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Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes.

ABSTRACT: The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. At baseline, higher relative apoC-III2 and apoC-III2/apoC-III1 ratios were associated with lower triglycerides and total cholesterol in both cohorts, and with lower small dense LDL in the RACED. Longitudinally, changes in apoC-III2/apoC-III1 were inversely associated with changes in triglycerides in both cohorts, and with total and small dense LDL in the RACED. apoC-III2/apoC-III1 was also higher in patients treated with PPAR-γ agonists and was associated with reduced cardiovascular events in the RACED control group. Ex vivo studies of apoC-III complexes with higher apoC-III2/apoC-III1 showed attenuated inhibition of VLDL uptake by HepG2 cells and LPL-mediated lipolysis, providing possible functional explanations for the inverse association between a higher apoC-III2/apoC-III1 and hypertriglyceridemia, proatherogenic plasma lipid profiles, and cardiovascular risk.

SUBMITTER: Koska J

PROVIDER: S-EPMC4847634 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes.

Koska Juraj J Yassine Hussein H Trenchevska Olgica O Sinari Shripad S Schwenke Dawn C DC Yen Frances T FT Billheimer Dean D Nelson Randall W RW Nedelkov Dobrin D Reaven Peter D PD

Journal of lipid research 20160303 5

The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RAC ...[more]

PMID: 26945091

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Project description:BackgroundThe identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up.MethodsIn the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110-125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman's coefficients. Kaplan-Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models.ResultsDuring a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA1c, and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan-Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds.ConclusionsThe plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations. Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509.

Project description:BackgroundDiabetes is a costly epidemic in the United States associated with both health and economic consequences. These consequences can be mitigated by participation in structured lifestyle change programs such as the National Diabetes Prevention Program (DPP) led by the Centers for Disease Control and Prevention. Mississippi consistently has among the highest rates of diabetes and prediabetes nationally. Implementing the National DPP through large health care systems can increase reach and accessibility for populations at the highest risk for diabetes. Translational research on the National DPP in Mississippi has not been studied.ObjectiveThis study aims to evaluate the implementation and impact of the National DPP delivered using telehealth modalities at the University of Mississippi Medical Center in Jackson, Mississippi.MethodsAn effectiveness-implementation hybrid type III research design is proposed. The study design is guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework and the Practical, Robust Implementation and Sustainability Model. Participants are being recruited via provider referral, and the DPP is being delivered by trained lifestyle coaches. Study participants include adult (≥18 years) patients eligible for the DPP with at least 1 encounter at 1 of 3 ambulatory clinic specialties (lifestyle medicine, family medicine, and internal medicine) between January 2019 and December 2023. The National DPP eligibility criteria include a BMI ≥25 kg/m2 and hemoglobin A1c between 5.7% and 6.4%. The University of Mississippi Medical Center criteria include Medicare or Medicaid beneficiaries. The University of Mississippi Medical Center's a priori implementation plan was developed using the Consolidated Framework for Implementation Research and includes 23 discrete strategies. The primary aim will use an embedded mixed method process analysis to identify and mitigate challenges to implementation. The secondary aim will use a nonrandomized quasi-experimental design to assess the comparative effectiveness of the DPP on health care expenditures. A propensity score matching method will be implemented to compare case subjects to control subjects. The primary outcomes include patient referrals, participant enrollment, retention, engagement, the incidence of diabetes, and health care resource use and costs.ResultsAt baseline, of the 26,151 patients across 3 ambulatory clinic specialties, 1010 (3.9%) had prediabetes and were eligible for the National DPP. Of the 1010 patients, more than half (n=562, 55.6%) were aged 65 years or older, 79.5% (n=803) were Medicare beneficiaries, 65.9% (n=666) were female, and 70.8% (n=715) were obese.ConclusionsThis is the first translational study of the National DPP in Mississippi. The findings will inform implementation strategies impacting the uptake and sustainability of the National DPP delivered in an academic medical setting using distance learning and telehealth modalities.Trial registrationClinicalTrials.gov NCT04822480; https://clinicaltrials.gov/study/NCT03622580.International registered report identifier (irrid)DERR1-10.2196/50183.

Dataset Information

Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes.

Publications

Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes.

Similar Datasets

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