sphingosine-1-phosphate and Diabetes-Mellitus--Type-2

Sphingosine 1-phosphate (S1P) is a bioactive metabolite of sphingomyelin. S1P activates a series of signaling cascades by acting on its receptors S1PR1-3 on endothelial cells (ECs), which plays an important role in endothelial barrier maintenance, anti-inflammation, antioxidant and angiogenesis, and thus is considered as a potential therapeutic biomarker for ischemic stroke, sepsis, idiopathic pulmonary fibrosis, cancers, type 2 diabetes and cardiovascular diseases. We presently review the levels of S1P in those vascular and vascular-related diseases. Plasma S1P levels were reduced in various inflammation-related diseases such as atherosclerosis and sepsis, but were increased in other diseases including type 2 diabetes, neurodegeneration, cerebrovascular damages such as acute ischemic stroke, Alzheimer's disease, vascular dementia, angina, heart failure, idiopathic pulmonary fibrosis, community-acquired pneumonia, and hepatocellular carcinoma. Then, we highlighted the molecular mechanism by which S1P regulated EC biology including vascular development and angiogenesis, inflammation, permeability, and production of reactive oxygen species (ROS), nitric oxide (NO) and hydrogen sulfide (H₂S), which might provide new ways for exploring the pathogenesis and implementing individualized therapy strategies for those diseases.

Topics: Diabetes Mellitus, Type 2; Endothelial Cells; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Ischemic Stroke; Lysophospholipids; Sepsis; Sphingosine

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite. The past decade has witnessed exponential growth in the field of S1P research, partly attributed to drugs targeting its receptors or kinases. Accumulating evidence indicates that changes in the S1P axis (i.e., S1P production, transport, and receptors) may modify metabolism and eventually mediate metabolic diseases. Dysfunction of the mitochondria on a master monitor of cellular metabolism is considered the leading cause of metabolic diseases, with aberrations typically induced by abnormal biogenesis, respiratory chain complex disorders, reactive oxygen species overproduction, calcium deposition, and mitophagy impairment. Accordingly, we discuss decades of investigation into changes in the S1P axis and how it controls mitochondrial function. Furthermore, we summarize recent scientific advances in disorders associated with the S1P axis and their involvement in the pathogenesis of metabolic diseases in humans, including type 2 diabetes mellitus and cardiovascular disease, from the perspective of mitochondrial function. Finally, we review potential challenges and prospects for S1P axis application to the regulation of mitochondrial function and metabolic diseases; these data may provide theoretical guidance for the treatment of metabolic diseases.

Topics: Diabetes Mellitus, Type 2; Humans; Lysophospholipids; Metabolic Diseases; Mitochondria; Sphingosine

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with multiple functions conveyed by the activation of cell surface receptors and/or intracellular mediators. A growing body of evidence indicates its important role in pancreatic insulin-secreting beta-cells that are necessary for maintenance of glucose homeostasis. The dysfunction and/or death of beta-cells lead to diabetes development. Diabetes is a serious public health burden with incidence growing rapidly in recent decades. The two major types of diabetes are the autoimmune-mediated type 1 diabetes (T1DM) and the metabolic stress-related type 2 diabetes (T2DM). Despite many differences in the development, both types of diabetes are characterized by chronic hyperglycemia and inflammation. The inflammatory component of diabetes remains under-characterized. Recent years have brought new insights into the possible mechanism involved in the increased inflammatory response, suggesting that environmental factors such as a westernized diet may participate in this process. Dietary lipids, particularly palmitate, are substrates for the biosynthesis of bioactive sphingolipids. Disturbed serum sphingolipid profiles were observed in both T1DM and T2DM patients. Many polymorphisms were identified in genes encoding enzymes of the sphingolipid pathway, including sphingosine kinase 2 (SK2), the S1P generating enzyme which is highly expressed in beta-cells. Proinflammatory cytokines and free fatty acids have been shown to modulate the expression and activity of S1P-generating and S1P-catabolizing enzymes. In this review, the similarities and differences in the action of extracellular and intracellular S1P in beta-cells exposed to cytokines or free fatty acids will be identified and the outlook for future research will be discussed.

Topics: Animals; Cytokines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids; Humans; Insulin-Secreting Cells; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Polymorphism, Single Nucleotide; Sphingosine

Insulin is the main anabolic hormone secreted by β-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic β-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D.

Topics: Adipocytes; Animals; Diabetes Mellitus, Type 2; Hepatocytes; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lysophospholipids; Obesity; Sphingosine

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

Topics: Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insulin; Lysophospholipids; Mammals; Obesity; Sphingosine

Metabolic disorders are associated with an increased risk of cardiovascular disease (CVD), and are commonly characterized by a low plasma level of high-density lipoprotein cholesterol (HDL-C). Although cholesterol lowering medications reduce CVD risk in these patients, they often remain at increased risk of CVD. Therapeutic strategies that raise HDL-C levels and improve HDL function are a potential treatment option for reducing residual CVD risk in these individuals. Over the past decade, understanding of the metabolism and cardioprotective functions of HDLs has improved, with preclinical and clinical studies both indicating that the ability of HDLs to mediate reverse cholesterol transport, inhibit inflammation and reduce oxidation is impaired in metabolic disorders. These cardioprotective effects of HDLs are supported by the outcomes of epidemiological, cell and animal studies, but have not been confirmed in several recent clinical outcome trials of HDL-raising agents. Recent studies suggest that HDL function may be clinically more important than plasma levels of HDL-C. However, at least some of the cardioprotective functions of HDLs are lost in acute coronary syndrome and stable coronary artery disease patients. HDL dysfunction is also associated with metabolic abnormalities. This review is concerned with the impact of metabolic abnormalities, including dyslipidemia, obesity and Type 2 diabetes, on the metabolism and cardioprotective functions of HDLs.

Topics: Animals; Anthropometry; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hyperglycemia; Inflammation; Insulin Resistance; Lipoproteins, HDL; Lysophospholipids; Metabolic Syndrome; Obesity; Oxidative Stress; Sphingosine

Aging is defined as the progressive deterioration of physiological function with age. Incidence of many pathologies increases with age, including neurological and cardiovascular diseases and cancer. Aging tissues become less adaptable and renewable, and cells undergo senescence, a process by which they "irreversibly" stop dividing. Senescence has been shown to serve as a tumor suppression mechanism with clear desirable effects. However, senescence also has deleterious consequences, especially for cardiovascular, metabolic, and immune systems. Sphingolipids are a major class of lipids that regulate cell biology, owing to their structural and bioactive properties and diversity. Their involvement in the regulation of aging and senescence has been demonstrated and studied in multiple organisms and cell types, especially that of ceramide and sphingosine-1-phosphate; ceramide induces cellular senescence and sphingosine-1-phosphate delays it. These discoveries could be very useful in the future to understand aging mechanisms and improve therapeutic interventions.

Topics: Aging; Alzheimer Disease; Animals; Atherosclerosis; Biomarkers; Cellular Senescence; Ceramides; Diabetes Mellitus, Type 2; Humans; Immune System; Lysophospholipids; Metabolic Networks and Pathways; Models, Biological; Neoplasms; Sphingolipids; Sphingosine

Insulin resistance is a complex metabolic disorder in which insulin-sensitive tissues fail to respond to the physiological action of insulin. There is a strong correlation of insulin resistance and the development of type 2 diabetes both reaching epidemic proportions. Dysfunctional lipid metabolism is a hallmark of insulin resistance and a risk factor for several cardiovascular and metabolic disorders. Numerous studies in humans and rodents have shown that insulin resistance is associated with elevations of non-esterified fatty acids (NEFA) in the plasma. Moreover, bioactive lipid intermediates such as diacylglycerol (DAG) and ceramides appear to accumulate in response to NEFA, which may interact with insulin signaling. However, recent work has also indicated that sphingosine 1-phosphate (S1P), a breakdown product of ceramide, modulate insulin signaling in different cell types. In this review, we summarize the current state of knowledge about S1P and insulin signaling in insulin sensitive cells. A specific focus is put on the action of S1P on hepatocytes, pancreatic β-cells and skeletal muscle cells. In particular, modulation of S1P-signaling can be considered as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Topics: Ceramides; Diabetes Mellitus, Type 2; Diglycerides; Fatty Acids, Nonesterified; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lysophospholipids; Muscle, Skeletal; Signal Transduction; Sphingosine

In the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure. Clinical studies have clearly shown a correlation between the accumulation of triglycerides and heart dysfunction. In this process, it is likely that there are also changes in the contents of sphingolipids. Sphingolipids are important structural and signaling molecules. One specific sphingolipid, ceramide, may cause cardiac dysfunction, whereas another, sphingosine 1-phosphate, is cardioprotective. In this review, the authors focus on the role of sphingolipids in the development and prevention of cardiac failure.

Topics: Apoptosis; Ceramides; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Lipid Metabolism; Lysophospholipids; Myocytes, Cardiac; Sphingolipids; Sphingosine

In recent years, the role of sphingolipids in physiology and pathophysiology of the heart attracted much attention. Ceramide was found to be involved in the pathogenesis of cardiac dysfunction in animal models of ischemia/reperfusion injury, Type 2 diabetes and lipotoxic cardiomyopathy. On the other hand, another member of this lipid family, namely sphingosine-1-phosphate, has been shown to possess potent cardioprotective properties. This chapter provides a review of the role of ceramide and other bioactive sphingolipids in physiology and pathophysiology of the heart. We describe the role of PPARs and exercise in regulation of myocardial sphingolipid metabolism. We also summarize the present state of knowledge on the involvement of ceramide and sphingosine-1-phosphate in the development and prevention of ischemia/reperfusion injury of the heart. In the last section of this chapter we discuss the evidence for a role of ceramide in myocardial lipotoxicity.

Topics: Animals; Cardiomyopathies; Ceramides; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Exercise; Heart Failure; Humans; Lysophospholipids; Mice; Myocardial Reperfusion Injury; Myocardium; Obesity; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Zucker; Receptors, Lysosphingolipid; Second Messenger Systems; Sphingolipids; Sphingosine

Sphingolipids have emerged as key signaling molecules involved in the regulation of a variety of cellular functions including cell growth and differentiation, proliferation and apoptotic cell death. Sphingolipids in blood constitute part of the circulating lipoprotein particles (HDL, LDL and VLDL), carried by serum albumin and also present in blood cells and platelets. Recent lipidomic and proteomic studies of plasma lipoproteins have provided intriguing data concerning the protein and lipid composition of lipoproteins in the context of disease. Sphingolipids have been implicated in several diseases such as cancer, obesity, atherosclerosis and sphingolipidoses; however, efforts addressing blood sphingolipidomics are still limited. The development of methods to determine levels of circulating bioactive sphingolipids in humans and validation of these methods to be a routine clinical laboratory test could be a pioneering approach to diagnose disease in the population. This approach would probably evolve to be analogous in implication to determining "good" and "bad" cholesterol and triglyceride levels in lipoprotein classes.

Topics: Animals; Apoptosis; Atherosclerosis; Blood Cells; Coronary Disease; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Lipid Metabolism, Inborn Errors; Lipoproteins; Lysophospholipids; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingosine

apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14,

Topics: Apolipoproteins M; Biomarkers; Black or African American; Diabetes Mellitus, Type 2; Disease-Free Survival; Female; Humans; Lysophospholipids; Male; Middle Aged; Sphingosine; Survival Rate

Herba Wanlenbergiae, named 'Lanhuashen' (LHS) in Chinese, is derived from the dried herba of Wahlenbergia marginata (Thunb.) A.DC. It is an abundant resource that has been used in traditional Chinese medicine (TCM) for over 600 years. LHS has the effects of enriching consumptive disease and relieving deficient heat, consistent with the therapy for type 2 diabetes mellitus (T2DM) in TCM. As the basic remedy of Yulan Jiangtang capsules, a listed Chinese medicine specifically for treating T2DM, LHS is a potential candidate for an anti-T2DM drug. However, due to the lack of pharmacodynamic studies and chemical component analysis, the application and development of LHS as a treatment for T2DM have been hindered.. To evaluate the regulation of the disorder of glucolipid metabolism using LHS extracts and its therapeutic potential in T2DM.. Chemical components in LHS extracts were analysed using UPLC-Q Exactive-Orbitrap-MS. Subsequently, high sucrose diet (HSD)-induced Drosophila melanogaster were used as suitable models for T2DM in vivo. Behavioural and biochemical tests were performed to evaluate the regulation of the disorder of glucolipid metabolism using LHS in T2DM flies. Furthermore, integrative metabolomic and transcriptomic analysis was applied to reveal the specific effects of LHS extracts on metabolites and genes. Meanwhile, bioinformatic analysis was carried out to predict the targeted transcription factors (TFs) and potentially effective components of LHS extracts.. We redefined the chemical profile of LHS with 76 identified chemical components, including 65 chemical components for the first time. As indicated by decreased trehalose, glucose and triglyceride levels and increased total protein levels, LHS extracts were perceived to alleviate the disorder of glucolipid metabolism in HSD-induced T2DM fruit flies. Integrative metabolomic and transcriptomic analysis revealed that LHS extracts eliminated the accumulation of sphingolipids and subsequently stimulated the positive cross-regulation mediated by the sphingosine 1-phosphate (S1P) axis, resulting in the activation of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signalling pathway and inhibition of lysosome-mediated apoptosis. Bioinformatic analysis revealed that the upstream TFs, transcriptional enhancer factor TEF-5 (TEAD3) and peroxisome proliferator-activated receptor alpha (PPARA), were the potential targets of atractylenolide III, dihydrokaempferol and syringaldehyde, the potentially effective components of LHS extracts. Therefore, this TF network was plausibly the basis for the efficacy.. LHS extracts broadly modulated TF-dependent gene expression and subsequently stimulated the positive cross-regulation mediated by the S1P axis to ameliorate the disorder of glucolipid metabolism. Our study provides critical evidence considering LHS as a potential drug candidate for T2DM, inspiring the discovery and development of innovative therapeutic agents based on the cross-regulation mediated by the S1P axis for treating T2DM and related complications.

Topics: Animals; Diabetes Mellitus, Type 2; Diet; Drosophila melanogaster; Glucose

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through 5 cognate G protein-coupled receptors (S1P1-S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and an S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates, adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist, SEW-2871, VPC23019, or their combination acts on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased messenger RNA levels of tumor necrosis factor-α and CD11c, whereas they increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor γ and its regulated genes. By contrast, VPC23019 did not cause any such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Glucose Intolerance; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine-1-phosphate (S1P) is emerging as a crucial sphingolipid modulating neuroinflammation and cognition. S1P levels in the brain have been found to be decreased in cognitive impairment. S1P lyase (S1PL) is the key enzyme in metabolizing S1P and has been implicated in neuroinflammation. This study evaluated the effect of S1PL inhibition on cognition in type 2 diabetic mice. Fingolimod (0.5 mg/kg and 1 mg/kg) rescued cognition in high-fat diet and streptozotocin-induced diabetic mice, as evident in the Y maze and passive avoidance test. We further evaluated the effect of fingolimod on the activation of microglia in the pre-frontal cortex (PFC) and hippocampus of diabetic mice. Our study revealed that fingolimod inhibited S1PL and promoted anti-inflammatory microglia in both PFC and hippocampus of diabetic mice as it increased Ym-1 and arginase-1. The levels of p53 and apoptotic proteins (Bax and caspase-3) were elevated in the PFC and hippocampus of type 2 diabetic mice which fingolimod reversed. The underlying mechanism promoting anti-inflammatory microglial phenotype was also explored in this study. TIGAR, TP53-associated glycolysis and apoptosis regulator, is known to foster anti-inflammatory microglia and was found to be downregulated in the brain of type 2 diabetic mice. S1PL inhibition decreased the levels of p53 and promoted TIGAR, thereby increasing anti-inflammatory microglial phenotype and inhibiting apoptosis in the brain of diabetic mice. Our study reveals that S1PL inhibition could be beneficial in mitigating cognitive deficits in diabetic mice.

Topics: Animals; Apoptosis Regulatory Proteins; Cognition; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fingolimod Hydrochloride; Mice; Microglia; Neuroinflammatory Diseases; Phosphates; Phosphoric Monoester Hydrolases; Sphingosine; Tumor Suppressor Protein p53

Obesity is considered a risk factor for type 2 diabetes mellitus, which has become one of the most important health problems, and is also linked with memory and executive function decline. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates cell death/survival and the inflammatory response via its specific receptors (S1PRs). Since the role of S1P and S1PRs in obesity is rather obscure, we examined the effect of fingolimod (an S1PR modulator) on the expression profile of genes encoding S1PRs, sphingosine kinase 1 (Sphk1), proteins engaged in amyloid-beta (Aβ) generation (ADAM10, BACE1, PSEN2), GSK3β, proapoptotic Bax, and proinflammatory cytokines in the cortex and hippocampus of obese/prediabetic mouse brains. In addition, we observed behavioral changes. Our results revealed significantly elevated mRNA levels of Bace1, Psen2, Gsk3b, Sphk1, Bax, and proinflammatory cytokines, which were accompanied by downregulation of S1pr1 and sirtuin 1 in obese mice. Moreover, locomotor activity, spatially guided exploratory behavior, and object recognition were impaired. Simultaneously, fingolimod reversed alterations in the expressions of the cytokines, Bace1, Psen2, and Gsk3b that occurred in the brain, elevated S1pr3 mRNA levels, restored normal cognition-related behavior patterns, and exerted anxiolytic effects. The improvement in episodic and recognition memory observed in this animal model of obesity may suggest a beneficial effect of fingolimod on central nervous system function.

Topics: Amyloid Precursor Protein Secretases; Animals; Anxiety; Aspartic Acid Endopeptidases; bcl-2-Associated X Protein; Cytokines; Diabetes Mellitus, Type 2; Fingolimod Hydrochloride; Gene Expression; Inflammation; Mice; Mice, Obese; Obesity; Receptors, Lysosphingolipid; RNA, Messenger

The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. There is increasing evidence that GDM is a heterogeneous disease with different subtypes. An important question in this context is whether impaired glucose tolerance (IGT), which is a typical feature of the disease, may already be present before pregnancy and manifestation of the disease. The latter type resembles in its clinical manifestation prediabetes that has not yet manifested as type 2 diabetes (T2DM). Altered lipid metabolism plays a crucial role in the disorder's pathophysiology. The aim was to investigate the role of lipids which are relevant in diabetes-like phenotypes in these both models with different time of initial onset of IGT.. Two rodent models reflecting different characteristics of human GDM were used to characterize changes in lipid metabolism occurring during gestation. Since the New Zealand obese (NZO)-mice already exhibit IGT before and during gestation, they served as a subtype model for GDM with preexisting IGT (preIGT) and were compared with C57BL/6 N mice with transient IGT acquired during gestation (aqIGT). While the latter model does not develop manifest diabetes even under metabolic stress conditions, the NZO mouse is prone to severe disease progression later in life. Metabolically healthy Naval Medical Research Institute (NMRI) mice served as controls.. In contrast to the aqIGT model, preIGT mice showed hyperlipidemia during gestation with elevated free fatty acids (FFA), triglycerides (TG), and increased atherogenic index. Interestingly, sphingomyelin (SM) concentrations in the liver decreased during gestation concomitantly with an increase in the sphingosine-1-phosphate (S1P) concentration in plasma. Further, preIGT mice showed impaired hepatic weight adjustment and alterations in hepatic FFA metabolism during gestation. This was accompanied by decreased expression of peroxisome proliferator-activated receptor alpha (PPARα) and lack of translocation of fatty acid translocase (FAT/CD36) to the hepatocellular plasma membrane.. The preIGT model showed impaired lipid metabolism both in plasma and liver, as well as features of insulin resistance consistent with increased S1P concentrations, and in these characteristics, the preIGT model differs from the common GDM subtype with aqIGT. Thus, concomitantly elevated plasma FFA and S1P concentrations, in addition to general shifts in sphingolipid fractions, could be an interesting signal that the metabolic disorder existed before gestation and that future pregnancies require more intensive monitoring to avoid complications. This graphical abstract was created with BioRender.com .

Topics: Animals; Diabetes Mellitus, Type 2; Diabetes, Gestational; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Lipid Metabolism; Lysophospholipids; Mice; Mice, Inbred C57BL; PPAR alpha; Pregnancy; Sphingolipids; Sphingomyelins; Sphingosine; Triglycerides

Early diagnosis of diabetic kidney disease (DKD) has long been a complex problem. This study aimed to analyze the metabolomic characteristics of plasma extracellular vesicles (EVs) at different stages of DKD in order to evaluate the metabolites of plasma EVs and select new biomarkers for the early diagnosis of DKD.. A total of 78 plasma samples were collected, including samples from 20 healthy controls, 20 patients with type 2 diabetes mellitus (T2DM), 18 patients with DKD stage III, and 20 patients with DKD stage IV. In addition, EVs were isolated for metabolomics analysis.. The results identified differences in EV metabolomic characteristics in DKD patients at different stages, as well as significant differences in EV metabolomics between T2DM patients without DKD and patients with DKD. Ten Significantly differential metabolites were associated with the occurrence and progression of DKD. Uracil, LPC(O-18:1/0:0), sphingosine 1-phosphate, and 4-acetamidobutyric acid were identified as potential early biomarkers for DKD, showing excellent predictive performance.. Uracil, LPC(O-18:1/0:0), sphingosine 1-phosphate, and 4-acetamidobutyric acid exhibited potential as suitable biomarkers for early DKD diagnosis. Unexpectedly, combining these four candidate metabolites resulted in enhanced predictive ability for DKD.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Extracellular Vesicles; Humans; Uracil

The pathogenesis of type 2 diabetes mellitus (T2DM) is very complicated. The currently well-accepted etiology is the "Ominous Octet" theory proposed by Professor Defronzo. Since presently used drugs for T2DM have limitations and harmful side effects, studies regarding alternative treatments are being conducted. Analyzing the pharmacological mechanism of biomolecules in view of pathogenesis is an effective way to assess new drugs. Sphingosine 1 phosphate (S1P), an endogenous lipid substance in the human body, has attracted increasing attention in the T2DM research field. This article reviews recent study updates of S1P, summarizing its effects on T2DM with respect to pathogenesis, promoting

Topics: Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Liver; Lysophospholipids; Signal Transduction; Sphingosine

Beta cell failure is one of the most important features of type 2 diabetes mellitus (T2DM). High-density lipoprotein (HDL) has been proposed to improve β-cell function. However, the mechanisms involved in this process are still poorly understood. The aim of this study was to investigate the contribution of sphingosine-1-phosphate (S1P) in the impact of HDL treatment on insulin secretion by pancreatic β-cells and to determine its mechanisms. Primary cultures of β-cells isolated from rat were treated with or without HDL in the presence or absence of S1P pathway inhibitors and insulin secretion response was analyzed. The S1P content of HDL (HDL-S1P) isolated from T2DM patients was analyzed and correlated to the HDL-induced insulin secretion. The expression of genes involved in the biosynthesis of the insulin was also evaluated. HDL as well as S1P treatment enhanced glucose-stimulated insulin secretion (GSIS). In HDL isolated from T2DM patients, while HDL-S1P was strongly correlated to its pro-secretory capacity (r = 0.633, p = 0.005), HDL-cholesterol and apolipoprotein AI levels were not. HDL-induced GSIS was blocked by the S1P1/3 antagonist but not by the S1P2 antagonist, and was also accompanied by increased intracellular S1P in β-cells. We also observed that HDL improved GSIS without significant changes in expression levels of insulin biosynthesis genes. Our present study highlights the importance HDL-S1P in GSIS in T2DM patients and demonstrates that HDL induces insulin secretion by a process involving both intra- and extra-cellular sources of S1P independently of an effect on insulin biosynthesis genes.

Topics: Aged; Animals; Diabetes Mellitus, Type 2; Female; Humans; Insulin Secretion; Insulin-Secreting Cells; Lipoproteins, HDL; Lysophospholipids; Male; Middle Aged; Primary Cell Culture; Rats; Sphingosine

Subjects with low serum HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the current study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by improving the mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the development of insulin resistance.

Topics: Adult; Animals; Apolipoproteins M; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fats; Female; Gene Expression Regulation; Glycated Hemoglobin; Hep G2 Cells; Humans; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Lysophospholipids; Male; Metabolome; Mice; Mice, Knockout; Middle Aged; Sphingosine

The aim of this study was to test the hypothesis that plasma sphingosine 1-phosphate (S1P) levels are associated with the risk of cardiovascular autonomic neuropathy (CAN) in type 2 diabetes patients. This cross-sectional study included 287 individuals with type 2 diabetes. CAN was evaluated using cardiovascular reflex tests. Logistic regression analyses were conducted to assess the relationship between plasma S1P levels and CAN. Plasma S1P concentrations were significantly lower in individuals with CAN than in those without CAN. There was a significant interaction between plasma S1P levels and sex with respect to CAN (p for interaction = 0.003). When stratified by sex, the association between plasma S1P levels and CAN exhibited a sex difference; in multivariable analysis, plasma S1P levels were significantly associated with CAN in women (odds ratio per standard deviation increase in the log-transformed value, 0.40; 95% confidence interval, 0.23-0.70, p = 0.001). However, there was no significant association between plasma S1P and CAN in men. Plasma S1P concentrations were inversely associated with CAN only in women with type 2 diabetes.

Topics: Adult; Aged; Autonomic Nervous System; Cardiovascular System; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Lysophospholipids; Male; Middle Aged; Nervous System Diseases; Odds Ratio; Prevalence; Regression Analysis; Risk Factors; Sphingosine

Roux-en-Y gastric bypass (RYGB) is associated with remission of type 2 diabetes. However, the cellular and molecular mechanisms remain unknown. We hypothesized that RYGB would increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (SIRT1), AMPK/pAMPK, and citrate synthase (CS) protein expression and decrease insulin resistance and these changes would be mediated by sphingolipids, including ceramides and the sphingolipid metabolite sphingosine-1 phosphate (S1P).. Male ZDF rats were randomized to RYGB (n = 7) or sham surgery (n = 7) and harvested after 28 days. Total tissue ceramide, ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1), and S1P were quantified in the white gastrocnemius muscle using LC-ESI-MS/MS after separation with HPLC. Total SIRT1, AMPK, PGC-1α, and CS protein expression were measured by Western blot.. Body weight, fasting glucose, insulin, and HOMA-IR decreased significantly after RYGB compared with sham control. These changes were paralleled by lower total ceramide (483.7 ± 32.3 vs. 280.1 ± 38.8 nmol/g wwt), C18:0 ceramide subspecies (P < 0.05), higher S1P (0.83 ± 0.05 vs. 1.54 ± 0.21 nmol/g wwt, P < 0.05), and a lower ceramide/S1P ratio (P < 0.05) in the RYGB versus sham group. AMPK, pAMPK, SIRT1, PGC-1α, and CS protein expression was also higher after RYGB (P < 0.05). The ceramide/S1P ratio correlated with weight loss (r = 0.48, P = 0.08), insulin resistance (r = 0.61, P = 0.02), PGC-1α (r = - 0.51, P < 0.06), CS (r = - 0.63, P = 0.01), and SIRT1 (r = - 0.54, P < 0.04).. Our data demonstrate that sphingolipid balance, and increased AMPK, SIRT1, PGC-1α, and CS protein expression are part of the mechanism that contributes to the remission of diabetes after RYGB surgery.

Topics: AMP-Activated Protein Kinases; Animals; Ceramides; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastric Bypass; Lysophospholipids; Male; Muscle, Skeletal; Obesity, Morbid; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Zucker; Signal Transduction; Sirtuin 1; Sphingosine; Tandem Mass Spectrometry; Up-Regulation

One of the hallmarks of diabetes is impaired endothelial function. Previous studies showed that HDL can exert protective effects on endothelium stimulating NO production and protecting from inflammation and suggested that HDL in obese people with diabetes and dyslipidemia may have lower endothelial protective function. We aimed to investigate whether type 2 diabetes impairs HDL endothelium protective functions in people with otherwise normal lipid profile.. In a case-control study (n = 41 per group) nested in the Cooper Center Longitudinal Study we tested the ability of HDL to protect endothelium by stimulating endothelial nitric oxide synthase activity and suppressing NFκB-mediated inflammatory response in endothelial cells. In parallel we measured HDL protein composition, sphinogosine-1-phosphate and P-selectin.. Despite similar levels of plasma HDL-C the HDL in individuals with type 2 diabetes lost almost 40% of its ability to stimulate eNOS activity (P<0.001) and 20% of its ability to suppress TNFα-dependent NFκB-mediated inflammatory response in endothelial cells (P<0.001) compared to non-T2D controls despite similar BMI and lipid profile (HDL-C, LDL-C, TC, TG). Significantly, the ability of HDL to stimulate eNOS activity was negatively associated with plasma levels of P-selectin, an established marker of endothelial dysfunction (r = -0.32, P<0.001). Furthermore, sphingosine-1-phosphate (S1P) levels were decreased in diabetic plasma (P = 0.017) and correlated with HDL-mediated eNOS activation.. Collectively, our data suggest that HDL in individuals with type 2 diabetes loses its ability to maintain proper endothelial function independent of HDL-C, perhaps due to loss of S1P, and may contribute to development of diabetic complications.

Topics: Aged; Animals; Case-Control Studies; Cattle; Cells, Cultured; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Lipoproteins, HDL; Longitudinal Studies; Lysophospholipids; Male; Middle Aged; NF-kappa B; Nitric Oxide Synthase Type III; P-Selectin; Sphingosine

Accumulating evidence has shown that sphingosine-1-phosphate (S1P) plays roles in glucose and fat metabolism. However, the association between plasma S1P levels and fat mass, especially visceral fat mass, remains unknown.. In this cross-sectional study, 80 men with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of plasma S1P levels with body fat parameters. Visceral (VFA) and subcutaneous fat (SFA) areas were evaluated by performing computed tomography scan, and fat mass (FM) and lean body mass (LBM) were examined by whole body dual-energy X-ray absorptiometry.. Multiple regression analysis adjusted for age, T2DM duration, serum creatinine, and body mass index (BMI) showed that S1P was significantly and positively associated with fasting plasma glucose (β = 0.25, p = 0.027), HbA1c (β = 0.28, p = 0.012), and urine C-peptide (β = 0.29, p = 0.014). Moreover, multiple regression analysis adjusted for age, T2DM duration, serum creatinine, HbA1c, and urine C-peptide showed that BMI (β = 0.32, p = 0.008), VFA (β = 0.33, p = 0.008), SFA (β = 0.26, p = 0.039), FM (β = 0.37, p = 0.003), and LBM (β = 0.35, p = 0.01). FM was significantly and positively associated with S1P after additional adjustment for LBM (β = 0.29, p = 0.028), whereas LBM was not after adjustment for FM. Moreover, VFA was significantly and positively associated with S1P after additional adjustment for SFA (β = 0.27, p = 0.039), whereas SFA was not after adjustment for VFA.. This is the first study to show that increased plasma S1P levels are associated with blood glucose levels and accumulation of fat mass, especially visceral fat mass, in men with T2DM.

Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Intra-Abdominal Fat; Lysophospholipids; Male; Middle Aged; Sphingosine

Metformin, an anti-diabetic drug, possesses anti-inflammatory property beyond its glucose-lowering activity, but its regulatory effect on mast cells and allergic responses remains unknown, wherein the aryl hydrocarbon receptor (AhR)-ligand axis is critical in controlling mast cell activation. Herein, we provide evidence supporting the role of metformin in modulating mast cell activation by FcεR1-, AhR-mediated signaling or their combination. Metformin at relatively low doses was shown to suppress FcεR1-mediated degranulation, IL-13, TNF-α and sphingosine-1-phosphate (S1P) secretion in murine bone marrow-derived mast cells (BMMCs). In contrast, metformin at the same doses potently inhibited all parameters in mast cells stimulated with an AhR ligand, 5,11-dihydroindolo[3,2-b]carbazole-6-carbaldehyde (FICZ). Further, metformin was shown to inhibit FcεR1- and AhR-mediated passive cutaneous anaphylaxis (PCA) in vivo, reversible by a S1P receptor 2 antagonist, JTE-013. Using AhR reporter cells, Huh7-DRE-Luc cells, a human mast cell line, HMC-1, and BMMCs, metformin's inhibitory effect was mediated through the suppression of FICZ-induced AhR activity, calcium mobilization and ROS generation. Notably, FICZ-mediated oxidation of S1P lyase (S1PL) and its reduced activity were reversed by metformin, resulting in decreased levels of S1P. Collectively, these results suggested the potential utility of metformin in treating allergic diseases, particularly in cases with comorbid type II diabetes mellitus.

Topics: Animals; Anti-Inflammatory Agents; Calcium Signaling; Carbazoles; Cell Degranulation; Cell Line; Diabetes Mellitus, Type 2; Humans; Hypersensitivity; Immunoglobulin E; Interleukin-13; Lysophospholipids; Mast Cells; Metformin; Mice; Mice, Inbred C57BL; Receptors, Aryl Hydrocarbon; Receptors, IgE; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha

The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect.. We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabetic patients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function.. Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.

Topics: Animals; Animals, Newborn; Case-Control Studies; Cell Survival; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dyslipidemias; Genotype; Glycated Hemoglobin; Glycosylation; Humans; Isolated Heart Preparation; Lipoproteins, HDL; Lysophospholipids; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidative Stress; Phenotype; Rats, Wistar; RNA Interference; Scavenger Receptors, Class B; Sphingosine; Time Factors; Transfection

Glucolipotoxic stress has been identified as a key player in the progression of pancreatic β-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic β-cells but also regulate β-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in β-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by β-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued β-cell damage clearly indicating an important role of the S1P2 in β-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β-cell dysfunction and the development of T2D.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lysophospholipids; Male; Mice; Mice, Obese; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

Sphingosine 1-phosphate (S1P) is carried in plasma by the HDL particles and albumin. It mediates several protective functions of HDL. Because of its barrier-enhancing effect, it has attracted attention in diseases associated with endothelial dysfunction. We examined the impact of circulating levels of S1P in diabetic nephropathy together with apoprotein M, a S1P-binding protein in HDL. Plasma levels of dimethylarginines were evaluated in this context.. Patients with type 2 diabetes mellitus were divided into three groups according to daily albumin excretion: normoalbuminuria, microalbuminuria and macroalbuminuria (n=30 in each). In addition to routine analysis, S1P and apo M in plasma were measured using the enzyme-linked immunosorbent assays. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and l-arginine were determined by HPLC. Tukey's or Mann-Whitney U-test was used for the statistics.. Plasma S1P levels showed a significant decline in parallel to kidney dysfunction. The highest significance was detected in the macroalbuminuric group. Although a significant increase in plasma SDMA in albuminuric groups was observed, apo M, l-arginine and ADMA levels were similar between the groups.. Low plasma levels of S1P seemed to be associated with diabetic nephropathy. The main reason for the decreased S1P levels in our patients seems to be severe urinary albumin loss due to nephropathy. Low levels of S1P in patients with nephropathy may adversely affect the endothelial integrity and barrier function, thus causing a vicious circle.

Topics: Albuminuria; Apolipoproteins; Apolipoproteins M; Arginine; Biological Transport; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Lipocalins; Lysophospholipids; Male; Middle Aged; Sphingosine; Triglycerides

Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo synthesis. In the present research we evaluated the effects of myriocin application on type 2 diabetes mellitus in three different types of skeletal muscles: (1) slow-oxidative (red gastrocnemius), (2) oxidative-glycolytic (soleus), and (3) glycolytic (white gastrocnemius). For these reasons the animals were randomly divided into four groups: "control" (C), "myriocin" (M), "high fat diet" (HFD), "high fat diet" (HFD), and "high fat diet + myriocin" (HFD + M). Our in vivo study demonstrated that ceramide synthesis inhibition reduces intramuscular ceramide, its precursor sphinganine, and its derivatives sphingosine and sphingosine-1-phosphate concentrations. Moreover, FFA and TG contents were also decreased after myriocin treatment. Thus, myriocin presents potential therapeutic perspectives with respect to the treatment of insulin resistance and its serious consequences in obese patients.

Topics: Animals; Ceramides; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Monounsaturated; Glycolysis; Insulin Resistance; Lysophospholipids; Male; Muscle, Skeletal; Oxygen; Rats; Rats, Wistar; Signal Transduction; Sphingolipids; Sphingosine

Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.. The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.. Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P2, was not able to inhibit insulin signalling.. These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P2 receptor to impair insulin signalling. In particular, S1P2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.

Topics: Animals; Blotting, Western; Chromatography, Liquid; Diabetes Mellitus, Type 2; Hepatocytes; Immunosuppressive Agents; Insulin; Insulin Resistance; Lysophospholipids; Male; Mice; Mice, Obese; Organophosphates; Palmitates; Rats; Rats, Wistar; Sphingosine

Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the protective function of HDL in type 2 diabetes mellitus (T2DM) is still unknown.. Immunochemical techniques demonstrated that glycated HDL loses its protective function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 ± 13.71 pmol/mg vs. 382.1 ± 24.45 pmol/mg, P < 0.05). Additionally, mRNA levels of S1P lyase enzymes and S1P phosphatase 1/2 were decreased in peripheral blood by real-time PCR. Antagonist of S1P receptor 1 and 3 (S1PR1/3) diminished the functional difference between apoHDL&PL (HDL containing the protein components and phospholipids) and diabetic apoHDL&PL (diabetic HDL containing the protein components and phospholipids). With different doses of S1P reconstituted on glycated HDL, its function in inducing the COX-2 expression was restored to the same level as diabetic HDL. The mechanism of S1P reconstituted HDL (rHDL) in the process of regulating COX-2 expression involved the phosphorylation of ERK/MAPK-CREB signal pathway.. S1P harbored on HDL is the main factor which restores its protective function in endothelial cells in T2DM. S1P and its receptors are potential therapeutic targets in ameliorating the vascular dysfunction in T2DM.

Topics: Cells, Cultured; Cytoprotection; Diabetes Mellitus, Type 2; Glycosylation; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins, HDL; Lysophospholipids; Sphingosine

Dysfunctional high-density lipoprotein (HDL) may have pro-inflammatory effects on the endothelial cells,which causes atherosclerosis in type 2 diabetes mellitus (T2DM). HDL is a major carrier of sphingosine-1-phosphate (S1P) in plasma while S1P exhibits multiple biological activities. However, potential role of HDL and S1P in T2DM remains unexplored. We hypothesized that diabetic HDL with higher contents of S1P exerts beneficial effects on the vascular system.. Subjects with T2DM with or without proved large arteries atherosclerosis and normal controls (n=15 for each group) were recruited in the present study. HDL was isolated from the subjects by ultracentrifugation. The levels of HDL-associated S1P were determined by UPLC-MS/MS. The protective function of diabetic HDL and S1P was evaluated by measuring cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release by human umbilical vein endothelial cells (HUVECs) using western blot and enzyme-linked immunosorbent assay (ELISA), respectively.. The S1P levels in isolated HDL were significantly increased in T2DM subjects compared with controls (235.6 ± 13.4 vs 195.0 ± 6.4 ng/mg, P< 0.05). The diabetic HDL exerted greater protective effects on inducing COX-2 expression and PGI-2 release by HUVECs than those of control HDL (p < 0.05, p < 0.01, respectively). Pertussis toxin, a common inhibitor of G-couple protein receptors, and VPC 23019, an antagonist of S1P receptor 1 and 3 significantly attenuated HDL-induced COX-2 expression and PGI-2 release.. Diabetic HDL carries higher level of S1P compared with normal HDL, which has the potential to contribute to protective effects on endothelial cells by inducing COX-2 expression and PGI-2 release. These findings provide a new insight of S1P function in T2DM patients, possibly leading to a new therapeutic target.

Topics: Adult; Aged; Cells, Cultured; Cyclooxygenase 2; Diabetes Mellitus, Type 2; Endothelial Cells; Epoprostenol; Female; Gene Expression Regulation, Enzymologic; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins, HDL; Lysophospholipids; Male; Middle Aged; Sphingosine; Up-Regulation