed to analyze ligand interactions with Nav1.5 in both single and dual-binding site configurations. All-atom simulations revealed localized residue fluctuations but were inadequate for capturing system-wide allosteric effects. Consequently, CG models were derived from atomistic trajectories to improve conformational sampling. Critical residues regulating binding sites were identified through B-factor analyses in three replicas of all-atom models. Harmonic restraints were subsequently applied to these residues within the CG models to simulate ligand-induced rigidity. Notably, in the dual-binding configurations, ertugliflozin’s additional oxygen established a hydrogen bond interaction with Y1767, a mutation site associated with pathological late I Na . This interaction was absent in single-site configurations and may elucidate the functional divergence between the two compounds. Furthermore, inter-residue distances between the IFMT motif, involving domains III and IV related to channel gating, were monitored to assess inactivation states across the various systems. This investigation underscores how dual-site occupancy and subtle chemical differences in ligands can impact Nav1.5 dynamics. The findings provide a foundation for structure-based design of selective modulators targeting sodium channels via allosteric mechanisms.

OBJECTIVES:While glucagon-like peptide-1 (GLP-1) production has been previously documented in human alpha cells, the steps regulating its production and secretion are poorly characterized. We investigated the enzymes implicated in proglucagon processing, characterizing their expression and localization in primary human alpha cells and αTC1/9 cells. METHODS:Human alpha cells and αTC1/9 cells were maintained in control conditions or exposed to proinflammatory and Akt-activating stimuli to enhance GLP-1 levels. Proglucagon and convertase enzyme gene expression, protein content, and subcellular localization were evaluated by qPCR, Western Blot, and immunofluorescent microscopy, respectively. RESULTS:Our data suggests that the canonical GLP-1-producing enzyme, Prohormone Convertase 1/3 (PC1/3), is poorly expressed and localized in alpha cells, while its homologue furin is optimally positioned for GLP-1 production. We also note that GLP-1 and glucagon processing occur in different subcellular compartments, creating two distinct pools of secretory granules which respond to similar secretory stimuli. CONCLUSION:Our study suggests that furin, rather than PC1/3, is positioned to process proglucagon into GLP-1, and despite coming from the same precursor molecule, GLP-1 and glucagon are separately packaged in primary human alpha cells.

The cardiac voltage-gated sodium ion channel (Nav1.5) serves as a crucial regulator of cardiac excitability and presents a potential therapeutic target. While the Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor dapagliflozin has exhibited cardioprotective effects, its structurally similar counterpart, ertugliflozin, which differs solely by an additional oxygen and methyl group, does not confer cardio-protection. To examine this discrepancy, a multiscale computational approach combining all-atom molecular dynamics (MD) and coarse-grained (CG) simulations was employed to analyze ligand interactions with Nav1.5 in both single and dual-binding site configurations. All-atom simulations revealed localized residue fluctuations but were inadequate for capturing system-wide allosteric effects. Consequently, CG models were derived from atomistic trajectories to improve conformational sampling. Critical residues regulating binding sites were identified through B-factor analyses in three replicas of all-atom models. Harmonic restraints were subsequently applied to these residues within the CG models to simulate ligand-induced rigidity. Notably, in the dual-binding configurations, ertugliflozin’s additional oxygen established a hydrogen bond interaction with Y1767, a mutation site associated with pathological late sodium current (late INa). This interaction was absent in single-site configurations and may elucidate the functional divergence between the two compounds. Furthermore, inter-residue distances between the IFMT motif, involving domains III and IV related to channel gating, were monitored to assess inactivation states across the various systems. This investigation underscores how dual-site occupancy and subtle chemical differences in ligands can impact Nav1.5 inactivation dynamics. The findings provide a foundation for structure-based design of selective modulators targeting sodium channels via allosteric mechanisms.

Background Sodium/glucose cotransporter 2 inhibitors (SGLT2is) like empagliflozin have demonstrated cardioprotective effects in patients with or without diabetes. SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INa is the primary mechanism in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene encoding Nav1.5. We investigated empagliflozin's effect on late INa in thirteen known LQT3 mutations located in distinct regions of the channel. Methods The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late INa in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation-contraction coupling. Results Empagliflozin selectively inhibited late INa in LQT3 mutations in the inactivation gate region of Nav1.5, without affecting peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late INa in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak INa or channel kinetics in channels with mutations in the putative empagliflozin binding region. Simulation results predict that empagliflozin may have a desirable therapeutic effect in LQT3 mutations in the inactivation gate region. Conclusions Empagliflozin selectively inhibits late INa, without affecting channel kinetics, in LQT3 mutations in the inactivation gate region. Empagliflozin may thus be a promising precision medicine approach for patients with specific LQT3 mutations.

AIM:To examine the likelihood of mortality or rehospitalization following acute coronary syndrome with glyburide versus gliclazide use in adults with type 2 diabetes undergoing cardiac catheterization. RESEARCH DESIGN AND METHODS:This retrospective cohort study used clinical data linked with administrative health data from Alberta, Canada between April 2008 and March 2021. Three methods were used to define exposure to glyburide and gliclazide in the year before catheterization. Multivariable logistic regression was used to compare the likelihood of a composite outcome of 1-year mortality or rehospitalization with use of glyburide versus use of gliclazide. RESULTS:A total of 11 140 individuals with type 2 diabetes had a cardiac catheterization for acute coronary syndrome. Their mean age was 66 years and 31% were female. In the year before catheterization, 5% used glyburide and 19% used gliclazide. Any glyburide or gliclazide exposure in the year before catheterization was associated with a similar likelihood of all-cause mortality or rehospitalization (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 0.93-1.41; p = 0.20). However, current glyburide exposure (aOR 1.37, 95% CI 1.06-1.79; p = 0.018) and long exposure to glyburide (aOR 1.37, 95% CI 1.03-1.83; p = 0.030) were associated with a higher likelihood of the composite outcome compared to current and long exposure to gliclazide, respectively. CONCLUSIONS:Current and long exposure to glyburide was associated with a greater likelihood of mortality or rehospitalization following cardiac catheterization for acute coronary syndrome, when compared to similar gliclazide exposure definitions. This study adds further evidence of the need to avoid using glyburide if a sulphonylurea is required for type 2 diabetes management.

Accurately assessing dehydration is crucial in many diverse clinical applications and the sports industry. Currently used methods for assessing dehydration rely on either skin pinch tests or analysis of urine. Therefore, there is a need for wearable non-invasive devices for continuous dehydration monitoring. This paper presents a novel sensor design for the monitoring of dehydration levels by the use of chipless microwave resonators. The sensor design incorporates a metallic layer beyond the tag sensor itself, resulting in an isolation of the dehydration sensing system from conflicting ambient signals that provide a targeted sensing system to the tissue itself with reduced interference. The sensitivity of the sensor is high, with a ~120 kHz shift for a 1% change in dehydration) at the resonance frequency between 0.9-1 GHz.

Over the past decade, planar microwave sensors have demonstrated their versatility across various applications, including glucose sensing. Among these, inter-digital sensors have garnered significant attention due to their uncomplicated structure, adaptability for fabrication on flexible substrates, and cost-effectiveness. Despite their relatively high sensitivity, they fall short of meeting the requirements for biomedical applications, emphasizing the need for sensitivity enhancement. This paper introduces a straightforward yet impactful sensitivity enhancement method employing single-transistor active circuitry. The application of this circuitry enhances the sensitivity of an inter-digital capacitor from 0.015 pF/mM/L. for glucose concentration to 1.5 pF/mM/L., proving suitable for numerous biomedical applications, notably glucose monitoring. Theoretical analyses, simulations, and experimental results verify the effectiveness of the proposed method.

Continuous glucose monitoring schemes that avoid finger pricking are of utmost importance to enhance the comfort and lifestyle of diabetic patients. To this aim, we propose a microwave planar sensing platform as a potent sensing technology that extends its applications to biomedical analytes. In this paper, a compact planar resonator-based sensor is introduced for noncontact sensing of glucose. Furthermore, in vivo and in-vitro tests using a microfluidic channel system and in clinical trial settings demonstrate its reliable operation. The proposed sensor offers real-time response and a high linear correlation (R2 ∼ 0.913) between the measured sensor response and the blood glucose level (GL). The sensor is also enhanced with machine learning to predict the variation of body glucose levels for non-diabetic and diabetic patients. This addition is instrumental in triggering preemptive measures in cases of unusual glucose level trends. In addition, it allows for the detection of common artifacts of the sensor as anomalies so that they can be removed from the measured data. The proposed system is designed to noninvasively monitor interstitial glucose levels in humans, introducing the opportunity to create a customized wearable apparatus with the ability to learn.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in membrane receptor PKD1 or cation channel PKD2. TACAN (also named TMEM120A), recently reported as an ion channel in neuron cells for mechano and pain sensing, is also distributed in diverse non-neuronal tissues such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes we found that TACAN inhibited the channel activity of PKD2 gain-of-function mutant F604P. The first and last transmembrane domains of TACAN were found to interact with the PKD2 C-and N-terminal portions, respectively. We showed that the TACAN N-terminus acted as a blocking peptide and that TACAN inhibits the PKD2 function through the PKD2/TACAN binding. By patch clamping in mammalian cells, we found that TACAN inhibits both the single channel conductance and open probability of PKD2 and mutant F604P. PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. Furthermore, we also found that TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish, in support of the in vitro inhibitory effects of TACAN. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechano sensitivity of the PKD2/TACAN channel complex.

Highly synchronized ion channel activity controls the rapid flux of various ion species across excitable-cell plasma membranes to generate electrical signals known as action potentials (APs). Entry of sodium and calcium ions via voltage-sensitive sodium and calcium channels is responsible for driving the AP upstroke, maintaining depolarization and providing calcium ions for intracellular signalling. In contrast, there are a wide variety of potassium channels that repolarize the membrane potential terminating the AP, oppose the generation of subsequent APs or stabilize the resting membrane potential. In order to achieve such coordinated feats on a millisecond time scale, ion channels must allow a high throughput of ions to generate the required rapid changes in transmembrane voltage. Importantly, ion channels must also possess high selectivity for the ion in question as the direction of ionic flow of any particular ion is critically dependent on the electrical and ionic concentration gradients across the cell membrane. Selective ion permeation is achieved through highly conserved amino acid residues in the pore region that form an ion-selective conduction pathway in the channel known as the selectivity filter. For example, the majority of potassium channels contain a TV(I)GYG amino acid motif that bestows potassium selectivity. Congenital mutations in and around this signature motif can drastically alter potassium selectivity, allowing other ions to be conducted, resulting in abnormal ion flow that can disperse normal electrochemical gradients, alter cellular excitability, lead to cell death and precipitate disease. In this regard, certain humanmutations in the pore region of G-protein-activated inward rectifier potassium (GIRK) channels, consisting of Kir3.x subunits, lead to a loss of potassium ion selectivity. GIRK channels play an important role in regulating cellular excitability in many tissue types including the central nervous system and heart, where their activity provides a tonic repolarizing influence, reducing cellular excitability (Hibino et al. 2010). Precisely how, at the atomic level, these GIRK channel mutations alter the potassium-selective conduction pathway and cause disease has remained elusive. In this issue of The Journal of Physiology, Chen et al. (2022) report a novel alternative conduction pathway in GIRK channels containing the disease-causing G156S pore mutation that changes the signature GYG pore sequence to SYG. Taking advantage of recent advances in potassium channel structures, the authors undertook a detailed biophysical analysis of the ion conducting pathways in GIRK channels and proposed a highly plausible molecular model by which these mutations lead to a loss of potassium selectivity. Chen et al. (2022) generated various point mutations in the pore region of the GIRK channel subunit Kir3.2 and measured whole cell currents in the Xenopus oocyte expression system using the two-electrode voltage clamp technique. To assess ion selectivity, the conduction of monovalent cations Li+, Na+ and K+ was then determined in wild-type and mutant Kir3.2 channels. The G156S mutation resulted in the introduction of Li+ and Na+ currents, indicating that this mutation causes a loss of K+ ion selectivity. This observed loss of K+ selectivity in the G156S mutant can potentially result from either the inability of the classical selectivity filter to discriminate K+ ions from other monovalent cations of similar atomic radii or the formation of a novel conduction pathway, separate from the classical TV(I)GYG selectivity filter. To test these two concepts, the authors used two known inhibitors of the classical conduction pathway, tertiapin Q and Ba2+ ions. Tertiapin Q is a 21-amino-acid peptide isolated from honey bee venom that blocks several types of potassium channels, includingGIRKchannels, by tightly binding to the extracellular vestibule immediately above the classical selectivity filter. In contrast, Ba2+ ions enter the selectivity filter but become lodged deep within the pore conduction pathway towards the intracellular face of the selectivity filter. The authors determined that tertiapin Q effectively blocked K+ ion conduction in G156S mutant channels but these channels were still able to conduct Li+ and Na+ ions. However, the conductance of Li+ and Na+ ions through the novel conduction pathway was reduced by Ba2+. These results indicate that the observed novel conduction pathway may involve the inner region of the classical selectivity filter to which Ba2+ ions bind. Moreover, as GIRK channels are tetramers, it is predicted that the G156S mutant would introduce four additional conduction pathways. This notion is supported by single channel analysis of G156S channels that revealed four distinct Li+ sub-conductance states. Taken together, these results suggest that the G156S mutation causes a conformational change in the tetrameric channel structure that generates multiple monovalent ion conduction pathways, in addition to the classical K+ selective permeation pathway. Additional data obtained from experimental (i.e. not disease associated) mutants, including T151A, suggest that the conduction pathways are immediately adjacent to the classical K+ selectivity filter conduction route. This study by Chen et al. (2022) advances our current knowledge of potassium channel structure by revealing a novel monovalent cation conduction pathway in the Kir3.2 G156S channel. From a physiological perspective, GIRK channels serve to facilitate repolarization of the AP and provide a stabilizing influence on the resting membrane potential. The introduction of this novel conduction pathway would lead to an increased permeability to Na+ ions, resulting in excessive Na+ entry, membrane potential depolarization and increased cellular excitability. Importantly, Kir3.2 mutations,

In diabetes, glucagon secretion from pancreatic α-cells is dysregulated. We examined α-cells from human donors and mice using combined electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α-cell exocytosis by reducing P/Q-type Ca2+ channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat-feeding of mice, α-cells shift towards a ‘β-cell-like’ electrophysiologic profile in concert with an up-regulation of the β-cell Na+ channel isoform Scn9a and indications of impaired α-cell identity. In human α-cells we identify links between cell membrane properties and cell surface signalling receptors, mitochondrial respiratory complex assembly, and cell maturation. Cell type classification using machine learning of electrophysiology data demonstrates a heterogenous loss of ‘electrophysiologic identity’ in α-cells from donors with T2D. Indeed, a sub-set of α-cells with impaired exocytosis is defined by an enrichment in progenitor markers suggesting important links between α-cell maturation state and dysfunction in T2D. Key findings α-cell exocytosis is suppressed by glucose-dependent inhibition of P/Q-type Ca2+ currents Dysfunction of α-cells in type 2 diabetes is associated with a ‘β-cell-like’ electrophysiologic signature Patch-seq links maturation state, the mitochondrial respiratory chain, and cell surface receptor expression to α-cell function α-cell dysfunction occurs preferentially in cells enriched in endocrine lineage markers

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute a promising drug treatment for heart failure patients with either preserved or reduced ejection fraction. Whereas SGLT2i were originally developed to target SGLT2 in the kidney to facilitate glucosuria in diabetic patients, it is becoming increasingly clear that these drugs also have important effects outside of the kidney. In this review we summarize the literature on cardiac effects of SGLT2i, focussing on pro-inflammatory and oxidative stress processes, ion transport mechanisms controlling sodium and calcium homeostasis and metabolic/mitochondrial pathways. These mechanisms are particularly important as disturbances in these pathways result in endothelial dysfunction, diastolic dysfunction, cardiac stiffness, and cardiac arrhythmias that together contribute to heart failure. We review the findings that support the concept that SGLT2i directly and beneficially interfere with inflammation, oxidative stress, ionic homeostasis, and metabolism within the cardiac cell. However, given the very low levels of SGLT2 in cardiac cells, the evidence suggests that SGLT2-independent effects of this class of drugs likely occurs via off-target effects in the myocardium. Thus, while there is still much to be understood about the various factors which determine how SGLT2i affect cardiac cells, much of the research clearly demonstrates that direct cardiac effects of these SGLT2i exist, albeit mediated via SGLT2-independent pathways, and these pathways may play a role in explaining the beneficial effects of SGLT2 inhibitors in heart failure.

Monitoring lactate levels is an established method for determining hyperlactatemia in critically ill patients and assessing aerobic fitness. It is a widely used gold-standard technique in both professional and serious amateur sports. Non-invasive real-time lactate monitoring offers significant advantages over the current technology of finger-prick blood sampling. Possible candidate technology for developing non-invasive real-time lactate monitoring should be highly sensitive, flexible, and capable of real-time monitoring of lactate levels in interstitial fluid or within specific working muscle groups depending on the type of sport. Herein we describe a planar, flexible, passive, chipless tag resonator that is electromagnetically coupled to a reader placed in proximity to the lactate sensor tag. The tag resonator is a thin metallic tracing that can be taped on the skin. The resonance frequency of the tag fluctuates proportionately with changing lactate concentrations in a solution mimicking human interstitial fluid with very high sensitivity. The spectrum of the tag is reflected in the spectrum of the reader, which is a planar microwave resonator designed at a different frequency. The reader could be embedded in a cellphone or an application-specific wearable device for data communication and processing. The tag can accurately and reproducibly measure lactate concentrations in the range of 1 to 10 mM, which is in the physiological range of lactate observed at rest and during intense physical activity. Furthermore, the chrematistics of this technology will allow monitoring of lactate in specific working muscle groups.

Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.

It is shown here that microwave sensors can be used to monitor glucose in serum concentration with minimum detectable as well as resolution of 1 mMol . L-1 (approximate to 18 mg . dL(-1)). The ultrasensitive detection technique relies on a split ring resonator, operating at the frequency of 1.156 GHz, as the core of the sensor where its loss is compensated to enhance the quality factor from similar to 190 (passive mode)to similar to 3850 (active mode) to enable high resolution (mod ified frequency detection error from +/- 12 kHz down to +/- 2.5 kHz) frequency-shift sensing. Initially, glucose concentrations of 100-1000 mMol . L-1 (1800-18000 mg . dL(-1)) in water were detected within 250 kHz of dynamic range (between two spectrum ends). Selectivity of the sensor to glucose is verified with respect to common interstitial fluid ingredients with biological levels. Finally, to enhance the resolution of the proposed sensor, its loss-compensation is further improved leading to increased accuracy of measuring glucose samples in a 0.9 % NaCl solution containing 10 % horse serum that closely resembles blood plasma and interstitial fluid. This allows exploration of lower concentrations in the physiological range 1-30 mMol . L-1 (18-540 mg . dL(-1)) with improved frequency detection error down to +/- 0.75 kHz for two cases of with/without serum solutions with dynamic range of 30 kHz/38 kHz. The highly accurate glucose monitoring technique could be utilized for developing noninvasive glucose sensors for biomedical applications in real-time glucose monitoring.