Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been proposed to benefit cardiometabolic health. However, the relationship between the intake of DHA and EPA and type 2 diabetes (T2D) risk remains equivocal, and the effects of DHA and EPA on skeletal muscle, the primary organ for glucose metabolism, merit further investigation. Here, we show that habitual fish oil supplementation was associated with a 9% lower T2D risk and significantly interacted with variants at GLUT4 in a prospective cohort of 48,358 people with prediabetes. Muscular metabolome analysis in the animal study revealed that DHA and EPA altered branched-chain amino acids, creatine, and glucose oxidation-related metabolites, concurrently with elevated muscular glycogen synthase and pyruvate dehydrogenase contents that promoted glucose disposal. Further myotube investigation revealed that DHA and EPA promoted muscular GLUT4 translocation by elevating Rab GTPases and target-SNARE expression. Together, DHA and EPA supplementation provides a promising approach for T2D prevention through targeting muscular glucose homeostasis, including enhancing GLUT4 translocation, glycogen synthesis, and aerobic glycolysis.

Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin αv as model targets, respectively, and can effectively overcome pseudotargets or target loss caused by shedding or mutating the extracellular domain of target receptors. Moreover, these ligands can be spontaneously embedded in the phospholipid layer of lipid carriers using a plug-and-play approach without chemical modification, with excellent tunability and immunocompatibility. Overall, this allosteric targeted drug delivery strategy can be applied to multiple receptor targets and drug carriers and offers promising therapeutic benefits in brain diseases.

Cardiac hypoxia triggers a cascade of responses and functional changes in myocardial and non-myocardial cells, profoundly affecting cellular metabolism, oxygen-sensing mechanisms, and immune responses. Myocardial cells, being the primary cell type in cardiac tissue, undergo significant alterations in energy metabolism, including glycolysis, fatty acid metabolism, ketone body utilization, and branched-chain amino acid metabolism, to maintain cardiac function under hypoxic conditions. Non-myocardial cells, such as fibroblasts, endothelial cells, and immune cells, although fewer in number, play crucial roles in regulating cardiac homeostasis, maintaining structural integrity, and responding to injury. This review discusses the metabolic reprogramming of immune cells, particularly macrophages, during ischemia-reperfusion injury and explores various therapeutic strategies that modulate these metabolic pathways to protect the heart during hypoxia. Understanding these interactions provides valuable insights and potential therapeutic targets for heart disease treatment.

Mesua ferrea L. has traditionally utilized in folk medicine for its antidiabetic properties, and contemporary pharmacological studies have confirmed its hypoglycemic activity. While, the specific components responsible for these effects have not yet been fully elucidated. In this study, we employed a bioactivity-guided fractionation approach to isolate 22 prenylated polyphenols from M. ferrea leaves, including two novel 4-phenylcoumarins, mesuol A (1) and mesuol B (2), along with 20 previously identified compounds. The majority of these compounds, including 13 4-phenylcoumarins and two xanthones, exhibited significant stimulatory effect on glucose uptake in 3 T3-L1 adipocytes. Notably, at a concentration of 2 μM, isomesuol (14), disparinol D (17), and isodisparinol A (19) exhibited glucose uptake stimulatory effect that were either superior or equivalent to that of insulin (positive control). The structure-activity relationship analysis revealed that cyclization of 4-phenylcoumarins to form a furan ring markedly diminished their glucose uptake stimulatory effects, thereby reducing their hypoglycemic potential. In contrast, non-cyclized and pyran ring-cyclized 4-phenylcoumarins demonstrated stronger glucose uptake-stimulatory activities. These findings highlight the non-cyclized and pyran ring-cyclized 4-phenylcoumarins as promising leads for the development of anti-diabetic agents, with M. ferrea leaves serving as a valuable source of these bioactive compounds.

The aberrant metabolic reprogramming endows TNBC cells with sufficient ATP and lactate required for survival and metastasis. Hence, the intervention of the metabolic network represents a promising avenue to alleviate the Warburg effect in TNBC cells to impair their invasive and metastatic potential. Multitudinous in-silico analysis identified Enolase1 (ENO1) and the surface transporter protein, GLUT4 to be the potential targets for the abrogation of the metabolic network. The expression profiles of ENO1 and GLUT4 genes showed anomalous expression in various cancers, including breast cancer. Subsequently, the functional and physiological interactions of the target proteins were analyzed from the protein-protein interaction network. The pathway enrichment analysis identified the prime cancer signaling pathways in which these proteins are involved. Further, docking results bestowed Silibinin as the concurrent inhibitor of ENO1 and GLUT4. Moreover, the stable interaction of Silibinin with both proteins deciphered the binding free energies values of -48.86 and -104.31 KJ/mol from MMPBSA analysis and MD simulation, respectively. Furthermore, the cell viability, ROS assay, and live-dead imaging underscored the pronounced cytotoxicity of Silibinin, illuminating its capacity to incur apoptosis within TNBC cells. Additionally, glycolysis assay and gene expression analysis demonstrated the silibinin-mediated inhibition of the glycolysis pathway. Eventually, a lipidomic reprogramming towards fatty acid metabolism was established from the elevated lipid droplet accumulation, exogenous fatty acid uptake and de-novo lipogenesis. Nevertheless, repression of EMT and Wnt pathway progression by Silibinin was perceived from the gene expression studies. Overall, the current study highlights the tweaking of intricate signaling crosstalk between glycolysis and the Wnt pathway in TNBC cells through inhibiting ENO1 and GLUT4.

We evaluated the effect of trans-resveratrol (RSV) in ameliorating biochemical and molecular alterations in obese Wister male rats fed on high-fat/high-fructose-fed. Male Wister rats were divided into eight groups and fed with either a standard diet (control), high fructose (HF), high fat (HFAT), or a high- fructose high- fat (HF/HFAT) diet and supplemented with RSV (30 mg/kg/day) for 4 weeks. The food intake, body weight, glycemic parameters, lipid profile, oxidative stress were assessed. SIRT1 gene expression, PGC-1α, cyto-c and GLUT-4 were evaluated by qRT-PCR in adipose tissue of normal and obese rats. The body weight gain, serum fasting glucose, insulin, and HOMA-IR values were significantly higher in the HF and HF/HFAT groups than in the HFAT and control groups. Hyperlipidemia was observed in high calorie diets fed rats compared to control group. The levels of total cholesterol, triglycerides and LDL-c were significantly elevated while HDL- c was significantly decreased in HF & HF/HFAT groups compared to HFAT group. The levels of serum malondialdhyde (MDA) and superoxide dismutase (SOD) activity in adipose tissue were elevated in all groups compared to control group, particularly in the groups that were kept on a high fructose diets (HF, HF/HFAT). SIRT-1, PGC-1α, Cyto-c, and GLUT-4 genes levels were significantly down regulated in HF, HFAT & HF/HFAT groups compared to control group. Supplementation of T-RSV restored the alteration in carbohydrates-lipid metabolism as well as oxidative stress and upregulation of SIRT-1, PGC-1α, Cyto-c, and GLUT-4 genes. RSV is a promising treatment in the management of pathologic consequences of obesity from high-calorie diet consumption via molecular alteration of target genes.

Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.

Glucose is the primary energy substrate and an essential precursor for cellular metabolism. Maintaining glucose homeostasis necessitates the presence of glucose transporters, as the hydrophilic nature of glucose prevents its passage across the cell membrane. The GLUT family is a crucial group of glucose transporters that facilitate glucose diffusion along the transmembrane glucose concentration gradient. Dysfunction in GLUTs is associated with diseases, such as GLUT1 deficiency syndrome, Fanconi-Bickel syndrome, and type 2 diabetes. Furthermore, elevated expression of GLUTs fuels aerobic glycolysis, known as the Warburg effect, in various types of cancers, making GLUT isoforms possible targets for antineoplastic therapies. To date, 30 GLUT and homolog structures have been released on the Protein Data Bank (PDB), showcasing multiple conformational and ligand-binding states. These structures elucidate the molecular mechanisms underlying substrate recognition, the alternating access cycle, and transport inhibition. Here, we summarize the current knowledge of human GLUTs and their role in cancer, highlighting recent advances in the structural characterization of GLUTs. We also compare the inhibition mechanisms of exofacial and endofacial GLUT inhibitors, providing insights into the design and optimization of GLUT inhibitors for therapeutic applications.

Type 2 diabetes mellitus (T2DM) and its associated complications represent a significant public health issue affecting hundreds of millions of people globally; thus, measures to prevent T2DM are urgently needed. Chuju has been proven to possess antihyperglycemic activity. However, the bioactive ingredients in chuju that contribute to its antihyperglycemic activity, as well as the relationship between its antihyperglycemic activity and the gut microbiota, remain unclear. To understand the potential effects that it has on T2DM, the glycolipid metabolism and gut microbiota regulation of flavonoid-rich extracts from chuju (CJE) were investigated. The results showed that the top ten flavonoid compounds in CJE are Apigenin 6, 8-digalactoside, Apigenin 6-C-glucoside 8-C-arabinoside, Luteolin-4'-O-glucoside, Isoshaftoside, Scutellarin, Quercetin 3-O-malonylglucoside, Chrysoeriol 7-O-glucoside, Quercetin-3,4'-O-di-beta-glucoside, Luteolin 6-C-glucoside 8-C-arabinoside, and Homoorientin. Furthermore, CJE mitigated hyperglycemia and glycolipid metabolism by reducing the abundance of Faecalibaculum, Coriobacteriaceae, and Romboutsia and increasing the abundance of Alistipes. In addition, the results of Western blot analysis showed that CJE could enhance glycogen synthesis and glucose transport by up-regulating the phosphorylation of IRS1-PI3K-Akt and AMPK-GLUT4. Simultaneously, CJE could decrease gluconeogenesis by down-regulating the phosphorylation of FoxO1/GSK 3β. In conclusion, the findings of this study provide new evidence supporting the hypothesis that CJE can be used as part of a therapeutic approach for treating disturbances in glycolipid metabolism via regulating the gut microbiota and mediating the IRS1-PI3K-Akt-FoxO1/GSK 3β and AMPK-GLUT4 pathways.

This study compares the pharmacokinetics and efficacy of various subcutaneously (SC) dosed insulin analogs, including rapid-acting, intermediate-acting, long-acting, and regular human insulin, using mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) models. These models were applied to data from euglycemic clamp studies in healthy volunteers, where insulin pharmacokinetics and its effects on glucose utilization were monitored. Data from published studies were digitized and modeled using MONOLIX (Version 2024). The PK model described insulin absorption via sequential first-order processes and linear elimination. The PD effects were captured using a model combination of biophase, indirect, and receptor down-regulation components. While PK parameters-especially absorption rates-varied between insulin types, a common set of nonlinear PD parameters was sought to account for dose-related differences in glucose utilization. The maximum glucose stimulation (S max ${{{\mathrm{S}}}_{{\mathrm{max}}}}$ ) was 163, and the insulin concentration for a half-maximal effect (S C 50 ${\mathrm{S}}{{{\mathrm{C}}}_{50}}$ ) were 1156 pmol/L for insulin lispro, regular human insulin, neutral protamine hagedorn (NPH) insulin, and insulin glargine; 674 pmol/L for insulin aspart; and 5335 pmol/L for insulin detemir. Insulin detemir showed similar overt effects as the other insulin types but with smaller clearances and lower potency. This mechanism-based glucose-insulin model demonstrated that most insulin analogs exhibit similar receptor- and transporter-related parameters. The model, with specific PK but unified PD parameters, may enable clinical optimization of insulin therapy by highlighting differences in pharmacokinetics and operating common intrinsic glucose utilization parameters.

Properly folded proteins are essential for virtually all cellular processes including enzyme catalysis, signal transduction, and structural support. The cells have evolved intricate mechanisms of control, such as the assistance of chaperones and proteostasis networks, to ensure that proteins mature and fold correctly and maintain their functional conformations. Here, we review the mechanisms governing the folding of key hormonal regulators or glucose homeostasis. The insulin synthesis in pancreatic β-cells begins with preproinsulin production. During translation, the insulin precursor involves components of the endoplasmic reticulum (ER) translocation machinery, which are essential for proper orientation, translocation, and cleavage of the signal peptide of preproinsulin. These steps are critical to initiate the correct folding of proinsulin. Proinsulin foldability is optimized in the ER, an environment evolved to support the folding process and the formation of disulfide bonds while minimizing misfolding. This environment is intricately linked to ER stress response pathways, which have both beneficial and potentially harmful effects on pancreatic β-cells. Proinsulin misfolding can result from excessive biosynthetic ER load, proinsulin gene mutations, or genetic predispositions affecting the ER folding environment. Misfolded proinsulin leads to deficient insulin production and contributes to diabetes pathogenesis. Understanding the mechanisms of protein folding is critical for addressing diabetes and other protein misfolding-related diseases.

The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.

The Irisin/FNDC5 protein family has emerged as a pivotal link between exercise and the prevention of age-associated diseases. Irisin is highly expressed during exercise from skeletal and cardiac muscle cells, playing a critical role in mediating systemic health benefits through its actions on various tissues. However, Irisin levels decline with age, correlating with a heightened incidence of diseases such as muscle weakness, cardiovascular disorders, and neurodegeneration. Notably, the administration of Irisin has shown significant potential in both preventing and treating these conditions. Recently, an Irisin/FNDC5 homolog was identified in an invertebrate Drosophila model, providing valuable insights into its conserved role in exercise physiology. Importantly, Irisin/FNDC5 has been demonstrated to regulate autophagy-a process essential for clearing excessive nutrients, toxic aggregates, and dysfunctional organelles-in both flies and mammals. Dysregulated autophagy is often implicated in age-related diseases, highlighting its relevance to Irisin/FNDC5's functions. These findings deepen our understanding of Irisin/FNDC5's roles and its potential as a therapeutic target for mitigating aging-related health decline. Further studies are needed to elucidate the precise mechanisms by which Irisin regulates autophagy and its broader impact on physiological aging and related diseases.

Receptors of insulin and insulin-like growth factors (IGFs) are receptor tyrosine kinases whose signalling controls multiple aspects of animal physiology throughout life. In addition to regulating metabolism and growth, insulin-IGF receptor signalling has recently been linked to a variety of new, cell type-specific functions. In the last century, key questions have focused on how structural differences of insulin and IGFs affect receptor activation, and how insulin-IGF receptor signalling translates into pleiotropic biological functions. Technological advances such as cryo-electron microscopy have provided a detailed understanding of how native and engineered ligands activate insulin-IGF receptors. In this Review, we highlight recent structural and functional insights into the activation of insulin-IGF receptors, and summarize new agonists and antagonists developed for intervening in the activation of insulin-IGF receptor signalling. Furthermore, we discuss recently identified regulatory mechanisms beyond ligand-receptor interactions and functions of insulin-IGF receptor signalling in diseases.

Type 2 diabetes mellitus (T2DM) is a global health burden, with hyperglycemia as the main hallmark. This review commences with a concise overview of the intricate mechanisms underlying glucose uptake and utilization in organisms. Notably, we emphasize that T2DM management strategies pivot on delaying carbohydrate digestion, augmenting insulin secretion, and enhancing insulin sensitivity in target tissues. Unfortunately, the drugs currently available in the market for the treatment of T2DM have unpleasant side effects, spurring an urgent quest for safer and more efficacious alternatives. Flavonoids, emerging as a promising class of bioactive compounds derived from plants, offer a multi-faceted approach to diabetes treatment. Specifically, they potently inhibit enzymes such as α-amylase, α-glucosidase, dipeptidyl peptidase-4 (DPP-4), glycogen phosphorylase (GP) and protein-tyrosine phosphatase-1B (PTP1B). Through an in-depth analysis, this review not only summarizes these inhibitory actions but also establishes the structure-activity relationship (SAR), providing a blueprint for rational drug design. However, the clinical translation of flavonoids has been hampered by their suboptimal water solubility and bioavailability, attributable to the characteristic carbonyl and hydroxyl groups. Ingeniously, this chemical quirk has been harnessed to engineer metal chelates, which exhibit enhanced pharmacokinetic profiles. Herein, we offer an exhaustive overview of the latest advancements in flavonoid metal complexes research, spotlighting their potential as next-generation diabetes therapeutics. Available data are poised to galvanize the development of novel flavonoid derivatives, be it as potent drugs or functional foods, for combating T2DM.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age characterized by a spectrum of clinical, metabolic, reproductive, and psychological abnormalities. This syndrome is associated with significant long-term health risks, necessitating elucidation of its pathophysiology, early diagnosis, and comprehensive management strategies. Several contributory factors in PCOS, including androgen excess and insulin resistance, collectively enhance oxidative stress, which subsequently leads to mitochondrial dysfunction. However, the precise mechanisms through which oxidative stress induces mitochondrial dysfunction remain incompletely understood. Comprehensive searches of electronic databases were conducted to identify relevant studies published up to 30 September 2024. Mitochondria, the primary sites of reactive oxygen species (ROS) generation, play critical roles in energy metabolism and cellular homeostasis. Oxidative stress can inflict damage on components, including lipids, proteins, and DNA. Damage to mitochondrial DNA (mtDNA), which lacks efficient repair mechanisms, may result in mutations that impair mitochondrial function. Dysfunctional mitochondrial activity further amplifies ROS production, thereby perpetuating oxidative stress. These disruptions are implicated in the complications associated with the syndrome. Advances in genetic analysis technologies, including next-generation sequencing, have identified point mutations and deletions in mtDNA, drawing significant attention to their association with oxidative stress. Emerging data from mtDNA mutation analyses challenge conventional paradigms and provide new insights into the role of oxidative stress in mitochondrial dysfunction. We are rethinking the pathogenesis of PCOS based on these database analyses. In conclusion, this review explores the intricate relationship between oxidative stress, mtDNA mutations, and mitochondrial dysfunction, offers an updated perspective on the pathophysiology of PCOS, and outlines directions for future research.

Caragana jubata (Pall.) Poir., a traditional Tibetan medicinal plant in China, is renowned in Tibetan medicine for its hypoglycemic properties and long-standing use in treating diabetes. Despite its extensive clinical use, the mechanisms underlying its blood sugar-lowering effects still need to be explored. Our investigation contributes a new understanding of the hypoglycemic mechanism of C. jubata, validating its traditional medicinal application by demonstrating its ability to increase GLUT4 expression and glucose uptake, crucial elements in treating type 2 diabetes mellitus (T2DM).

This study investigated the potential anti-diabetic effects of C. jubata ethanol extract (CJEE) by upregulating GLUT4 expression and promoting its integration into the plasma membrane in L6 skeletal muscle cells and diabetic mice. Additionally, the research aimed to uncover the mechanisms involved, particularly focusing on the involvement of the PKC signaling pathway and Ca2⁺ release.

The chemical composition of CJEE was evaluated using UPLC-Q-TOF/MS. Glucose uptake, GLUT4 expression, and plasma membrane fusion in L6 cells were assessed through a glucose oxidase kit, Western blotting, and laser confocal microscopy, respectively. The modulation of GLUT4 by Akt, AMPK, and PKC signaling pathways was investigated utilizing specific inhibitors. The impact of CJEE on intracellular Ca2⁺ concentration was determined with Fluo-4 dye. Additionally, an in vivo study was conducted on high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice to evaluate the effects of CJEE on blood glucose levels, insulin resistance, lipid metabolism, and pancreatic function.

Chemical analysis of CJEE revealed 18 major constituents, primarily flavonoids. In L6 cells, CJEE was found to significantly enhance glucose uptake, increase GLUT4 expression, and facilitate its fusion with the plasma membrane. The study illustrated that CJEE predominantly activates the PKC pathway, with minimal involvement of the Akt pathway, emphasizing the critical role of Ca2⁺ release in GLUT4 regulation. Diabetic mice treated with CJEE exhibited decreased fasting blood glucose levels, enhanced oral glucose tolerance, reduced insulin resistance, and ameliorated lipid metabolism disorders. Additionally, CJEE elevated GLUT4 expression in insulin-sensitive tissues and alleviated pancreatic and hepatic lesions.

Our results demonstrated that the activation of the PKC pathway and release of Ca2⁺ by CJEE induce GLUT4 expression, promoting its fusion with the plasma membrane. Consequently, this process boosts glucose uptake and enhances insulin sensitivity, underscoring CJEE as a promising option for managing T2DM.

Cardiovascular complications are a primary focus in the clinical management of type 2 diabetes, as they are the leading causes of disability and mortality in individuals with diabetes. Insulin resistance and endothelial dysfunction commonly coexist in diabetic patients. An increasing body of research indicates a reciprocal and interconnected association between endothelial function and insulin resistance. Insulin resistance can manifest in two distinct forms: endothelial and metabolic, with the former predominantly affecting vascular endothelial cells and the latter primarily impacting peripheral cells. The understanding of endothelial insulin resistance is crucial in comprehending the pathophysiology of cardiovascular complications in type 2 diabetes. Hence, the objective of this study is to examine the correlations, interplays, and molecular pathways linking endothelial insulin resistance and metabolic insulin resistance, with the aim of offering novel insights and scholarly resources for the prevention and management of diabetic vascular complications.

The role of non-receptor type Protein Tyrosine Phosphatase (PTPases) in controlling pathways related to diabetes and Hepatocellular Carcinoma (HCC) is significant. The insulin signal transduction pathway is regulated by the steady-state phosphorylation of tyrosyl residues of the insulin receptor and post-receptor substrates. PTPase has been shown to have a physiological role in the regulation of reversible tyrosine phosphorylation. There are several non-receptor type PTPases. PTPase containing the SH-2 domain (SHP-2) and the non-receptor type PTPase (PTP1B; encoded by the PTPN1 gene) are involved in negative regulation of the insulin signaling pathway, thereby indicating that the pathway can be made more efficient by the reduction in the activity of specific PTPases. Reduction in insulin resistance may be achieved by drugs targeting these specific enzymes. The modifications in the receptor and post-receptor events of insulin signal transduction give rise to insulin resistance, and a link between insulin-resistant states and HCC has been established. The cancer cells thrive on higher levels of energy and their growth gets encouraged since insulin-resistant states lead to greater glucose levels. Cancer, hyperglycemia, and hypoglycemia are highly linked through various pathways hence, clarifying the molecular mechanisms through which non-receptor type PTPase regulates the insulin signal transduction is necessary to find an effective target for cancer. Targeting the pathways related to PTPases; both receptor and non-receptor types, may lead to an effective candidate to fight against diabetes and HCC.

Maintaining blood glucose homeostasis during fasting and feeding is crucial for the prevention of dysregulation that can lead to either hypo- or hyperglycaemia. Here we identified feimin, encoded by a gene with a previously unknown function (B230219D22Rik in mice, C5orf24 in humans), as a key modulator of glucose homeostasis. Feimin is secreted from skeletal muscle during feeding and binds to its receptor, receptor protein tyrosine kinase Mer (MERTK), promoting glucose uptake and inhibiting glucose production by activation of AKT. Administration of feimin and insulin synergistically improves blood glucose homeostasis in both normal and diabetic mice. Notably, a specific single nucleotide polymorphism (rs7604639, G>A) within the MERTK gene, causing an amino acid substitution (R466K) within the feimin-MERTK binding region, leads to reduced association with feimin and elevated postprandial blood glucose and insulin levels in humans. Our findings underscore a role of the feimin-MERTK signalling axis in glucose homeostasis, providing valuable insights into potential therapeutic avenues for diabetes.

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

Insulin resistance (IR) is a common pathology in women with polycystic ovarian syndrome (PCOS) involved in increased rates of cardiometabolic disease such as diabetes and cardiovascular disease. Low serum vitamin D is often associated with insulin resistance but there is no consensus on whether vitamin D supplementation can ameliorate markers of IR in PCOS.

We assessed evidence on the effects of vitamin D supplementation (≥ 1000 IU/day), without the use of additional supplements or other pharmacological treatments known to affect IR, on markers of IR and glycemic control in women with PCOS.

A systematic search was conducted using PubMed, Medline and Web of Science databases from January 2000 up to November 2023. Randomized controlled trials that assessed the effects of vitamin D supplementation in women with PCOS, on fasting glucose, fasting insulin, glycated haemoglobin (HbA1c) or homeostatic model assessment for insulin resistance (HOMA-IR) were included.

9 studies were identified. Study populations ranged from 28 to 180 participants, with mean ages ranging from 22 to 30 years. Daily vitamin D doses ranged from 1714-12,000 IU. Of the included studies, 3 reported statistically significant reductions in fasting glucose, 2 reported reductions in fasting insulin, 2 reported reductions in HOMA-IR, none reported reductions in HbA1c and 5 reported no differences in any of the relevant outcomes.

In conclusion, in RCTs of vitamin D supplementation in women with PCOS, the majority of studies do not report statistically significant improvements in fasting glucose, fasting insulin, HbA1c or HOMA-IR. However, as a minority of studies report some statistically significant results, further investigation may be warranted.

PROSPERO ID: CRD42023486144.

Glucose Transporter 4 (GLUT4) is a crucial protein facilitating glucose uptake and metabolism across cell membranes in mammals. However, information on GLUT4 in birds has historically been limited. In this study, we investigated the dynamic expression profile of chicken GLUT4 using real-time quantitative PCR (RT-qPCR) and examined its potential effects and mechanisms via GLUT4 overexpression and RNA sequencing (RNA-seq) in chicken primary skeletal muscle satellite cells (CP-SMSCs). Our results demonstrated that chicken GLUT4 is differentially expressed across tissues, with predominant expression in skeletal muscles, and across developmental stages of CP-SMSCs, with notable upregulation during the phases of cell proliferation and early differentiation. Notably, 0.1 μM insulin for 60 min significantly elevated the expression of GLUT4 in CP-SMSCs (P < 0.05). GLUT4 overexpression in CP-SMSCs promoted cell proliferation, as evidenced by Cell Counting Kit-8 (CCK-8) (P < 0.05) and 5-Ethynyl-2'-Deoxyuridine (EDU) assays (P < 0.05), and enhanced glucose consumption following 0.1 μM insulin treatment (P < 0.05). However, it inhibited glucose consumption 12 h after the addition of 5 g/L glucose (P < 0.05). After overexpressing GLUT4, we identified 302 differentially expressed genes (DEGs) in CP-SMSCs, with 134 upregulated and 168 downregulated. These DEGs are primarily enriched in pathways such as oxidative phosphorylation, ribosome, cardiac muscle contraction, ATP metabolic processes, and mitochondrial protein complexes. Specifically, in the enriched oxidative phosphorylation pathway, the upregulated DEGs (12) encode mitochondrial proteins, while the downregulated DEGs (6) are nuclear genome-derived. The ribosomal pathway is predominantly inhibited, accompanying with the downregulation of the translocase of outer mitochondrial membrane 7 (TOMM7)/translocase of inner mitochondrial membrane 8 (TIMM8A) complex responsible for mitochondrial protein transport, and a reduction in 28S (LOC121106978) and 18S (LOC112533601) ribosomal rRNAs. In conclusion, chicken GLUT4 is dynamically modulated during development and acts as an insulin responder that significantly regulates cellular glucose uptake and cell proliferation. This regulation occurs mainly through enhancing the mitochondrial oxidative phosphorylation and inhibiting ribosomal pathway.

Sarcopenia is a progressive muscle wasting disorder that severely impacts the quality of life of elderly individuals. Although the natural aging process primarily causes sarcopenia, it can develop in response to other conditions. Because muscle function is influenced by numerous changes that occur with age, the etiology of sarcopenia remains unclear. However, recent characterizations of the aging muscle transcriptional landscape, signaling pathway disruptions, fiber and extracellular matrix compositions, systemic metabolomic and inflammatory responses, mitochondrial function, and neurological inputs offer insights and hope for future treatments. This review will discuss age-related changes in healthy muscle and our current understanding of how this can deteriorate into sarcopenia. As our elderly population continues to grow, we must understand sarcopenia and find treatments that allow individuals to maintain independence and dignity throughout an extended lifespan.

Diabetes mellitus (DM) is becoming increasingly prominent, posing a serious threat to human health. Its prevalence is rising every year, and often affects young people. In the past few decades, research on marine algae has been recognized as a major field of drug discovery. Seaweed active substances, including algal polysaccharides, algal polyphenols, algal unsaturated fatty acids, and algal dietary fiber, have unique biological activities. This article reviews the effects and mechanisms of the types, structures, and compositions of seaweed on inhibiting glucose and lipid metabolism disorders, with a focus on the inhibitory effect of active substances on blood glucose reduction. The aim is to provide a basis for the development of seaweed active substance hypoglycemic drugs.

Skeletal muscle is one of the predominant sites involved in glucose disposal, accounting for ∼80% of postprandial glucose uptake, and plays a critical role in maintaining glycemic homeostasis. Dysregulation of energy metabolism in skeletal muscle is involved in developing insulin resistance and type 2 diabetes (T2D). Transcriptomic responses of skeletal muscle to exercise found that the expression of Klf3 was increased in T2D Goto-Kakizaki (GK) rats and decreased after exercise with improved hyperglycemia and insulin resistance, implying that Klf3 might be associated with insulin sensitivity and glucose metabolism. We also found that knockdown of Klf3 promoted basal and insulin-stimulated glucose uptake in L6 myotubes, whereas overexpression of Klf3 resulted in the opposite. Through pairwise comparisons of L6 myotubes transcriptome, we identified 2,256 and 1,988 differentially expressed genes in Klf3 knockdown and overexpression groups, respectively. In insulin signaling, the expression of Slc2a4, Akt2, Insr, and Sorbs1 was significantly increased by Klf3 knockdown and decreased with Klf3 overexpression; Ptprf and Fasn were markedly downregulated in Klf3 reduced group and upregulated in Klf3 overexpressed group. Moreover, downregulation of Klf3 promoted the expression of glucose transporter 4 (GLUT4) and protein kinase B (AKT) proteins, as well as the translocation of GLUT4 to the cell membrane in the basal situation, and enhanced insulin sensitivity, characterized by increased insulin-stimulated GLUT4 translocation and AKT, TBC1 domain family member 1 (TBC1D1) and TBC1 domain family member 4 (TBC1D4) phosphorylation, whereas overexpression of Klf3 showed contrary results. These results suggest that Klf3 affects glucose uptake and insulin sensitivity via insulin signal transduction and intracellular metabolism, offering a novel potential treatment strategy for T2D.NEW & NOTEWORTHY The knockdown of Klf3 increased glucose uptake and improved insulin sensitivity in L6 myotubes, whereas its overexpression had the opposite effect. To explore the underlying mechanisms, we evaluated the transcriptional profiles of L6 myotubes after Klf3 knockdown and overexpression and revealed that metabolism and insulin-related pathways were significantly impacted. Klf3 also influenced the expression or modification of glucose transporter 4 (GLUT4), protein kinase B (AKT), TBC1 domain family member 1 (TBC1D1), and TBC1 domain family member 4 (TBC1D4) in the insulin signaling pathway, affecting insulin sensitivity and glucose uptake.

Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models.

Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD).

In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose.

Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.

Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Obesity-induced type 2 diabetes (T2D) increases the risk of metabolic syndrome due to the high calorie intake. The role of sugar beet pulp (SBP) in T2D and the mechanism of its action remain unclear, though it is abundant in phenolics and has antioxidant activity. In this study, we isolated and purified ferulic acid from SBP, referred to as SBP-E, and studied the underlying molecular mechanisms in the regulation of glucose and lipid metabolism developing high glucose/high fat diet-induced diabetic models in vitro and in vivo. SBP-E showed no cytotoxicity and reduced the oxidative stress by increasing glutathione (GSH) in human liver (HepG2) and rat skeletal muscle (L6) cells. It also decreased body weight gain, food intake, fasting blood glucose levels (FBGL), glucose intolerance, hepatic steatosis, and lipid accumulation. Additionally, SBP-E decreased the oxidative stress and improved the antioxidant enzyme levels in high-fat diet (HFD)-induced T2D mice. Further, SBP-E reduced plasma and liver advanced glycation end products (AGEs), malondialdehyde (MDA), and pro-inflammatory cytokines, and increased anti-inflammatory cytokines in HFD-fed mice. Importantly, SBP-E significantly elevated AMPK, glucose transporter, SIRT1 activity, and Nrf2 expression and decreased ACC activity and SREBP1 levels in diabetic models. Collectively, our study results suggest that SBP-E treatment can improve obesity-induced T2D by regulating glucose and lipid metabolism via SIRT1/AMPK signalling and the AMPK/SREBP1/ACC1 pathway.

The two clathrin isoforms, CHC17 and CHC22, mediate separate intracellular transport routes. CHC17 performs endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, shuttles the glucose transporter GLUT4 from the ERGIC (endoplasmic-reticulum-to-Golgi intermediate compartment) directly to an intracellular GLUT4 storage compartment (GSC), from where GLUT4 can be mobilized to the plasma membrane by insulin. Here, molecular determinants distinguishing CHC22 from CHC17 trafficking are defined. We show that the C-terminal trimerization domain of CHC22 interacts with SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. In tandem, an isoform-specific patch in the CHC22 N-terminal domain separately mediates binding to p115. This dual mode of clathrin recruitment, involving interactions at both N- and C-termini of the heavy chain, is required for CHC22 targeting to ERGIC membranes to mediate the Golgi-bypass route for GLUT4 trafficking. Interference with either interaction inhibits GLUT4 targeting to the GSC, defining a bipartite mechanism regulating a key pathway in human glucose metabolism.

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing1-4. Several genetic interventions have been found to ameliorate old brain function5-8, but systematic functional testing of genes in old NSCs-and more generally in old cells-has not been done. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR-Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age. Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.

RNA modifications play a crucial role in cancer development, profoundly influencing various stages of the RNA lifecycle. These stages encompass nuclear processing, nuclear export, splicing, and translation in the cytoplasm. Among RNA modifications, RNA ac4C modification, also known as N4-acetylcytidine, stands out for its unique role in acetylation processes. Specific proteins regulate RNA ac4C modification, maintaining the dynamic and reversible nature of these changes. This review explores the molecular mechanisms and biological functions of RNA ac4C modification. It examines the intricate ways in which RNA ac4C modification influences the pathogenesis and progression of cancer. Additionally, the review provides an integrated overview of the current methodologies for detecting RNA ac4C modification. Exploring the potential applications of manipulating this modification suggests avenues for novel therapeutic strategies, potentially leading to more effective cancer treatments in the future.

Fenugreek (Trigonella foenum-graecum) is a widely grown dietary herb in Asia, and its seeds are traditionally used for several diseases, including diabetes. The seeds and leaves possess a variety of compounds that play an important role in regulating their hypoglycemic effect. However, so far, no extensive systematic review exists on its antidiabetic effect, highlighting the molecular mechanisms and isolated compounds. The purpose of this review is to summarize the preclinical and clinical antidiabetic properties of fenugreek and its isolated compounds by focusing on underlying mechanisms. PubMed, Google Scholar, Science Direct, and Scopus databases were searched to retrieve articles until June, 2024. Preclinical studies demonstrated that the antidiabetic effect of fenugreek was mostly associated with enhanced glucose transporter type-4 (GLUT4) translocation and hexokinase activity, decreased glucose-6-phosphatase and fructose-1,6-bisphosphatase activities, inhibited α-amylase and maltase activities, protected β cells, and increased insulin release. Furthermore, few studies have reported its role as a glucagon-like peptide-1 (GLP-1) modulator, 5'-AMP-activated kinase (AMPK) activator, and dipeptidyl peptidase-IV (DPP-IV) inhibitor. Further clinical trials showed that fenugreek seeds improved blood glucose levels, insulin resistance, insulin sensitivity, and lipid profiles. This study highlights significant evidence of the antidiabetic effect of fenugreek and its isolated compounds; therefore, it could be a potential therapy for diabetes.

Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment (TME), all of which present new opportunities for targeted therapies. However, studying these metabolic networks is challenging in traditional 2D cell cultures, which often fail to replicate the three-dimensional architecture and dynamic interactions of real tumors. To address this, organoid models have emerged as powerful tools. Tumor organoids are 3D cultures, often derived from patient tissue, that more accurately mimic the structural and functional properties of actual tumor tissues in vivo, offering a more realistic model for investigating cancer metabolism. This review explores the unique metabolic adaptations of breast cancer and discusses how organoid models can provide deeper insights into these processes. We evaluate the most advanced tools for studying cancer metabolism in three-dimensional culture models, including optical metabolic imaging (OMI), matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and recent advances in conventional techniques applied to 3D cultures. Finally, we explore the progress made in identifying and targeting potential therapeutic targets in breast cancer metabolism.

Mitochondria and lysosomes play a very important role in maintaining cellular homeostasis, and the dysfunction of these organelles is closely related to many diseases. Recent studies have revealed direct interactions between mitochondria and lysosomes, forming mitochondria-lysosome contact sites that regulate organelle network dynamics and mediate the transport of metabolites between them. Impaired function of these contact sites is not only linked to physiological processes such as glucose and cholesterol transport but also closely related to the pathological processes of metabolic diseases. Here, we highlight the recent progress in understanding the mitochondria-lysosome contact sites, elucidate their role in regulating metabolic homeostasis, and explore the potential implications of this pathway in metabolic disorders.

The human gut microbiota is increasingly recognized as a pivotal factor in diabetes management, playing a significant role in the body's response to treatment. However, it is important to understand that long-term usage of medicines like metformin and other diabetic treatments can result in problems, gastrointestinal discomfort, and dysbiosis of the gut flora. Advanced sequencing technologies have improved our understanding of the gut microbiome's role in diabetes, uncovering complex interactions between microbial composition and metabolic health. We explore how the gut microbiota affects glucose metabolism and insulin sensitivity by examining a variety of -omics data, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, and metagenomics. Machine learning algorithms and genome-scale modeling are now being applied to find microbiological biomarkers associated with diabetes risk, predicted disease progression, and guide customized therapy. This study holds promise for specialized diabetic therapy. Despite significant advances, some concerns remain unanswered, including understanding the complex relationship between diabetes etiology and gut microbiota, as well as developing user-friendly technological innovations. This mini-review explores the relationship between multiomics, precision medicine, and machine learning to improve our understanding of the gut microbiome's function in diabetes. In the era of precision medicine, the ultimate goal is to improve patient outcomes through personalized treatments.

Fenitrothion (FNT) is a common organophosphorus pesticide that is widely used in both agricultural and domestic pest control. FNT has been frequently detected in various environmental media, including the human body, and is a notable contaminant. Epidemiological investigations have recently shown the implications of exposure to FNT in the incidence of various metabolic diseases, such as diabetes mellitus in humans, indicating that FNT may be a potential endocrine disruptor. However, the effects of FNT exposure on glucose homeostasis and their underlying mechanisms in model organisms remain largely unknown, which may limit our understanding of the health risks of FNT. In this study, FNT (4 5, 90, 180, and 4 50 μM) exposure model of rat hepatocytes (Buffalo Rat Liver, BRL cells) was established to investigate the effects and potential mechanisms of its toxicity on glucose metabolism. Several key processes of glucose metabolism were detected in this study. The results showed significantly increased glucose levels in the culture medium and decreased glycogen content in the FNT-exposed BRL cells. The results of quantitative real-time PCR and enzymology showed the abnormal expression of genes and activity/content of glucose metabolic enzymes involved in glucose metabolism, which might promote gluconeogenesis and inhibit glucose uptake, glycolysis, and glycogenesis. Furthermore, gluconeogenesis and glycolytic were carried out in the mitochondrial membrane. The abnormal of mitochondrial membrane potential may be a potential mechanism underlying FNT-induced glucose metabolism disorder. In addition, the mRNA and protein expression implicated that FNT may disrupt glucose metabolism by inhibiting the AMPKα and IRS1/PI3K/AKT signaling pathways. In conclusion, results provide in vitro evidence that FNT can cause glucose metabolism disorder, which emphasizes the potential health risks of exposure to FNT in inducing diabetes mellitus.