02453nas a2200265 4500008004100000022001400041245009900055210006900154260001600223300001100239520164100250100002201891700002001913700002501933700002201958700002301980700001702003700002402020700002402044700001902068700001802087700002202105700002402127856003602151 2021 eng d a1539-726200aPlasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.0 aPlasma Ceramides containing Saturated Fatty Acids are Associated c2021 Sep 20 a1001193 a

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 and sphingomyelin 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 (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dL or non-fasting 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 ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (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 ceramide species were: 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.

1 aFretts, Amanda, M1 aJensen, Paul, N1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aHoward, Barbara, V1 aUmans, Jason1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aDjoussé, Luc1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/890902982nas a2200397 4500008004100000022001400041245011500055210006900170260001300239300001100252490000700263520181400270653001202084653002202096653002802118653003002146653001602176653001102192653002002203653002402223100002402247700002002271700002102291700002202312700002002334700002302354700002402377700002202401700002002423700001902443700002402462700002002486700002202506700002002528856003602548 2022 eng d a2352-396400aPlasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.0 aPlasma epoxyeicosatrienoic acids and diabetesrelated cardiovascu c2022 Sep a1041890 v833 a

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

10aAnimals10aArachidonic Acids10aCardiovascular Diseases10aDiabetes Mellitus, Type 210aEicosanoids10aHumans10aIschemic Stroke10aProspective Studies1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aZeigler, Maxwell1 aFretts, Amanda, M1 aUmans, Jason, G1 aHoward, Barbara, V1 aSitlani, Colleen, M1 aMcKnight, Barbara1 aGharib, Sina, A1 aKing, Irena, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aTotah, Rheem, A uhttps://chs-nhlbi.org/node/9171