Alterations in plasma triglycerides and ceramides: links with cardiac function in humans with type 2 diabetes.
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SUBMITTER: Peterson LR
PROVIDER: S-EPMC7328042 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here, we investigated associations of 15 ceramide (Cer) and SM species (i.e., all sphingolipids, measured with coefficient of variation less than 20%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease among elderly adults who were followed from 1989 to 2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dl or nonfasting glucose ≥200 mg/dl; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of Cer with acylated palmitic acid (Cer-16), stearic acid containing Cer (Cer-18), arachidic acid containing Cer (Cer-20), and behenic acid containing Cer (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each Cer species were as follows: 1.21 (95% CI: 1.09-1.34) for Cer-16, 1.23 (95% CI: 1.10-1.37) for Cer-18, 1.14 (95% CI: 1.02-1.26) for Cer-20, and 1.18 (95% CI: 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.
| S-EPMC8517199 | biostudies-literature
Project description:Mitochondrial dysfunction plays a key pathophysiological role in type 2 diabetes mellitus (T2DM). Data delineating relationships between mitochondrial and endothelial dysfunction in humans with T2DM are lacking.In 122 human subjects (60 with T2DM, 62 without T2DM), we measured endothelial function by brachial artery ultrasound (flow mediated dilation) and digital pulse amplitude tonometery. Endothelial function in arterioles isolated from gluteal subcutaneous adipose was measured by videomicroscopy. In arterioles and mononuclear cells, we measured inner mitochondrial membrane potential (??(m)), mitochondrial mass, and mitochondrial superoxide production using fluorophores. Endothelial function was impaired in T2DM subjects versus control subjects. ??(m) magnitude was larger and mitochondrial mass was lower in arterioles and mononuclear cells in T2DM. Mononuclear mitochondrial mass correlated with flow-mediated dilation and pulse amplitude tonometery (?=0.38 and 0.33, P=0.001 and 0.02, respectively), and mononuclear mitochondrial superoxide production inversely correlated with flow-mediated dilation (?=-0.58, P=0.03). Low doses of 2 different mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenyl hydrazone and 2,4-dinitrophenol) that reduce ??(m) magnitude and a mitochondrial-targeted antioxidant (MitoTEMPOL) improved endothelial function and reduced mitochondrial superoxide levels in T2DM arterioles.Mitochondrial dysfunction may play a central role in the impairment of endothelial dysfunction in T2DM.
| S-EPMC3570053 | biostudies-literature
Project description:Background/objectivesElevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects.Subjects/methodsHemopexin (HPX) was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both the reproductive fat pads and livers of mice representing three strains, LG/J (n=25), SM/J (n=27) and C57Bl/6J (n=19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n=18) and of metabolically normal (n=24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n=18).ResultsHPX expression in mouse adipose tissue, but not in liver, was regulated by dietary fat regardless of genetic background. HPX increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of HPX based on metabolic disease status (P<0.05), and circulating HPX levels were correlated with serum triglycerides in these subjects (r=0.33; P=0.03). HPX was also found in an unbiased proteomic screen of human atherosclerotic plaques and shown to display differential abundance based on the extent of disease and triglyceride content (P<0.05).ConclusionsOur findings suggest that HPX is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.
| S-EPMC5586146 | biostudies-literature
Project description:AimsThe role of ceramides in the pathogenesis of type 2 diabetes mellitus (T2DM) is incompletely characterized. Given that ceramides represent therapeutic targets to disrupt the euglycemia-T2DM transition, we aimed to characterize their association with prevalent and incident T2DM in a novel cohort.MethodsWe examined the cross-sectional and longitudinal association of baseline ceramides with prevalent and incident T2DM among 1423 adults (47% women; median (range) baseline age 72 (51-95) years) in the Mayo Clinic Study of Aging cohort. We examined the associations of ceramides with prevalent T2DM (adjusted odds ratio [95% confidence interval]) at baseline and incident T2DM (adjusted hazard ratio [95% confidence interval]) during median follow-up of 6.2 years, after adjusting for demographic and metabolic factors.ResultsAmong 1423 adults, there were 222 prevalent and 37 incident cases of T2DM. In cross-sectional analyses, higher levels of ceramide C16:0 were associated with lower odds of prevalent T2DM (aOR 0.84 [0.71-0.99];P = 0.03) whereas C18:0 (aOR 1.27 [1.06-1.42];P = 0.01), C18:0/16:0 (aOR 1.41 [1.22-1.62]; P < 0.001) and C18:0/24:0 (aOR 1.22 [1.05-1.41]; P = 0.01) were associated with higher odds. In Cox hazard regression models, C18:0/16:0 (aHR 1.63 [1.26-2.10];P < 0.001) and C18:0 (aHR 1.53 [1.12-2.08];P = 0.01) were associated with increased risk of incident T2DM.ConclusionsIn this prospective population-based cohort, ceramides were associated with prevalent T2DM (C16:0,C18:0, C18:0/C16:0 ratio, C18:0/C24:0 ratio) and incident T2DM (C18:0, C18:0/C16:0 ratio) and could suggest targets for the primary and secondary prevention of T2DM.
| S-EPMC8478833 | biostudies-literature
Project description:Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known. To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk. In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023. Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons. Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk. Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]). The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.
| S-EPMC10656644 | biostudies-literature
Project description:Ambient light intensity is signaled directly to hypothalamic areas that regulate energy metabolism. Observational studies have shown associations between ambient light intensity and plasma glucose and lipid levels, but human data on the acute metabolic effects of light are scarce. Since light is the main signal indicating the onset of the diurnal phase of physical activity and food intake in humans, we hypothesized that bright light would affect glucose and lipid metabolism. Therefore, we determined the acute effects of bright light on plasma glucose and lipid concentrations in 2 randomized crossover trials: (1) in 8 healthy lean men and (2) in 8 obese men with type 2 diabetes. From 0730 h, subjects were exposed to either bright light (4000 lux) or dim light (10 lux) for 5 h. After 1 h of light exposure, subjects consumed a 600-kcal mixed meal. Primary endpoints were fasting and postprandial plasma glucose levels. In healthy men, bright light did not affect fasting or postprandial plasma glucose levels. However, bright light increased fasting and postprandial plasma triglycerides. In men with type 2 diabetes, bright light increased fasting and postprandial glucose levels. In men with type 2 diabetes, bright light did not affect fasting triglyceride levels but increased postprandial triglyceride levels. We show that ambient light intensity acutely affects human plasma glucose and triglyceride levels. Our findings warrant further research into the consequences of the metabolic effects of light for the diagnosis and prevention of hyperglycemia and dyslipidemia.
| S-EPMC5423535 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort. METHODS:A total of 1557 participants in the Dallas Heart Study without type 2 diabetes underwent measurements of metabolic biomarkers, fat depots by MRI and plasma ceramides by liquid chromatography-mass spectrometry. Diabetes outcomes were assessed after 7 years. Associations of body fat and insulin resistance with ceramides at baseline and of ceramides with incident diabetes outcomes were analysed. RESULTS:The cohort had a mean age of 43 years, with 58% women, 45% black participants and a mean BMI of 28 kg/m2. Total cholesterol levels were associated with all ceramides, but higher triacylglycerols and lower HDL-cholesterol and adiponectin were associated only with saturated fatty acid chain ceramides (p?<?0.0003). After adjusting for clinical characteristics and total body fat, visceral adipose tissue was positively associated with saturated fatty acid ceramides (per SD, ??=?0.16 to 0.18) and inversely associated with polyunsaturated fatty acid ceramides (??=?-0.14 to -0.16, p?<?0.001 for all). Lower-body subcutaneous fat showed an opposite pattern to that for visceral fat. HOMA-IR was positively associated with saturated (??=?0.08 to 0.09, p?<?0.001) and inversely with polyunsaturated ceramides (??=?-0.06 to -0.07, p?<?0.05). Ceramides were not associated with incident type 2 diabetes after adjustment for clinical factors. CONCLUSIONS/INTERPRETATION:Plasma ceramides demonstrate a biologically complex relationship with metabolic and imaging indicators of dysfunctional adiposity. The role of ceramides in a shared pathway of metabolic dysfunction linking visceral adiposity and insulin resistance requires further investigation.
| S-EPMC6219923 | biostudies-literature
Project description:apoE, a key regulator of plasma lipids, mediates altered functionalities in lipoprotein metabolism and thus affects the risk of coronary artery disease (CAD). The significance of different apoE polymorphisms remains unclear; although the ε4 allele is clearly associated with increased cholesterol levels (which inform CAD risk), direct studies about apoE polymorphisms on CAD risk and development have yielded controversial results. Furthermore, certain species of ceramides-complex lipids abundant in plasma LDL-are markers of increased risk of myocardial infarction and cardiovascular death. Using a high-throughput MS approach, we quantified 30 molecular plasma ceramide species from a cohort of 2,160 apoE-genotyped (rs7412, rs429358) young adults enrolled in the population-based Cardiovascular Risk in Young Finns Study. We then searched this lipidome data set to identify new indications of pathways influenced by apoE polymorphisms and possibly related to CAD risk. This approach revealed a previously unreported association between apoE polymorphism and a consistently documented high-risk CAD marker, Cer(d18:1/16:0). Compared with the apoE ε3/3 reference group, plasma levels of apoE ε4 were elevated and those of apoE ε2 were lowered in all subjects without evidence of apoE-by-sex interactions. apoE associated with seven ceramides that are connected to atherogenically potent macrophages and/or lipoprotein particles; these associations could indicate a plausible linkage between apoE polymorphism and ceramide metabolism, leading to adverse plasma LDL metabolism and atherogenesis. In conclusion, new evidence from plasma ceramides links apoE polymorphism with an increased risk of CAD and extends our understanding of the role of apoE in health and disease.
| S-EPMC6718445 | biostudies-literature
Project description:BackgroundDysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed.MethodsLipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis.ResultsIntra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors.ConclusionsCeramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides.
| S-EPMC8502393 | biostudies-literature
Project description:BackgroundAlthough ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM.MethodsWe measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively.ResultsIn linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized β coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized β coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized β coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized β coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use.ConclusionsThe results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables.
| S-EPMC9312999 | biostudies-literature