Glucokinase Activity Research Articles

Ancient duplications, multidimensional specializations, and defense role of hexokinases in wheat.

Hexokinases (HXKs), which sense and catalyze cellular sugar, play a critical role in the growth and development of various plants, including wheat, a primary source of human calories frequently attacked by fungal pathogens. However, the evolutionary dynamics and functional diversification of HXKs in wheat, particularly their roles in plant defense, remain unclear. Here, we discovered that the wheat hexokinase gene family originated through multiple ancient gene duplications across different plant lineages and has undergone comprehensive, multidimensional functional specialization in gene expression, subcellular localization, enzyme activity, and regulation of plant defense responses. Gene expression analysis suggests that two-thirds of the TaHXK genes are responsive to fungal infection. Subcellular analysis reveals that while six TaHXKs are localized in mitochondria, three TaHXKs from different phylogenetic branches are sorted into other cellular compartments. Notably, biochemical analysis shows that TaHXKs in mitochondria differ in their glucose-catalyzing activity, with TaHXK5 and TaHXK3 exhibiting the highest and lowest enzyme activity, respectively. Consistently, transient expression analysis suggests that TaHXK5 induces various plant defense responses, while TaHXK3 is defective in activating some plant defense responses. Furthermore, inactivation of the glucokinase activity of TaHXK5 compromised its function in defense activation, suggesting that mitochondrial TaHXKs display functional divergence in both enzyme activity and defense-inducing activity that are intrinsically connected. Overall, our findings reveal that the multidimensional specialization events following the ancient duplication events may have shaped the functional diversity of HXKs in wheat, shedding light on their evolutionary dynamics and potentially contributing to the improvement of wheat defense.

The correlation between S-nitrosylation and type 2 diabetes mellitus: a review.

Type 2 diabetes mellitus (T2DM) represents a chronic metabolic disorder, constituting over 90% of all diabetes cases. Its primary characteristics include insulin deficiency and insulin resistance. The aetiology of T2DM is complex, which is attributed to a convergence of genetic and environmental factors. Moreover, it can engender various complications such as diabetes retinopathy, diabetes nephropathy, and diabetes neuropathy. T2DM cannot be cured fundamentally, it can only delay the development of the disease by controlling the blood sugar level. If the blood sugar is at a high level for a long time, it will aggravate the disease progress, and even lead to death in serious cases. Therefore, understanding the pathogenesis of diabetes, early detection, and intervention are the main means of treatment. S-nitrosylation (SNO), a post-translational modification of proteins based on redox, possesses the capacity to regulate a variety of physiological and pathological processes, and it is also involved in the occurrence and development of T2DM. However, the relationship between the dysregulation of SNO homeostasis and the occurrence of diabetes is not fully understood. This article reviews the correlation between SNO and T2DM, elucidating the mechanism by which SNO contributes to T2DM, encompassing diminishing insulin secretion, inducing insulin resistance, and affecting glucokinase activity. Understanding the correlation between SNO and T2DM provides a new research direction for the pathogenesis and treatment targets of diabetes.

Exploring cutting-edge approaches in diabetes care: from nanotechnology to personalized therapeutics.

Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.

7890 Combination of Dorzagliatin and Canagliflozin Improves β-cell Function and Alleviates Hepatic Steatosis in db/db Mice

Abstract Disclosure: Z. Zhang: None. S. Chen: None. S. Ji: None. Q. Zhao: None. J. Qiao: None. M. Liu: None. Introduction: Early combination of anti-hyperglycemic medications with different targets is an optimal choice for patients with type 2 diabetes (T2D) who do not achieve targeted HbA1c with monotherapy. Dorzagliatin is a novel dual-acting glucokinase activator that has been shown to be effective in both drug-naive and metformin-treated patients with T2D. However, the effect of combination of dorzagliatin and sodium-glucose cotransporter-2 inhibitor (SGLT2i) remains unknown. Methods: Ten-week-old db/db mice were treated daily with either dorzagliatin (30mg/kg of body weight) alone, or canagliflozin (30mg/kg of body weight) alone, or dorzagliatin plus canagliflozin, or vehicle only by gavage for 6 weeks. Body weight and fasting blood glucose were monitored weekly. Plasma insulin, triglyceride, and cholesterol were measured every two weeks. The morphology of islets and liver was evaluated by chemical staining and immunofluorescence. Results: The 6-week treatment of dorzagliatin had no significant effect on fasting blood glucose and fasting plasma insulin but reduced body weight in db/db mice compared to those treated with vehicle. It also caused a significant decrease of islet size and β-cell number. Surprisingly, dorzagliatin alleviated hepatic steatosis but did not affect serum lipid levels. The combination of dorzagliatin and canagliflozin lowed fasting blood glucose and improved glucose tolerance without affecting bodyweight, and the anti-diabetic effect was stronger than the canagliflozin-only treatment group. Combination treatment group also showed an increased islet size and β-cell number, and alleviated liver steatosis compared with vehicle group. Conclusion: The combination of dorzagliatin and canagliflozin had better antidiabetic effects than single-agent administration, providing clinical guidance for the combination therapy of dorzagliatin and SGLT2i in the treatment of type 2 diabetes. Presentation: 6/2/2024

Molecular Docking, Pharmacophore Modeling, and ADMET Prediction of Novel Heterocyclic Leads as Glucokinase Activators.

A pivotal impetus has driven the development of numerous small molecules aiming to improve therapeutic strategies for type 2 diabetes. Glucokinase (GK) activation has been offered a new realm of therapeutic antidiabetic activity with novel heter-ocyclic derivatives. In the context of antidiabetic drug design, GK is an interesting and newly validated target. A key enzyme needed for blood glucose homeostasis is Glucokinase, which is dysfunctional in individuals with type 2 diabetes. Heterocyclic derivatives are utilized in this innovative approach to activate GK enzymes as medicinal agents that will significantly improve type 2 diabetes management. To address type 2 diabetes, as well as minimize unwanted side effects, this research endeavor aimed to develop activators of glucokinase. A rigorous scrutiny was conducted of the Maybridge online repository, which houses a formidable collection of 53,000 lead compounds. A collection of 125 compounds that contain the thiazolidinedione core was selected from this extensive collection. The struc-tures were generated using ChemDraw 2D, stabilized conformation with ChemBioDraw Ul-tra, and docked using Auto Dock Vina 1.5.6 in this methodology. In addition, log P was pre-dicted online using the Swiss ADME algorithm. The PKCSM software was used to predict the toxicity of the leading compounds. The highest binding affinity was found for AS72 and AS108 to GK receptors. GI absorption and excretion of these compounds were efficient due to Lipinski's Rule of Five compliance. When compared with the standard drugs Dorzagliatin (GKA) and MRK (co-crys-tallized ligand), these substances demonstrated a notable lack of AMES toxicity, skin sensiti-zation, and hepatotoxicity. In recent studies, lead molecules that possess enhanced pharmacokinetic profiles, increased binding affinity, and lower toxicity were developed to act as glucokinase activators.

Unveiling the genetic basis and metabolic rewiring behind the galactose-positive phenotype in a Streptococcus thermophilus mutant

Streptococcus thermophilus (S. thermophilus) is a widely used starter culture in dairy fermentation, but most strains are galactose-negative and only metabolize glucose from lactose hydrolysis. In this study, we aimed to uncover the mechanisms underlying the acquisition of a stable galactose-positive (Gal+) phenotype in a mutant strain of S. thermophilus IMAU10636. By treating the wild-type strain with the mutagenic agent N-methyl-N-nitro-N-nitrosoguanidine, we successfully isolated a Gal+ mutant, S. thermophilus IMAU10636Y. Comparative enzyme activity assays revealed that the mutant exhibited higher β-galactosidase and galactokinase activities, but lower glucokinase and pyruvate kinase activities compared to the wild-type. High-performance liquid chromatography analysis confirmed the mutant’s enhanced ability to utilize lactose and galactose, leading to increased glucose secretion. Integrated genome and transcriptomics analyses provided deeper insights into the underlying genetic and metabolic mechanisms. We found that the metabolism regulatory network of the glycolysis / Leloir pathway was altered in the mutant, possibly due to the upregulation of the gene expression in the galR-galK intergenic region. This likely led to increased RNA polymerase binding and transcription of the gal operon, ultimately promoting the Gal+ phenotype. Additionally, we identified a mutation in the scrR gene, encoding a LacI family transcriptional repressor, which also contributed to the Gal+ phenotype. These findings offer new perspectives on the metabolic rewiring and regulatory mechanisms that enable S. thermophilus to acquire the ability to metabolize galactose. This knowledge can inform strategies for engineering and selecting Gal+ strains with desirable fermentation characteristics for dairy applications.

Modern Challenges in Type 2 Diabetes: Balancing New Medications with Multifactorial Care.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder characterized by insulin resistance and progressive beta cell dysfunction, presenting substantial global health and economic challenges. This review explores recent advancements in diabetes management, emphasizing novel pharmacological therapies and their physiological mechanisms. We highlight the transformative impact of Sodium-Glucose Cotransporter 2 inhibitor (SGLT2i) and Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), which target specific physiological pathways to enhance glucose regulation and metabolic health. A key focus of this review is tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. Tirzepatide illustrates how integrating innovative mechanisms with established physiological pathways can significantly improve glycemic control and support weight management. Additionally, we explore emerging treatments such as glimins and glucokinase activators (GKAs), which offer novel strategies for enhancing insulin secretion and reducing glucose production. We also address future perspectives in diabetes management, including the potential of retatrutide as a triple receptor agonist and evolving guidelines advocating for a comprehensive, multifactorial approach to care. This approach integrates pharmacological advancements with essential lifestyle modifications-such as dietary changes, physical activity, and smoking cessation-to optimize patient outcomes. By focusing on the physiological mechanisms of these new therapies, this review underscores their role in enhancing T2DM management and highlights the importance of personalized care plans to address the complexities of the disease. This holistic perspective aims to improve patient quality of life and long-term health outcomes.

Glucokinase activity controls subpopulations of β-cells that alternately lead islet Ca2+ oscillations.

Oscillations in insulin secretion, driven by islet Ca2+ waves, are crucial for glycemic control. Prior studies, performed with single-plane imaging, suggest that subpopulations of electrically coupled β-cells have privileged roles in leading and coordinating the propagation of Ca2+ waves. Here, we used 3D light-sheet imaging to analyze the location and Ca2+ activity of single β-cells within the entire islet at >2 Hz. In contrast with single-plane studies, 3D network analysis indicates that the most highly synchronized β-cells are located at the islet center, and remain regionally but not cellularly stable between oscillations. This subpopulation, which includes 'hub cells', is insensitive to changes in fuel metabolism induced by glucokinase and pyruvate kinase activation. β-cells that initiate the Ca2+ wave ('leaders') are located at the islet periphery, and strikingly, change their identity over time via rotations in the wave axis. Glucokinase activation, which increased oscillation period, reinforced leader cells and stabilized the wave axis. Pyruvate kinase activation, despite increasing oscillation frequency, had no effect on leader cells, indicating the wave origin is patterned by fuel input. These findings emphasize the stochastic nature of the β-cell subpopulations that control Ca2+ oscillations and identify a role for glucokinase in spatially patterning 'leader' β-cells.

Novel glucokinase activators: A structure-based pharmacophore modeling, QSAR analysis, and molecular dynamics approach

Novel glucokinase activators: A structure-based pharmacophore modeling, QSAR analysis, and molecular dynamics approach

Identification of small molecule glucokinase activators for the treatment of diabetes based on plants from the traditional Chinese medicine: In silico analysis

Mutations in glucokinase (GCK) can either enhance or inhibit insulin secretion, leading to different forms of diabetes, including gestational diabetes. While many glucokinase activators (GKAs) have been explored as treatments, their long-term effectiveness has often been unsatisfactory. However, recent interest has surged with the introduction of dorzagliatin and TTP399. This study investigates the efficacy of four previously studied compounds (Swertiamarin, Apigenin, Mangiferin, and Tatanan A) in activating GCK using computational methods.Initial molecular docking revealed binding affinities ranging from −6.7 to −8.6 kcal/mol. The compounds were then evaluated for drug-likeness and pharmacokinetic properties. Re-docking studies were performed for validation. Based on their favorable binding affinities and compliance with Lipinski's rule and ADMET criteria, three compounds (Swertiamarin, Apigenin, and Tatanan A) were selected for molecular dynamics (MD) simulations.MD simulations demonstrated that Swertiamarin showed excellent stability, as indicated by analyses of RMSD, RMSF, radius of gyration (Rg), hydrogen bonding, and principal component analysis (PCA). These results suggest that Swertiamarin holds promise for further investigation in in vivo and clinical settings to evaluate its potential in enhancing GCK activity and treating diabetes.This study assessed the potential of four compounds as GCK activators using molecular docking, pharmacokinetic profiling, and MD simulations. Swertiamarin, in particular, showed significant stability and adherence to drug-likeness criteria, making it a promising candidate for further research in combating diabetes.

Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants

Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.

Dorzagliatin: A Breakthrough Glucokinase Activator Coming on Board to Treat Diabetes Mellitus.

Dorzagliatin, an innovative dual-acting allosteric oral glucokinase activator that targets glucose homeostasis and insulin resistance, has gained approval for treating type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The effectiveness of existing antidiabetic treatments in enhancing beta cell (β-cell) activity is restricted. Currently, there are no satisfactory medications available to address the fundamental deficiency in glucose sensing for glucokinase-maturity-onset diabetes of the young (GCK-MODY), which is caused by mutations in the glucokinase gene; researchers have embarked on glucokinase activators. Dorzagliatin enhances the affinity of glucokinase for glucose and glucose-sensing capacity, improves β-cell function, and reduces insulin resistance. Two phase 3 studies, an adjunct trial of dorzagliatin with metformin for T2DM patients and a monotherapy trial for drug-naïve T2DM patients, are key clinical trials that have shown a favorable safety and tolerability profile. They also demonstrated a rapid, sustained reduction in glycated hemoglobin (HbA1c) and a significant decrease in postprandial blood glucose. This review will summarize the substantial clinical evidence supporting the safety and efficacy of dorzagliatin in treating diabetes mellitus (DM) and clarify the molecular mechanisms underlying its action.

Managing Post-Transplant Diabetes Mellitus after Kidney Transplantation: Challenges and Advances in Treatment.

Kidney transplantation is the most effective treatment for end-stage renal failure but is associated with complications, including post-transplant diabetes mellitus (PTDM). It affects the quality of life and survival of patients and the transplanted organ. It can cause complications, including infections and episodes of acute rejection, further threatening graft survival. The prevalence of PTDM, depending on the source, can range from 4 to 30% in transplant patients. This article aims to discuss issues related to diabetes in kidney transplant patients and the latest treatments. Knowledge of the mechanisms of action of immunosuppressive drugs used after transplantation and their effect on carbohydrate metabolism is key to the rapid and effective detection of PTDM. Patient therapy should not only include standard management such as lifestyle modification, insulin therapy or pharmacotherapy based on well-known oral and injection drugs. New opportunities are offered by hypoglycemic drugs still in clinical trials, including glucokinase activators, such as dorzagliatin, ADV-1002401, LY2608204, TMG-123, imeglimine, amycretin and pramlintide. Although many therapeutic options are currently available, PTDM often creates uncertainty about the most appropriate treatment strategy. Therefore, more research is needed to individualize therapeutic plans and monitor these patients.

Dietary allicin improves behavior, physiology, growth, and disease resistance in the sea cucumber Apostichopus japonicus

It is important to establish a cost-effective method to improve behavior, physiology, growth, and resistance to Vibrio in sea cucumber aquaculture. The present study found that feeding behavior was significantly higher in sea cucumbers fed with dietary allicin (50.50 ± 10.94 times) than that of those fed without allicin (24.38 ± 1.86 times) (P = 0.049). Consistently, food intake significantly increased in sea cucumbers fed with allicin (P < 0.001). Further, dietary allicin significantly increased the height of intestinal folds in sea cucumbers. Glucose showed no significant difference between sea cucumbers fed with and without allicin. Glucokinase activity was significantly higher in sea cucumbers fed with allicin (103.96 ± 5.59 U/L) than those without dietary allicin (82.36 ± 6.18 U/L) (P = 0.041). This suggests that the increase of food intake induced by allicin in diet leads to an elevated glucose level in sea cucumbers, potentially maintaining a stable intracellular glucose level through the action of glucokinase to convert glucose into glycogen. In this study, the relative weight gain rate was significantly higher in sea cucumbers fed with allicin (0.270 ± 0.053) than those fed without allicin (0.011 ± 0.007) (P = 0.008). This suggests that dietary allicin stimulates the growth of sea cucumbers.Feeding behavior (P < 0.001) and crawling behavior (P = 0.001) of sea cucumbers fed with dietary allicin were significantly better than those of individuals fed without allicin after being soaked by bacterial liquid. Further, this study found that sea cucumbers fed with dietary allicin showed significantly higher levels of catalase (P < 0.001) and total superoxide dismutase (P = 0.001) than those fed without allicin, following the immersion in V. harveyi solution. The results suggest that allicin enhances the behavior and physiology of sea cucumbers exposed to V. harveyi.This study provides a cost-effective method to enhance production efficiency in sea cucumber aquaculture.

Hypoglycemic Action of Glycocar on Insulin and Glucose Metabolism In Vivo

Background: Diabetes mellitus, particularly type 2, presents a growing global health challenge, with an estimated 700 million people expected to be affected by 2045. The disease is characterized by insulin resistance and impaired insulin secretion, necessitating effective treatments. This study aimed to explore the hypoglycemic mechanisms of Glykokar, a herbal formulation, in rats with alloxan-induced diabetes. The objective of this study was to investigate the hypoglycemic mechanisms of Glykokar, a herbal formulation. Methods: Eighteen rats with alloxan-induced diabetes were divided into groups receiving Glykokar at doses of 50 mg/kg or 100 mg/kg, and a control group receiving saline. The study measured the effects of Glykokar on C-peptide levels, glycogen content in liver and muscle, and the activity of hexokinase and phosphorylase enzymes over 7 and 14 days. Results: Results demonstrated that Glykokar significantly increased C-peptide levels, with the 100 mg/kg dose showing the greatest effect, enhancing C-peptide by 87.5% on day 14 compared to controls. Glycogen content in liver and muscle tissues was also elevated, particularly at the 100 mg/kg dose, which increased liver glycogen by 86% and muscle glycogen by 50%. Enzyme activity studies revealed that Glykokar reduced phosphorylase activity in diabetic muscle tissue and significantly boosted hexokinase and glucokinase activities, with the highest effects seen at the 100 mg/kg dose. Conclusion: The findings suggest that Glykokar’s hypoglycemic action is mediated through enhanced glucose metabolism in tissues, driven by increased enzymatic activity and glycogen storage. This study provides evidence for the potential of Glykokar as a therapeutic agent in managing hyperglycemia by improving glucose utilization and insulin secretion.

Hypoglycemic Response to Dorzagliatin in a Patient With GCK-MODY.

Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear. We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded. Oral glucose-lowering drugs, including thiazolidinediones, dipeptidyl peptidase 4 inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level. Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin.

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

BackgroundGlucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction.MethodsUsing publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR).ResultsGenetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57–46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78–4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54–0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results.ConclusionsImpaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

Dengue Virus dependence on glucokinase activity and glycolysis Confers Sensitivity to NAD(H) biosynthesis inhibitors

Viruses have developed sophisticated strategies to control metabolic activity of infected cells in order to supply replication machinery with energy and metabolites. Dengue virus (DENV), a mosquito-borne flavivirus responsible for dengue fever, is no exception. Previous reports have documented DENV interactions with metabolic pathways and shown in particular that glycolysis is increased in DENV-infected cells. However, underlying molecular mechanisms are still poorly characterized and dependence of DENV on this pathway has not been investigated in details yet. Here, we identified an interaction between the non-structural protein 3 (NS3) of DENV and glucokinase regulator protein (GCKR), a host protein that inhibits the liver-specific hexokinase GCK. NS3 expression was found to increase glucose consumption and lactate secretion in hepatic cell line expressing GCK. Interestingly, we observed that GCKR interaction with GCK decreases DENV replication, indicating the dependence of DENV to GCK activity and supporting the role of NS3 as an inhibitor of GCKR function. Accordingly, in the same cells, DENV replication both induces and depends on glycolysis. By targeting NAD(H) biosynthesis with the antimetabolite 6-Amino-Nicotinamide (6-AN), we decreased cellular glycolytic activity and inhibited DENV replication in hepatic cells. Infection of primary organotypic liver cultures (OLiC) from hamsters was also inhibited by 6-AN. Altogether, our results show that DENV has evolved strategies to control glycolysis in the liver, which could account for hepatic dysfunctions associated to infection. Besides, our findings suggest that lowering intracellular availability of NAD(H) could be a valuable therapeutic strategy to control glycolysis and inhibit DENV replication in the liver.

Prediction of Protein-Drug Interactions, Pharmacophore Modeling, and Toxicokinetics of Novel Leads for Type 2 Diabetes Treatment.

Small heterocyclic compounds have been crucial in pioneering advances in type 2 diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic derivatives aimed at stimulating the activation of Glucokinase (GK). A pharmaceutical intervention for diabetes is increasingly targeting GK as a legitimate target. Diabetes type 2 compromises Glucokinase's function, an enzyme vital for maintaining the balance of blood glucose levels. Medicinal substances strategically positioned to improve type 2 diabetes management are used to stimulate the GK enzyme using heterocyclic derivatives. The research endeavor aimed to craft novel compounds, drawing inspiration from the inherent coumarin nucleus found in nature. The goal was to evoke the activity of the glucokinase enzyme, offering a tailored approach to mitigate the undesired side effects typically associated with conventional therapies employed in the treatment of type 2 diabetes. Coumarin, sourced from nature's embrace, unfolds as a potent and naturally derived ally in the quest for innovative antidiabetic interventions. Coumarin was extracted from a variety of botanical origins, including Artemisia keiskeana, Mallotus resinosus, Jatropha integerrima, Ferula tingitana, Zanthoxylum schinifolium, Phebalium clavatum, and Mammea siamensis. This inclusive evaluation was conducted on Muybridge's digital database containing 53,000 hit compounds. The presence of the coumarin nucleus was found in 100 compounds, that were selected from this extensive repository. Utilizing Auto Dock Vina 1.5.6 and ChemBioDraw Ultra, structures generated through this process underwent docking analysis. Furthermore, these compounds were accurately predicted online log P using the Swiss ADME algorithm. A predictive analysis was conducted using PKCSM software on the primary compounds to assess potential toxicity. Using Auto Dock Vina 1.5.6, 100 coumarin derivatives were assessed for docking. Glucokinase (GK) binding was significantly enhanced by most of these compounds. Based on superior binding characteristics compared with Dorzagliatin (standard GKA) and MRK (co-crystallized ligand), the top eight molecules were identified. After further evaluation through ADMET analysis of these eight promising candidates, it was confirmed that they met the Lipinski rule of five and their pharmacokinetic profile was enhanced. The highest binding affinity was demonstrated by APV16 at -10.6 kcal/mol. A comparison between the APV16, Dorzagliatin and MRK in terms of toxicity predictions using PKCSM indicated that the former exhibited less skin sensitization, AMES toxicity, and hepatotoxicity. Glucokinase is most potently activated by 100 of the compound leads in the database of 53,000 compounds that contain the coumarin nucleus. APV12, with its high binding affinity, favorable ADMET (adjusted drug metabolic equivalents), minimal toxicity, and favorable pharmacokinetic profile warrants consideration for progress to in vitro testing. Nevertheless, to uncover potential therapeutic implications, particularly in the context of type 2 diabetes, thorough investigations and in-vivo evaluations are necessary for benchmarking before therapeutic use, especially experiments involving the STZ diabetic rat model.

Potential Therapeutic Targets for the Management of Diabetes Mellitus Type 2.

Diabetes is one of the lifelong chronic metabolic diseases which is prevalent globally. There is a continuous rise in the number of people suffering from this disease with time. It is characterized by hyperglycemia, which leads to severe damage to the body's system, such as blood vessels and nerves. Diabetes occurs due to the dysfunction of pancreatic β -cell which leads to the reduction in the production of insulin or body cells unable to use insulin produce efficiently. As per the data shared International diabetes federation (IDF), there are around 415 million affected by this disease worldwide. There are a number of hit targets available that can be focused on treating diabetes. There are many drugs available and still under development for the treatment of type 2 diabetes. Inhibition of gluconeogenesis, lipolysis, fatty acid oxidation, and glucokinase activator is emerging targets for type 2 diabetes treatment. Diabetes management can be supplemented with drug intervention for obesity. The antidiabetic drug sale is the second-largest in the world, trailing only that of cancer. The future of managing diabetes will be guided by research on various novel targets and the development of various therapeutic leads, such as GLP-1 agonists, DPP-IV inhibitors, and SGLT2 inhibitors that have recently completed their different phases of clinical trials. Among these therapeutic targets associated with type 2 diabetes, this review focused on some common therapeutic targets for developing novel drug candidates of the newer generation with better safety and efficacy.