Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Guitton, Jeanne; Bandet, Cécile; Mariko, Mohamed L; Tan-Chen, Sophie; Bourron, Olivier; Benomar, Yacir; Hajduch, Éric; Stunff, Hervé Le

doi:10.3390/cells9071682

Cited by 49 publications

(45 citation statements)

References 115 publications

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“…In addition to the previously reported metabolites, we also identified several novel ones, including sphingosine. As the precursor of sphingosine-1-phosphate (S1P), sphingosine plays an important part in sphingolipid metabolism [ 47 ]. In vitro studies revealed that elevated levels of sphingosine could inhibit glucose uptake in muscle cells, while S1P could upregulate glucose-stimulated insulin secretion in pancreatic β-cells [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Changes in Plasma Metabolome Profiles Following Oral Glucose Challenge among Adult Chinese

et al. 2021

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Little is known about changes in plasma metabolome profiles during the oral glucose tolerance test (OGTT) in Chinese. We aimed to characterize plasma metabolomic profiles at 0 and 2 h of OGTT and their changes in individuals of different glycemic statuses. A total of 544 metabolites were detected at 0 and 2 h of OGTT by a nontarget strategy in subjects with normal glucose (n = 234), prediabetes (n = 281), and newly diagnosed type 2 diabetes (T2D) (n = 66). Regression model, mixed model, and partial least squares discrimination analysis were applied. Compared with subjects of normal glucose, T2D cases had significantly higher levels of glycerone at 0 h and 22 metabolites at 2 h of OGTT (false discovery rate (FDR) < 0.05, variable importance in projection (VIP) > 1). Seven of the twenty-two metabolites were also significantly higher in T2D than in prediabetes subjects at 2 h of OGTT (FDR < 0.05, VIP > 1). Two hours after glucose challenge, concentrations of 35 metabolites (normal: 18; prediabetes: 23; T2D: 13) significantly increased (FDR < 0.05, VIP > 1, fold change (FC) > 1.2), whereas those of 45 metabolites (normal: 36; prediabetes: 29; T2D: 18) significantly decreased (FDR < 0.05, VIP > 1, FC < 0.8). Distinct responses between cases and noncases were detected in metabolites including 4-imidazolone-5-acetate and 4-methylene-L-glutamine. More varieties of distinct metabolites across glycemic statuses were observed at 2 h of OGTT compared with fasting state. Whether the different patterns and responsiveness of certain metabolites in T2D reflect a poor resilience of specific metabolic pathways in regaining glucose homeostasis merits further study.

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Section: Discussionmentioning

confidence: 99%

Changes in Plasma Metabolome Profiles Following Oral Glucose Challenge among Adult Chinese

et al. 2021

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“…4 Sphingosine-1 phosphate (S1P) is a sphingolipid mediator present at high levels in the plasma of healthy individuals, where it is believed to play an important role in maintaining vascular health. [5][6][7][8][9][10][11][12] Endothelium and erythrocytes contribute, primarily, to the plasma pool of S1P, and the apoM-component of high-density lipoprotein (HDL) is the major carrier in plasma. 5,13 Not surprisingly, S1P and HDL-bound S1P are reduced in pathologies or conditions associated with endothelial injury, including diabetes, [14][15][16][17][18][19][20][21] metabolic syndrome, 22 myocardial infarction, 20,21 sepsis, 23,24 in-stent restenosis, 25 and in coronary and peripheral artery disease.…”

Section: Introductionmentioning

confidence: 99%

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Bergougnan

Andersen

Plum‐Mörschel

et al. 2020

Brit J Clinical Pharma

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agonist designed to activate endothelial S1P 1 and provide endothelial-protective properties, while limiting S1P 1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P 1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flowmediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. Results: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] −0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. The authors confirm that the Principal Investigators for the clinical study were Grit Anderson and Leona Plum-Mörschel and that they had direct clinical responsibility for patients at the Neuss and Mainz sites, respectively. In addition, Grit Andersen was coordinating principal investigator.

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“…The SphK1 and SphK2 effect on pancreatic β cell activity is believed to be antagonistic. Saturated fatty acids stimulate the SphK1/S1P axis by inhibiting lipotoxicity-induced β cell apoptosis ( 55 ).…”

Section: Sphingosine-1-phosphatementioning

confidence: 99%

Ceramides and Sphingosino-1-Phosphate in Obesity

2021

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Obesity is a growing worldwide problem, especially in developed countries. This disease adversely affects the quality of life and notably contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disorders. It is characterised by excessive lipids accumulation in the subcutaneous and visceral adipose tissue. Considering the secretory function of adipose tissue, this leads to impaired adipokines and cytokines release. Changes in adipose tissue metabolism result in chronic inflammation, pancreatic islets dysfunction and peripheral insulin resistance. In addition to saturating various adipocytes, excess lipids are deposited into non-adipose peripheral tissues, which disturbs cell metabolism and causes a harmful effect known as lipotoxicity. Fatty acids are metabolised into bioactive lipids such as ceramides, from which sphingolipids are formed. Ceramides and sphingosine-1-phosphate (S1P) are involved in intracellular signalling, cell proliferation, migration, and apoptosis. Studies demonstrate that bioactive lipids have a crucial role in regulating insulin signalling pathways, glucose homeostasis and β cell death. Data suggests that ceramides may have an opposite cellular effect than S1P; however, the role of S1P remains controversial. This review summarises the available data on ceramide and sphingolipid metabolism and their role in obesity.

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Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Cited by 49 publications

References 115 publications

Changes in Plasma Metabolome Profiles Following Oral Glucose Challenge among Adult Chinese

Changes in Plasma Metabolome Profiles Following Oral Glucose Challenge among Adult Chinese

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Ceramides and Sphingosino-1-Phosphate in Obesity

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