Search Results (424)

Pharmacological compounds can disrupt glucose homeostasis, leading to impaired glucose tolerance, hyperglycemia, or newly diagnosed diabetes, as well as worsening glycemic control in patients with pre-existing diabetes. Traditional risk factors alone cannot explain the rapidly growing global incidence of diabetes. Therefore, prevention of insulin resistance could represent an effective strategy. Achieving this goal requires a deeper understanding of the mechanisms underlying the development of insulin resistance, with particular attention to the aryl hydrocarbon receptor (AhR). AhR, a transcription factor functioning as a xenobiotic sensor, plays a key role in various molecular pathways regulating normal homeostasis, organogenesis, and immune function. Activated by a range of exogenous and endogenous ligands, AhR is involved in the regulation of glucose and lipid metabolism as well as insulin sensitivity. However, current findings remain contradictory regarding whether AhR activation exerts beneficial or detrimental effects. This narrative review summarizes recent studies exploring the role of the AhR pathway in insulin secretion and glucose homeostasis across different tissues, and discusses molecular mechanisms involved in this process. Considering that several drugs act as AhR ligands, the review also compares how these ligands affect metabolic pathways of glucose and lipid metabolism and insulin sensitivity, producing either positive or negative effects. Full article

Glucagon-like peptide-1 receptor (GLP1R) agonists, such as semaglutide, are used for treating type 2 diabetes mellitus and promoting weight loss. This study investigates genetic and molecular mechanisms underlying GLP1R activation using a novel in silico approach to identify effects on metabolism, glucose and insulin production, gastrointestinal motility, behavior, and satiety. This approach used three separate searchable web-based programs and databases (STRING, Pathway Commons, and BioGRID) to identify and analyze functional gene and protein interactions with mechanisms to query GLP1R and related metabolic and appetite regulatory networks with disease associations. We examined integrated gene–gene and protein–protein interactions, pathways, molecular functions, associated diseases, and biological processes for GLP1R, that reportedly involved in diabetes and obesity. GLP1R signaling cascades were described with the activation of the adenylate cyclase-modulating G protein-coupled receptor and increased intracellular cyclic AMP, collectively impacting glucagon production, insulin, glycogenolysis, vasoactive intestinal peptide, and other peptides and hormones required for satiety. Additional factors found were obesity-related peptides (i.e., POMC), hormone signaling, renin secretion, electrolytes and diuresis, circadian rhythm, and insulin secretion. These associations and interactions shift from hypoglycemia to broader endocrine dysfunction. A relationship was noted for GNAS having a role in growth, electrolytes, and skeletal disturbances with specific hormone sensitivity patterns. Understanding established and new interactions with genetics and gene-protein variants that impact type 2 diabetes and obesity would provide further insight into therapeutic GLP1R agonists response and consequences. Potential long-term systemic effects should be monitored, studied, and recorded with treatment protocols adjusted accordingly. Full article

Obesity is a chronic systemic disease characterised by insulin resistance, inflammation, and mitochondrial dysfunction. Hyperbaric oxygen therapy (HBOT), which involves the administration of 100% oxygen under elevated atmospheric pressure, has a well-established clinical application in the treatment of non-healing wounds and ischemia, and it is currently being investigated as an adjunctive therapy for obesity and metabolic disorders. The aim of this review is to provide a critical synthesis of recent (2012–2025) evidence regarding the mechanisms of HBOT action in the human body. Furthermore, it examines the metabolic effects and safety profile of HBOT in the context of obesity, with particular attention to experimental and preliminary clinical research. Preclinical studies have demonstrated that HBOT enhances insulin sensitivity, reduces adipose tissue inflammation, and modulates lipid metabolism. The proposed mechanisms include activation of Akt/AMPK signalling and GLUT4 translocation in skeletal muscle, resulting in improved glucose uptake and oxidation, as well as stimulation of thermogenesis in brown adipose tissue. In rodent models of obesity, HBOT has been shown to reduce adipose tissue mass, improve lipid profiles, and restore normal β-oxidation of fatty acids by normalising the expression of peroxisome proliferator-activated receptor-α and carnitine palmitoyl transferase 1B in muscle tissue. Preliminary clinical studies in humans indicate that HBOT enhances both systemic and tissue insulin sensitivity, accompanied by improved mitochondrial function and reduced endoplasmic reticulum stress. Despite these promising findings, data on the long-term efficacy, optimal treatment protocols, and safety of HBOT in obese individuals remain limited. In conclusion, HBOT appears to be a promising adjunctive approach in the management of obesity through the multidirectional improvement in metabolic functions. However, high-quality clinical trials are required to confirm its effectiveness, durability of outcomes, and safety profile across diverse patient populations. Full article

Background/Objectives: Rosiglitazone (RSG), a potent PPARγ agonist for type 2 diabetes mellitus (T2DM), induces adverse adipogenic effects that limit clinical use. We investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone, EMO), a natural anthraquinone, mitigates RSG-induced complications while enhancing its insulin-sensitizing benefits in severe obesity. Methods: Male ob/ob mice with established obesity and diabetes were treated for 4 weeks with RSG (10 mg kg⁻¹ day⁻¹), EMO (200 or 400 mg kg⁻¹ day⁻¹) or their combination. Metabolic profiling, organ function, and adipose histology were analyzed. RNA sequencing and mechanistic studies (Western blot, RT-qPCR, luciferase assays) in inguinal subcutaneous adipose tissue (iSAT), epididymal white adipose tissue (eWAT), and 3T3-L1 adipocytes were used to define EMO’s actions. Results: EMO co-treatment dose-dependently reduced RSG-induced weight gain, visceral adiposity (iSAT and eWAT mass, p < 0.05), and ectopic lipid deposition while ameliorating hepatorenal dysfunction. EMO synergistically enhanced RSG’s glucose-lowering effects. Mechanistically, EMO suppressed sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis (Srebp1, Acc, Fasn, Scd1; p < 0.05) and enhanced PPARγ-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-driven thermogenesis via enhanced PPARγ transactivation and nuclear translocation. Thermogenic genes (Ucp1, Ppargc1a, Cidea; p < 0.05) were upregulated, with maximal uncoupling protein 1 (UCP1) induction in iSAT at 400 mg/kg EMO. Conclusions: EMO selectively enhances RSG’s glycemic benefits while attenuating its adipogenic effects in severe obesity by dual PPARγ modulation-inhibiting adipogenic pathways while amplifying thermogenesis. This strategy mitigates RSG’s adverse effects while improving insulin sensitivity, supporting the potential of EMO as a PPARγ adjunct therapy. Full article

Lipid metabolism and lipid-derived signaling together ensure cellular and systemic homeostasis. Their dysregulation causes obesity, type 2 diabetes, cardiovascular disease, NAFLD/MASH, and neurodegeneration throughout life. This review integrates central pathways, such as ACC–FASN-mediated de novo lipogenesis, lipid-droplet lipolysis, and mitochondrial and peroxisomal β-oxidation, and their regulation by insulin–PI3K–Akt, glucagon–cAMP–PKA, SREBPs, PPARs, and AMPK. We emphasize the mechanisms by which bioactive lipids like diacylglycerols, ceramides, eicosanoids, and endocannabinoids serve as second messengers linking nutrient state to insulin signaling, inflammation, and stress response; pathologic accumulation of these species enhances insulin resistance and lipotoxicity. Aging disrupts these axes via diminished catecholamine-stimulated lipolysis, defective fatty-acid oxidation, mitochondrial failure, and adipose depot redistribution, facilitating ectopic fat and postprandial dyslipidemia. We suggest a pathway-to-phenotype paradigm that connects lipid species and tissue environment to clinical phenotypes, allowing for mechanism-to-intervention alignment. Therapeutic avenues range from lipid lowering for atherogenic risk to novel agents targeting ACLY, ACC, FASN, CPT1, and nuclear receptors, with precision lifestyle intervention in diet and exercise. Translation is still heterogeneous because of isoform-dependent effects, safety trade-offs, and inconsistent adherence. We prioritize harmonization of lipidomics with multi-omics for stratifying patients, enriching responders, and bridging gaps between mechanistic understanding and clinical outcome, with focus on age-sensitive prevention and treatment for lipid-mediated metabolic disease. Full article

Introduction/Objectives: Ginsenoside F1, a pharmacologically active saponin derived from Panax ginseng, exhibits diverse bioactivities, but its use is limited because it is difficult to purify and has high production costs. To overcome these challenges, a ginsenoside F1-enriched extract named SGB121 was developed. This study aimed to evaluate the therapeutic efficacy of SGB121 in a high-fat, high-carbohydrate (HFHC) diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mouse model and to elucidate its mechanism of action using F1-based cellular assays. Methods: Male C57BL/6 mice (6 weeks old) were fed an HFHC diet to induce MAFLD and were treated with SGB121. Hepatic lipid accumulation, oxidative stress markers, and metabolic parameters were analyzed. In parallel, human hepatocellular carcinoma (HepG2) cells exposed to free fatty acids (FFAs) were used to assess oxidative stress and lipid accumulation. Mechanistic studies were conducted using purified F1 to examine adenosine monophosphate-activated protein kinase (AMPK) activation and related pathways. Results: SGB121 reduced hepatic lipid accumulation, malondialdehyde (MDA) levels, and fasting insulin while restoring glutathione (GSH) content and improving the homeostasis model assessment of insulin resistance (HOMA-IR) in MAFLD mice. In FFA-treated HepG2 cells, both SGB121 and F1 decreased reactive oxygen species (ROS), suppressed sterol regulatory element-binding protein 1 (SREBP1), enhanced peroxisome proliferator-activated receptor-α (PPARα) and β-oxidation, and restored insulin receptor substrate (IRS)/protein kinase B (Akt)/glucose transporter 2 (GLUT2) signaling. Conclusions: SGB121 ameliorates MAFLD and related metabolic dysfunction through antioxidant, lipid-regulating, and insulin-sensitizing actions, highlighting its potential as a safe multifunctional nutraceutical for MAFLD management. Full article

Background: It is widely accepted that low-grade chronic inflammation in obesity worsens the metabolic state and threatens patients’ lives in a long-term manner. In fact, diet therapy is the first-line treatment in which relevant nutrients such as the omega-3 polyunsaturated fatty acids (ω-3 PUFA) must be adequately consumed to counteract the established inflammation. In particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been identified as agonists of cellular receptors, including the free fatty acid receptor 4 (FFAR4), which regulates anti-inflammatory pathways associated with enhanced insulin sensitivity. However, the expression and activation of this receptor in peripheral blood mononuclear cells (PBMC) remains poorly investigated in humans. Objective: This study aimed to evaluate the effect of a diet supplemented with marine ω-3 PUFA on FFAR4 receptor activation and inflammatory markers in peripheral blood mononuclear cells in subjects with obesity. Methodology: A double-blind, randomized clinical trial (NCT05068557) was conducted over two months (eight weeks) in 55 obese individuals (aged 25–59 years). Participants were randomly assigned to one of two groups: an active placebo group (1.6 g/day of alpha-linolenic acid) or a marine ω-3 group (1080 mg of EPA and 720 mg of DHA). Both groups followed a dietary regimen with progressive calorie restriction (−200 kcal/day during weeks 0–4 and −400 kcal/day during weeks 4–8) in addition to supplementation. Results: Following the intervention, both groups showed significant improvements in body composition and biochemical parameters. Supplementation with EPA and DHA enhanced FFAR4 activation at the end of the intervention. Moreover, there was a reduction in the expression of JNK and IKKβ genes, as well as in serum levels of TNF-α, IL-6, and IL-18. In contrast, IL-10 levels increased significantly both within and between the groups. Conclusions: Marine ω-3 PUFA supplementation, in the context of a dietary intervention, promotes FFAR4 activation, thereby contributing to the modulation of the inflammatory response in human PBMC. Full article

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase that plays a central role in extracellular matrix (ECM) remodeling, angiogenesis, immune cell trafficking, and cytokine activation. Dysregulated MMP-9 activity has been implicated in the pathogenesis of diverse conditions, including atherosclerosis, aneurysm formation, chronic obstructive pulmonary disease (COPD), asthma, neurodegeneration, and malignancy. Although broad-spectrum synthetic MMP inhibitors were initially developed as therapeutic agents, clinical trials failed due to lack of selectivity, poor tolerability, and impairment with physiological tissue repair. This outcome has shifted attention toward indirect pharmacological modulation of MMP-9 using drugs that are already approved for other indications. In this paper, we review the evidence supporting MMP-9 modulation by established therapeutics and adjunctive strategies. Cardiometabolic agents such as statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), metformin, and pioglitazone reduce MMP-9 expression and enzymatic activity, contributing to vascular protection, improved insulin sensitivity, and attenuation of aneurysm progression. Anti-inflammatory and respiratory drugs, including glucocorticoids, phosphodiesterase-4 (PDE4) inhibitors, macrolide antibiotics, montelukast, and nonsteroidal anti-inflammatory drugs (NSAIDs), suppress MMP-9-driven airway inflammation and pathological tissue remodeling in asthma, COPD, and acute lung injury. Tetracycline derivatives, particularly sub-antimicrobial dose doxycycline, directly inhibit MMP-9 activity and are clinically validated in the treatment of periodontal disease and vascular remodeling. Hormone-related therapies such as rapamycin, estradiol, and tamoxifen exert tissue- and disease-specific effects on MMP-9 within endocrine and oncologic pathways. In parallel, nutritional interventions—most notably omega-3 polyunsaturated fatty acids and antioxidant vitamins—provide adjunctive strategies for mitigating MMP-9 activity in chronic inflammatory states. Taken together, these findings position MMP-9 as a modifiable and clinically relevant therapeutic target. The systematic integration of approved pharmacologic agents with lifestyle and nutritional interventions into disease-specific treatment paradigms may facilitate safer, context-specific modulation of MMP-9 activity and unveil novel opportunities for therapeutic repurposing. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance, progressive β-cell dysfunction, and persistent hyperglycemia. While GLP-1 receptor agonists have revolutionized the management of T2D by improving glycemic control and reducing body weight, their insulinotropic effects increase the workload on pancreatic β-cells, which may hasten β-cell decline in certain individuals. Peptide YY (PYY), a gut-derived hormone secreted alongside glucagon-like peptide-1 (GLP-1) from L-cells, presents a unique and complementary therapeutic approach. In contrast to GLP-1, PYY does not directly induce insulin release but confers metabolic advantages by suppressing appetite through Y2 receptor pathways, enhancing insulin sensitivity via peripheral Y1/Y4 receptors, and slowing gastric emptying to minimize postprandial glucose surges. Notably, recent research suggests PYY supports the preservation and restoration of pancreatic islets by improving their structure and function without increasing the secretory demand. PYY levels are substantially increased after bariatric surgery, where it plays a pivotal role in weight-loss-independent improvements in glycemic regulation and islet hormone dynamics. These attributes position PYY as a strong candidate for use in combination with GLP-1 analogs, especially in individuals with advanced β-cell impairment or those who respond inadequately to GLP-1 monotherapy. This review discusses PYY’s physiological functions, mechanistic actions, and therapeutic opportunities in T2D, highlighting its potential as a valuable adjunct or alternative in gut-hormone-oriented treatment strategies. Full article

Obesity has become increasingly prevalent, impacting up to 41 percent of women in the United States between 2021 and 2023, leading to a rise in short- and long-term adverse health events. With regard to reproductive health, obesity is associated with menstrual irregularities, poorer reproductive and obstetric outcomes, and an increased risk of endometrial cancer. Obesity can lead to hyperandrogenism and anovulation, which is consistent with polycystic ovarian syndrome (PCOS). The prevalence of obesity is higher in women with PCOS compared to the general population. Although PCOS increases the risk of obesity, not all women with PCOS are obese, and not all women with obesity develop PCOS. However, individuals with both PCOS and obesity often present with a more extreme phenotype, with increased risk of chronic anovulation, glucose intolerance, dyslipidemia, metabolic syndrome, vitamin D deficiency, and decreased fertility. Therefore, weight loss is the backbone of patient management in women with obesity and PCOS, and is associated with improvement in cardiovascular risk, as well as improvement in menstrual cycles, ovulation, and pregnancy rate. Lifestyle modifications are often the first-line intervention, with data supporting low glycemic index diets, including ketogenic and DASH diets, along with vitamin D supplementation to improve hormonal imbalances, insulin sensitivity, and menstrual cycles in those who do not have normal vitamin D levels. Furthermore, with the recent widespread adoption of newer FDA-approved medications for weight loss, including GLP-1 (glucagon-like peptide) receptor agonists, new data are emerging regarding the impact of PCOS and longer-term cardiovascular risk. The treatment of PCOS requires a personalized approach, with consideration of a patient’s reproductive goals, tolerance of risk, and acceptance of behavioral and financial commitments, as well as consideration of other medical comorbidities. This narrative review explores different weight loss treatment options, comparing lifestyle modifications (including diet, physical activity, mindfulness, stress management, and cognitive behavioral training), weight loss medications, and bariatric surgery and their respective impact on PCOS to assist clinicians in guiding their patients towards an effective, individualized intervention. Full article

Obesity is a multifactorial metabolic disease characterized by chronic low-grade inflammation, extracellular matrix (ECM) dysfunction, and systemic metabolic dysregulation. Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are key regulators of ECM remodeling and inflammation in obesity. This narrative review aimed to synthesize and critically discuss current evidence on the effects of bariatric surgery and pharmacological therapies, including GLP-1 and dual GLP-1/GIP receptor agonists, on MMP activity and metabolic outcomes. Literature from PubMed and Scopus and Web of Science (2015–2024) was analyzed, focusing on studies evaluating MMPs, inflammation, and metabolic parameters. Bariatric surgery consistently reduces MMP-9 levels and normalizes MMP-2 activity, contributing to improved ECM integrity, reduced inflammation, and enhanced insulin sensitivity. Pharmacological therapies achieve substantial weight loss and glycemic control, but evidence regarding their direct effects on MMP activity remains limited. This review highlights bariatric surgery as the most effective strategy for modulating obesity-related MMP dysregulation and emphasizes the need for further research into the mechanistic effects of modern pharmacotherapy on ECM remodeling. Full article

Obesity-associated adipose tissue dysfunction represents a key driver of metabolic disorders, including type 2 diabetes, cardiovascular diseases, and fatty liver disease. Emerging evidence highlights the vitamin D/vitamin D receptor (VD/VDR) axis as an important regulator of adipose tissue homeostasis. Beyond its classical role in mineral metabolism, vitamin D influences adipogenesis, inflammation, and insulin sensitivity, thereby modulating systemic metabolic health. In this review, we summarize the current understanding of the VD/VDR axis in adipose tissue biology, from molecular pathways controlling lipid turnover and immune responses to experimental and clinical evidence linking vitamin D status with obesity-related complications. We also discuss the role of genetic variability and tissue-specific VDR signaling in shaping metabolic outcomes. While results from supplementation trials remain inconsistent, maintaining adequate vitamin D levels appears crucial for the prevention of adipose tissue dysfunction and its cardiometabolic consequences. Future studies are warranted to define optimal strategies for harnessing the VD/VDR axis in therapeutic approaches to obesity and metabolic disease. Full article

Diabetes mellitus is a chronic metabolic disorder that facilitates the formation of advanced glycation end products (AGEs), which contribute to oxidative stress, inflammation, and vascular damage, causing complications including nephropathy, neuropathy, and atherosclerosis. AGEs are primarily synthesized through the Maillard reaction, alongside various signaling pathways. Activation of the receptor for AGE (RAGE) triggers inflammatory signaling pathway cascades, exacerbating tissue damage. Phenolic compounds found in plant-based foods, such as quercetin and resveratrol, have shown promise in counteracting AGE-related complications through their antioxidant and anti-inflammatory effects that inhibit AGE formation, reduce oxidative stress, and modulate RAGE signaling, while also enhancing insulin sensitivity and improving glucose homeostasis. Indeed, quercetin can help prevent AGE accumulation and reduce diabetic nephropathy, while resveratrol activates the SIRT1 pathway, improving insulin sensitivity. This review examines the mechanisms through which phenolic compounds mitigate AGE-induced diabetic complications, using computational, in vitro, preclinical, and clinical evidence. This review also explores the synergistic effects of these compounds with conventional antidiabetic drugs, addresses bioavailability challenges, and suggests future research directions. Overall, this review offers a comprehensive understanding of the role of phenolic compounds in managing diabetes, underscoring their potential as complementary agents in diabetes therapy and developing more effective natural treatments. Full article

The parallel global increase in obesity and Alzheimer’s disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine–inflammation–metabolism axis in obesity-associated AD. Full article

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article