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

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

Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia-related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)-induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow-derived macrophages (BMDMs) were differentiated in high-glucose (HG; 30 mM) or low-glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia-related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ-induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia-related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. Dual-immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia-modulated M1/M2 polarization. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia-modulated M1/M2 polarization and attenuated inflammation. In conclusion, our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.

Topics: Aged; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Liver; Liver Diseases; Liver Transplantation; Lysophospholipids; Macrophages; Male; Mice; Middle Aged; Reperfusion Injury; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Streptozocin; Thiazolidines

Topics: Animals; Cell Movement; Diabetes Mellitus, Type 1; Disease Models, Animal; Gene Expression Regulation; Integrin alpha5; Integrin alpha5beta1; Lysophospholipids; Mice; Mice, Inbred NOD; Receptors, Lysosphingolipid; Sphingosine; T-Lymphocytes; Thymocytes

Diabetes is considered a major public health problem affecting millions of individuals worldwide. Remarkably, scientific reports regarding salivary glands sphingolipid metabolism in diabetes are virtually non-existent. This is odd given the well-established link between the both in other tissues (e.g., skeletal muscles, liver) and the key role of these glands in oral health preservation. The aim of this paper is to examine sphingolipids metabolism in the salivary glands in (pre)diabetes (evoked by high fat diet feeding or streptozotocin). Wistar rats were allocated into three groups: control, HFD-, or STZ-diabetes. The content of major sphingolipid classes in the parotid (PSG) and submandibular (SMSG) glands was assessed via chromatography. Additionally, Western blot analyses were employed for the evaluation of key sphingolipid signaling pathway enzyme levels. No changes in ceramide content in the PSG were found, whereas an increase in ceramide concentration for SMSG of the STZ group was observed. This was accompanied by an elevation in SPT1 level. Probably also sphingomyelin hydrolysis was increased in the SMSG of the STZ-diabetic rats, since we observed a significant drop in the amount of SM. PSG and SMSG respond differently to (pre)diabetes, with clearer pattern presented by the later gland. An activation of sphingomyelin signaling pathway was observed in the course of STZ-diabetes, that is, metabolic condition with rapid onset/progression. Whereas, chronic HFD lead to an inhibition of sphingomyelin signaling pathway in the salivary glands (manifested in an inhibition of ceramide de novo synthesis and accumulation of S1P).

Topics: Animals; Ceramides; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diet, High-Fat; Insulin Resistance; Lysophospholipids; Male; Obesity; Parotid Gland; Phosphotransferases (Alcohol Group Acceptor); Rats, Wistar; Signal Transduction; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingosine; Sphingosine N-Acyltransferase; Streptozocin; Submandibular Gland

Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D.. ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

Topics: Adult; Apolipoproteins; Apolipoproteins M; Biomarkers; Case-Control Studies; Cells, Cultured; Chromatography, Liquid; Diabetes Mellitus, Type 1; E-Selectin; Endocytosis; Endothelial Cells; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inflammation; Lipocalins; Lipoproteins, HDL; Lysophospholipids; Male; Middle Aged; Receptors, Lysosphingolipid; Risk Factors; Sphingosine; Sphingosine-1-Phosphate Receptors; Tandem Mass Spectrometry; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Pancreatic islet transplantation is a promising clinical treatment for type 1 diabetes, but success is limited by extensive β-cell death in the immediate posttransplant period and impaired islet function in the longer term. Following transplantation, appropriate vascular remodeling is crucial to ensure the survival and function of engrafted islets. The sphingosine kinase (SK) pathway is an important regulator of vascular beds, but its role in the survival and function of transplanted islets is unknown. We observed that donor islets from mice deficient in SK1 (

Topics: Animals; Cell Movement; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelial Cells; Flow Cytometry; Islets of Langerhans; Islets of Langerhans Transplantation; Lysophospholipids; Mice; Mice, Knockout; Neovascularization, Physiologic; Phosphotransferases (Alcohol Group Acceptor); Real-Time Polymerase Chain Reaction; Sphingosine; Transplants

During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.

Topics: 14-3-3 Proteins; Adiponectin; Adult; Age Factors; Aged; Aging; Animals; Arthritis, Rheumatoid; Autoimmunity; B-Lymphocytes; Cadherins; Cell Adhesion; Cell Movement; Diabetes Mellitus, Type 1; Female; Gene Expression Regulation; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lysophospholipids; Male; Mice; Middle Aged; Peptides; Receptors, Adiponectin; Sphingosine; T-Lymphocytes; Young Adult

Phospholipids and sphingolipids are major components of HDL. They play a critical role in HDL functionality and protective effects against atherosclerosis. As HDL are dysfunctional in type 1 diabetic patients, we ascertained whether they presented abnormalities in their phospholipid and sphingolipid profile, despite normal HDL cholesterol concentration.. Using liquid chromatography-tandem mass spectrometry, we quantified the main species of phosphatidylcholines, sphingomyelins, lysophophatidylcholines, phosphatidylethanolamines, phosphatidylinositols, ceramides, plasmalogens and sphingosines 1-phosphate in the HDL2 and HDL3 from 54 type 1 diabetic patients and 50 controls.. Serum HDL cholesterol was similar in the 2 groups of subjects. When data were expressed relative to the total amount of phospholipids and sphingolipids, sphingosines-1-phosphate (S1P) were 11.7% (NS) and 14.4% (p = 0.0062) lower in HDL2 and HDL3, respectively, from type 1 diabetic patients than from controls. Ceramides were 23% (p = 0.005) and 24% (borderline significance) lower in HDL2 and HDL3, respectively. The concentration of apolipoprotein M, the carrier of S1P, was similar in patients and controls. In type 1 diabetic patients compared to controls, the concentration of d18:1-S1P, the main S1P species, was decreased in total plasma (-17.0%, p < 0.0001), HDL fraction (-21.9%, p < 0.0001) and non-HDL fraction (-13.7%, p = 0.012). The concentration of ceramides was decreased in total plasma (-24.4%, p < 0.0001), HDL fraction (-27.9%, p = 0.0006) and non-HDL fraction (-22.0%, p = 0.0087).. Despite normal HDL cholesterol level, the phospholipid + sphingolipid profile is impaired in HDL from type 1 diabetic patients. These abnormalities, especially the decrease in S1P, could contribute to the impaired HDL functionality observed in these patients.

Topics: Adult; Ceramides; Cholesterol, HDL; Chromatography, Liquid; Diabetes Mellitus, Type 1; Female; Humans; Lipids; Lipoproteins, HDL; Lysophospholipids; Male; Middle Aged; Phospholipids; Plasmalogens; Sphingolipids; Sphingosine; Tandem Mass Spectrometry

FTY720 modulates lymphocyte trafficking through blood (peripheral blood lymphocyte, PBL) and peripheral lymph nodes (PLN). Treatment with FTY720 causes retention of most blood lymphocytes in PLN. Long-term treatment can slow and/or prevent Type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse model. B and T cells are both affected by FTY720 binding to sphingosine-1-phosphate receptor 1 (S1P₁). However, little has been done to elucidate which T-cell subsets are differentially affected by FTY720 under healthy conditions, and how this affects disease pathogenesis in T1D. In healthy C57BL/6J (B6) mice, total CD4(+) and CD8(+) T-cell subsets were diminished by FTY720, but recently activated and memory subsets were spared and constituted significantly higher percentage of remaining T cells in blood. FTY720 also lowered PBL counts in NOD mice, but less severely than in B6 mice. This is consistent with a different ratio of naïve, activated, and memory cells in NOD mice compared to those in B6 mice, as well as alterations in S1P₁ and sphingosine-1-phosphate (S1P) levels in PBLs and blood of NOD mice, respectively. To address the functional consequences of PBL T-cell depletion, we studied the effects of FTY720 on disease progression in a timed adoptive transfer model of T1D. Continuous treatment with FTY720 eliminated T1D, if treatment was started before splenocyte transfer. FTY20 treatment started after disease onset slowed disease progression. The inability to fully suppress memory and effector T-cell circulation may explain why FTY720 is only partially effective in the NOD adoptive transfer model of T1D.

Topics: Adoptive Transfer; Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Fingolimod Hydrochloride; Immunomodulation; Immunosuppressive Agents; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Propylene Glycols; Sphingosine; T-Lymphocytes

Alterations in lipid metabolism may contribute to diabetic complications. Sphingolipids are essential components of cell membranes and have essential roles in homeostasis and in the initiation and progression of disease. However, the role of sphingolipids in type 1 diabetes remains largely unexplored. Therefore, we sought to quantify sphingolipid metabolites by LC-MS/MS from two animal models of type 1 diabetes (streptozotocin-induced diabetic rats and Ins2(Akita) diabetic mice) to identify putative therapeutic targets and biomarkers. The results reveal that sphingosine-1-phosphate (So1P) is elevated in both diabetic models in comparison to respective control animals. In addition, diabetic animals demonstrated reductions in plasma levels of omega-9 24:1 (nervonic acid)-containing ceramide, sphingomyelin, and cerebrosides. Reduction of 24:1-esterfied sphingolipids was also observed in liver and heart. Nutritional stress via a high-fat diet also reduced 24:1 content in the plasma and liver of mice, exacerbating the decrease in some cases where diabetes was also present. Subcutaneous insulin corrected both circulating So1P and 24:1 levels in the murine diabetic model. Thus, changes in circulating sphingolipids, as evidenced by an increase in bioactive So1P and a reduction in cardio- and neuro-protective omega-9 esterified sphingolipids, may serve as biomarkers for type 1 diabetes and represent novel therapeutic targets.

Topics: Alleles; Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Fatty Acids; Female; Insulin; Liver; Lysophospholipids; Male; Mice; Mutation; Myocardium; Rats; Sphingolipids; Sphingosine

Endothelial activation is a key early event in vascular complications of Type 1 diabetes. The nonobese diabetic (NOD) mouse is a well-characterized model of Type 1 diabetes. We previously reported that Type 1 diabetic NOD mice have increased endothelial activation, with increased production of monocyte chemoattractant protein (MCP)-1 and IL-6, and a 30% increase of surface VCAM-1 expression leading to a fourfold increase in monocyte adhesion to the endothelium. Sphingosine-1-phosphate (S1P) prevents monocyte:endothelial interactions in these diabetic NOD mice. Incubation of diabetic NOD endothelial cells (EC) with S1P (100 nmol/l) reduced ERK1/2 phosphorylation by 90%, with no significant changes in total ERK1/2 protein. In the current study, we investigated the mechanism of S1P action on ERK1/2 to reduce activation of diabetic endothelium. S1P caused a significant threefold increase in mitogen-activated kinase phosphatase-3 (MKP-3) expression in EC. MKP-3 selectively regulates ERK1/2 activity through dephosphorylation. Incubation of diabetic NOD EC with S1P and the S1P(1)-selective agonist SEW2871 significantly increased expression of MKP-3 and reduced ERK1/2 phosphorylation, while incubation with the S1P(1)/S1P(3) antagonist VPC23019 decreased the expression of MKP-3, both results supporting a role for S1P(1) in MKP-3 regulation. To mimic the S1P-mediated induction of MKP-3 diabetic NOD EC, we overexpressed MKP-3 in human aortic endothelial cells (HAEC) cultured in elevated glucose (25 mmol/l). Overexpression of MKP-3 in glucose-cultured HAEC decreased ERK1/2 phosphorylation and resulted in decreased monocyte:endothelial interactions in a static monocyte adhesion assay. Finally, we used small interfering RNA to MKP-3 and observed increased monocyte adhesion. Moreover, S1P was unable to inhibit monocyte adhesion in the absence of MKP-3. Thus, one mechanism for the anti-inflammatory action of S1P in diabetic EC is inhibition of ERK1/2 phosphorylation through induction of MKP-3 expression via the S1P-S1P(1) receptor axis.

Topics: Animals; Cell Adhesion; Cells, Cultured; Diabetes Mellitus, Type 1; Disease Models, Animal; Dual Specificity Phosphatase 6; Endothelial Cells; Glucose; Humans; Inflammation; Lysophospholipids; Mice; Mice, Inbred NOD; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocytes; Phosphorylation; Receptors, Lysosphingolipid; RNA Interference; Sphingosine; Transfection

Non-obese diabetic (NOD) mice develop spontaneous type 1 diabetes. We have shown that sphingosine-1-phosphate (S1P) reduces activation of NOD diabetic endothelium via the S1P1 receptor. In the current study, we tested the hypothesis that S1P could inhibit CD4(+) T-cell activation, further reducing inflammatory events associated with diabetes.. CD4(+) T-cells were isolated from diabetic and nondiabetic NOD mouse splenocytes and treated in the absence or presence of S1P or the S1P1 receptor-specific agonist, SEW2871. Lymphocyte activation was examined using flow cytometry, cytokine bead assays, and a lymphocyte:endothelial adhesion assay.. Diabetic T-cells secreted twofold more gamma-interferon (IFN-gamma) and interleukin-17 than nondiabetic lymphocytes. Pretreatment with either S1P or SEW2871 significantly reduced cytokine secretion by approximately 50%. Flow cytometry analysis showed increased expression of CD69, a marker of lymphocyte activation, on diabetic T-cells. Both S1P and SEW2871 prevented upregulation of CD69 on CD4(+) cells. Quantitative RT-PCR showed that lymphocytes from diabetic NOD mice had 2.5-fold lower hypoxia-inducible factor (HIF)-1alpha short isoform I.1 (HIF1alphaI.1) mRNA levels than control. HIF1alphaI.1 is a negative regulator of lymphocyte activation. S1P significantly increased HIF1alpha I.1 mRNA levels in both control and diabetic groups. IFN-gamma production and surface CD69 expression was significantly increased in lymphocytes of HIF1alphaI.1-deficient mice. S1P did not reduce either CD69 or IFN-gamma expression in lymphocytes from HIF1alphaI.1-deficient mice.. S1P acts through the S1P1 receptor and HIF1alpha I.1 to negatively regulate T-cell activation, providing a potential therapeutic target for prevention of diabetes and its vascular complications.

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cytokines; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Flow Cytometry; Hypoxia-Inducible Factor 1, alpha Subunit; Lectins, C-Type; Lymphocyte Activation; Lysophospholipids; Mice; Mice, Inbred NOD; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Sphingosine; Spleen; T-Lymphocytes

Monocyte recruitment and adhesion to vascular endothelium are key early events in atherosclerosis. We examined the role of sphingosine-1-phosphate (S1P) on modulating monocyte/endothelial interactions in the NOD/LtJ (NOD) mouse model of type 1 diabetes. Aortas from nondiabetic and diabetic NOD mice were incubated in the absence or presence of 100 nmol/L S1P. Fluorescently labeled monocytes were incubated with the aortas. Aortas from NOD diabetic mice bound 7-fold more monocytes than nondiabetic littermates (10+/-1 monocytes bound/field for nondiabetic mice vs 74+/-12 monocytes bound/field for diabetic mice, P<0.0001). Incubation of diabetic aortas with 100 nmol/L S1P reduced monocyte adhesion to endothelium by 90%. We found expression of S1P1, S1P2, and S1P3 receptors on NOD aortic endothelial cells. The S1P1 receptor-specific agonist SEW2871 inhibited monocyte adhesion to diabetic aortas. Studies in diabetic S1P3-deficient mice revealed that the S1P3 receptor did not play a pivotal role in this process. S1P reduced endothelial VCAM-1 induction in type 1 diabetic NOD mice, most likely through inhibition of nuclear factor kappaB translocation to the nucleus. Thus, S1P activation of the S1P1 receptor functions in an antiinflammatory manner in type 1 diabetic vascular endothelium to prevent monocyte/endothelial interactions. S1P may play an important role in the prevention of vascular complications of type 1 diabetes.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Biological Transport; Cell Adhesion; Cell Nucleus; Chemokine CCL2; Diabetes Mellitus, Type 1; Endothelium, Vascular; Intercellular Adhesion Molecule-1; Interleukin-6; Lysophospholipids; Mice; Mice, Inbred NOD; Monocytes; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Vascular Cell Adhesion Molecule-1

Topics: Animals; Atherosclerosis; Blood Vessels; Diabetes Mellitus, Type 1; Glucose; Humans; Lysophospholipids; Sphingosine