Low apoA-I is associated with insulin resistance in patients with impaired glucose tolerance: a cross-sectional study
© The Author(s). 2017
Received: 4 December 2016
Accepted: 8 March 2017
Published: 4 April 2017
Low apolipoprotein A-I (apoA-I) is an independent risk factor for atherosclerotic cardiovascular diseases. Insulin resistance predicts the progression of abnormal glucose metabolism, which is the main cause of atherosclerotic cardiovascular disease. In this study, we assessed the potential association between apoA-I levels and insulin resistance in patients with impaired glucose tolerance (IGT) and the possible link between apoA-I and IGT.
This study evaluated a cross-sectional study of 108 participants with impaired glucose tolerance (IGT group) and 84 controls (control group). ApoA-I and clinical characteristics were measured, and a homeostasis model assessment of insulin resistance (HOMA-IR) was calculated.
The IGT group exhibited significantly lower apoA-I and higher HOMA-IR levels than the control group (apoA-I: 1.37 ± 0.36 vs 1.57 ± 0.39 g/L; HOMA-IR: 4.21 ± 1.56 vs 2.15 ± 0.99; P < 0.001 for both). ApoA-I was negatively correlated with HOMA-IR in both the IGT and control groups (IGT group: r = −0.269, P = 0.005; control group: r = −0.262, P = 0.016). Multiple stepwise regression analysis showed that low apoA-I levels (β = −1.470, P = 0.002) were independently correlated with high HOMA-IR levels in the IGT group. Moreover, logistic regression analysis identified that low apoA-I was an independent influencing factor for IGT (β = −1.170, OR = 0.310, P = 0.007).
ApoA-I is inversely associated with insulin resistance in patients with impaired glucose tolerance, and low apoA-I is an independent risk factor for impaired glucose tolerance. These results indicate that apoA-I plays an important role in regulating insulin sensitivity and glucose metabolism in patients with IGT.
KeywordsInsulin resistance Apolipoprotein A-I Impaired glucose tolerance
Insulin resistance predicts the development of type 2 diabetes  and atherosclerotic cardiovascular disease (ASCVD)  and begins to increase considerably before the onset of diabetes. Impaired glucose tolerance (IGT), which is characterized by high postprandial blood glucose levels, causes the development of type 2 diabetes  and ASCVD . Postprandial blood glucose levels are frequently associated with elevated insulin resistance, which may have a more damaging effect on the vasculature including the activation of inflammatory pathways, increased oxidative stress, an extensive procoagulant state, and abnormal vasomotion .
High-density lipoprotein cholesterol (HDL-C) is involved in cardiovascular protection . Apolipoprotein A-I (apoA-I) is the major apolipoprotein constituent of HDL-C . Both HDL-C and apoA-I play important roles in reverse cholesterol transport and exhibit anti-atherogenic activities, including anti-thrombotic, anti-oxidative, and anti-inflammatory activities, which are independent of their reverse cholesterol transport activities . Based on the results of many epidemiological studies, HDL-C has been considered an independent negative risk factor for ASCVD; however, in the INTERHEART STUDY, apoA-I levels were shown to have a stronger effect in preventing the development of ASCVD than HDL-C levels . This finding suggests that it is necessary to focus not simply on decreases in HDL-C levels but on the fact that decreases in apoA-I levels are important for the induction of ASCVD. Moreover, apoA-I has been documented to independently promote insulin secretion and glucose uptake  and to be negatively correlated with insulin resistance in patients with type 2 diabetes .
Studies have shown that insulin secretion and islet β-cell function are elevated several years before the onset of diabetes and then decrease until the time of diagnosis . A compensatory period (i.e., a compensatory increase in insulin production that is secondary to high insulin resistance and the elevated secreting load of islet β-cells with subtle changes in glucose levels) has been identified before the onset of diabetes, and insulin production decreases after the diagnosis of diabetes . Insulin resistance might be considered to be responsible for the increase in the secreting load of islet β-cells and insulin secretion during the compensatory period. Furthermore, reduced levels of apoA-I occur years before the development of type 2 diabetes . Therefore, it is of interest to assess the possible association between apoA-I and insulin resistance in patients with impaired glucose tolerance and the potential correlation between apoA-I and IGT. However, these associations have not been well-characterized. In this study, we assessed the possible association between apoA-I and insulin resistance in patients with impaired glucose tolerance and the link between apoA-I and the probability of being IGT.
All participants (both genders, ranging in age from 30 to 70 years) were recruited from March 2015 to March 2016.
In total, 108 patients with impaired glucose tolerance were recruited for this study from a group of outpatients at the Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. Participants diagnosed with IGT as defined by the American Diabetes Association criteria  were eligible for the study. The following exclusion criteria for the IGT group were applied: normal glucose tolerance, impaired fasting glucose, and diabetes.
Eighty-four people were recruited to the control group from the community and people undergoing routine medical check-ups. None of these people were diagnosed with prediabetes (including impaired glucose tolerance and impaired fasting glucose) or diabetes.
Moreover, people with hypertension, coronary artery disease, endocrine disease, systemic inflammatory disease, infectious disease, cancer, liver or renal function impairment, pregnancy or lactation were excluded from both groups. People taking agents known to influence glucose or insulin metabolism and/or people being treated with lipid-lowering drugs were also excluded from both groups.
The study protocol was approved by the Medicine and Pharmacy Ethics Committee of Beijing Chao-Yang Hospital, Capital Medical University. Written informed consent was obtained from each participant.
Clinical and biochemical measurements
A standard questionnaire was used to collect information about the participants’ health status and medications. Height and weight were measured without shoes and in light clothing to the nearest 0.1 cm and 0.1 kg, respectively, by the same trained group. Body mass index (BMI) was calculated as weight (kg) / [height (m)]2. Blood pressure was measured using a calibrated standard mercury sphygmomanometer. All readings were measured from the non-dominant arm after a 5-min resting period with the patients in the sitting position.
Fasting blood samples were collected in the morning after an 8-h overnight fast. All patients underwent 75 g oral glucose tolerance tests (OGTT). Blood samples were collected at 0 min and 120 min following the OGTT. Total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apoA-I, apolipoprotein B (apoB), fasting blood glucose (FBG), 2-h postchallenge glucose (2hPG), glycated hemoglobin (HbA1c) and fasting insulin (FINS) levels were measured in the Central Laboratory of Beijing Chao-Yang Hospital, Capital Medical University.
Serum insulin levels were determined by the electrochemiluminescence method using an Elecsys-2010 Automatic Electrochemical Immuno-analyser (Roche Corporation). Blood glucose levels were measured using the hexokinase-UV/NAD method (Olympus). Blood lipids were measured as follows: TC levels were measured using the cholesterol oxidase-HDAOS method (Wako); TG levels were measured using the GPO-HDAOS glycerol blanking method (Wako); HDL-C levels were measured using the immunoinhibition (direct) method (Wako); LDL-C levels were measured using the selective protection enzymatic (direct) method (Wako), and apoA-I and apoB levels were measured using the immunoturbidimetric method (Olympus). Serum glucose and lipid levels were analysed using an Olympus AU5400 Automatic Biochemistry Analyser (Olympus Corp, Japan). HbA1c analysis was performed by high-performance liquid chromatography using a HLC-723 G8 Automatic Analyser (Tosoh Corp, Japan). Insulin resistance was measured using the following method: homeostasis model assessment of insulin resistance (HOMA-IR) = FINS (mIU/L) * FBG (mmol/L) / 22.5.
All analyses were performed using Statistical Package for Social Sciences version 19.0 (SPSS, Inc., Chicago, IL, USA). The normality of the data distribution was verified using the Kolmogorov-Smirnov test. Normally distributed data were expressed as the means ± standard deviations. Non-normally distributed data were expressed as medians with 25th and 75th percentiles. Comparisons of the clinical and biochemical markers between the two groups were performed using the independent sample t test and the Mann-Whitney U Test. Proportions were analysed using the chi-squared test. Association was tested using Pearson’s correlation coefficient analyses, multiple stepwise regression analyses, and logistic regression analysis. In all statistical tests, P values < 0.05 were considered significant, and all tests were two-sided.
Clinical characteristics of individuals in the IGT and control groups
Clinical characteristics of the study participants
IGT group (n = 108)
Control group (n = 84)
57.31 ± 7.21
56.83 ± 7.55
26.43 ± 4.83
24.26 ± 3.44
128.11 ± 6.86
126.46 ± 6.89
75.62 ± 6.50
74.14 ± 7.38
5.15 ± 1.06
4.92 ± 0.91
1.34 ± 0.27
1.58 ± 0.37
3.10 ± 0.74
2.85 ± 0.75
2.37 (1.99, 2.79)
1.09 (0.71, 1.48)
1.37 ± 0.36
1.57 ± 0.39
0.97 ± 0.22
0.90 ± 0.23
0.99 (0.91, 1.10)
0.99 (0.85, 1.11)
6.30 (5.60, 6.98)
5.58 (5.24, 5.82)
9.30 (8.63, 9.80)
6.50 (6.08, 6.73)
6.30 (6.00, 6.40)
5.90 (5.60, 6.10)
15.70 (10.80, 18.30)
8.17 (5.39, 11.97)
4.21 ± 1.56
2.15 ± 0.99
Levels of apoA-I in the IGT and control groups
Values of HOMA-IR in the IGT and control groups
Correlation between apoA-I and HOMA-IR
Multiple regression analyses of anthropometric parameters and lipid profile associated with HOMA-IR
Multiple regression of parameters associated with HOMA-IR in patients with IGT (n = 108)
3.282 ~ 6.274
0.209 ~ 0.870
−2.382 ~ −0.558
Multiple regression of parameters associated with HOMA-IR in controls (n = 84)
−1.332 ~ 1.667
0.020 ~ 0.143
Logistic regression analysis of the anthropometric parameters and lipid profile associated with IGT
Logistic regression of anthropometric parameters and lipid profile associated with IGT (n = 182)
0.133 ~ 0.725
1.029 ~ 1.209
In the present study, patients with impaired glucose tolerance presented significantly lower levels of HDL-C and apoA-I than the controls. HDL-C is an anti-atherogenic lipoprotein. ApoA-I is a major functional component of HDL-C and is extensively involved in the cardiovascular protective effects of HDL-C . HDL-C and apoA-I transport cholesterol from cells into peripheral tissues, reduce oxidative stress, suppress inflammatory pathways , neutralize procoagulant properties of anionic phospholipids and attenuate the excessive stimulation of blood coagulation , and prevent LDL-C oxidation by removing oxidized phospholipids from LDL-C and from arterial wall cells . Therefore, the administration of apoA-I has been proposed for use as a potential therapeutic strategy to protect the cardiovascular system [16, 17]. Transgenic mice over-expressing apoA-I exhibit high HDL-C levels and low vascular lesions . Laboratory studies have shown that apoA-I reduces the lipid and macrophage content of arteries and decreases lesion formation in mouse and rabbit models of atherosclerosis [19, 20]. ApoA-I infusion has been documented to reduce atheroma volume in patients with coronary atherosclerosis compared with baseline . In addition, pharmacological strategies that target apoA-I, including the upregulation of its production with the bromodomain and extraterminal protein inhibitor RVX-208, the development of short peptide sequences that mimic its action, and its administration as a component of reconstituted HDL-C (containing apoA-I as its only protein and a phospholipid as its only lipid) have beneficial effects on inflammatory factors that are known to be involved in atherosclerosis and plaque stability [16, 22]. However, it has been demonstrated that TaqIB polymorphism in the cholesterol ester transfer protein gene has a significant impact on HDL-C levels, while the effect of a 75G/A polymorphism in the apoA-I gene was not significant . Although several clinical studies have indicated that low apoA-I levels are an independent risk factor for ASCVD [24–26], the underlying mechanism linking apoA-I with the delay of atherosclerotic plaque progression remains unknown. The results of various studies have supported the notion that apoA-I protection against cardiovascular events might at least in part be mediated through improving insulin sensitivity.
In our study, the IGT group exhibited higher HOMA-IR and FINS than the control group, a finding that might support the notion that IGT promotes the progression of ASCVD due to insulin resistance and hyperinsulinemia. Hyperinsulinemia caused by insulin resistance directly stimulates the in vitro migration of neutrophils and monocytes in response to chemokines that are secreted by atherosclerotic plaques . Hyperinsulinemia might promote atherosclerotic plaque necrosis by accelerating macrophage death . In particular, hyperinsulinemia induces the production of matrix metalloproteinase-9 (MMP-9), which provokes plaque instability and rupture . Pharmacological and behavioural treatments to reduce insulin resistance have been shown to repress MMP-9 secretion . Moreover, insulin resistance might intensify a serious atherothrombotic state by elevating platelet resistance to antiaggregating agents  and accelerating the production of procoagulatory factors . Thus, the evidence strongly supports an emerging role of insulin resistance in plaque instability and rupture.
The present cross-sectional study identified the inverse association between apoA-I and insulin resistance in patients with impaired glucose tolerance; this finding is similar to that of a previous study in patients with type 2 diabetes . Recent studies have reported that HDL-C and apoA-I improve pancreatic β-cell function. In human islet cell culture and animal studies, exogenous HDL-C has been found to attenuate the inflammation-induced apoptosis of pancreatic β-cells . The infusion of exogenous reconstituted HDL-C potentiated both insulin secretion and skeletal muscle glucose uptake in a small trial with type 2 diabetic patients . ApoA-I treatment was found to increase glucose-stimulated insulin secretion in mice that were fed a high-fat diet [33, 34] and ameliorated β-cell dysfunction by inhibiting β-cell apoptosis [9, 35]. The favourable effects of apoA-I on improving insulin sensitivity have been further investigated in human skeletal muscle cells and adipocytes, in which both HDL-C and apoA-I promoted glucose uptake independently of insulin stimulation [32, 36, 37]. The mechanism connecting low apoA-I to high insulin resistance has been unclear. However, recent studies have supported the hypothesis that apoA-I might exert beneficial effects on ameliorating insulin resistance through different pathways. Recently, a new concept has been accepted suggesting that insulin resistance might primarily start in the vascular endothelium . Endothelial nitric oxide synthase (eNOS) dysfunction might reduce microcirculatory blood flow and decrease the delivery of insulin within hormone-sensitive organs. Insulin-mediated glucose uptake has been found to be inhibited in eNOS−/− mice compared with wild type mice . Thus, the restoration of eNOS function can decrease insulin resistance . It has been proposed that apoA-I is fundamental for the process by which HDL-C activates eNOS . ApoA-I binding to the scavenger receptor-BI is required for the HDL-C activation of eNOS . Furthermore, apoA-I is responsible for the effects of endothelial cell migration. ApoA-I has been proven to prevent endothelial apoptosis that is induced by oxidized-LDL-C  and tumour necrosis factor α . It has been suggested that inflammation might be crucial for the development of insulin resistance and β-cell dysfunction . Inflammatory cytokines and acute-phase reactants are positively correlated with insulin resistance in patients with metabolic syndrome . The anti-inflammatory effects of apoA-I have been observed in both in vitro and in vivo studies. Reconstituted HDL-C has been found to inhibit the expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selection in activated endothelial cells growing in tissue culture . In macrophages, apoA-I has been shown to prevent inflammation by suppressing cluster of differentiation 40 L-induced activation of nuclear factor-κ-gene binding . A recent study has reported that changes in apoA-I but not in HDL-C are negatively correlated with changes in high-sensitivity C-reactive protein (hs-CRP), which is a predictor of the development of cardiovascular events . The increase of apoA-I that follows pitavastatin treatment is an independent predictor of decreased levels of hs-CRP . Hence, apoA-I might decrease insulin resistance by improving vascular endothelium function and inhibiting inflammation.
Therefore, we speculated that decreased insulin resistance due to increased apoA-I levels may partially explain the protective effects of apoA-I on the cardiovascular system that have been observed in clinical trials [24–26]. Increased insulin sensitivity that is mediated through high apoA-I levels favours the transport of glucose from the circulation into tissues and has potential clinical relevance in terms of reducing cardiovascular complications by removing excess glucose from the circulation and in providing adequate glucose to tissues for energy production, particularly in the context of cardiovascular events .
Importantly, the finding that apoA-I is negatively related to insulin resistance might partially explain our result that low apoA-I is an independent factor influencing impaired glucose tolerance. Recent studies have documented that insulin resistance is a major determinant of the development and progression of abnormal glucose metabolism . Increased insulin resistance drives a compensatory increase in insulin secretion during the early stage of abnormal glucose metabolism . However, the chronic overload of islet β-cells will lead to the deterioration of β-cell function, if sustained. When insulin secretion is insufficient and blood glucose levels rise, IGT and diabetes ultimately become overt. Therefore, IGT might be the result of chronic exposure to severe insulin resistance, which is at least partly induced by low apoA-I levels and which portends the earlier initiation of hyperglycaemia . Therefore, low apoA-I levels might be an independent risk factor for IGT.
The limitations of our study are as follows. First, our study population was limited to Chinese individuals. Therefore, our findings may not be directly applicable to other populations. Second, our sample size was small; thus, our findings were not powerful enough to account for potentially confounding factors in our analyses, and our results might have been improperly influenced by some outliers due to the small sample size. Third, the cross-sectional design of the present study does not allow us to determine the existence of a causal relationship but rather provides evidence for the association between low apoA-I levels and high insulin resistance in patients with impaired glucose tolerance. Our study certainly raises credible hypotheses that remain be confirmed and extended by future prospective cohort and mechanistic studies. Fourth, our study estimated insulin resistance based on HOMA-IR rather than by precise methods, such as the hyperinsulinemic euglycaemic clamp technique.
Here, we report a negative association between apoA-I and insulin resistance in patients with impaired glucose tolerance and demonstrate a correlation between low apoA-I levels and impaired glucose tolerance. These results indicate that apoA-I plays an important role in regulating insulin sensitivity and glucose metabolism in patients with impaired glucose tolerance.
2-hour postchallenge glucose
Atherosclerotic cardiovascular disease
Body mass index
Diastolic blood pressure
Endothelial nitric oxide synthase
Fasting blood glucose
High-density lipoprotein cholesterol
Homeostasis model assessment of insulin resistance
High-sensitivity C-reactive protein
Impaired glucose tolerance
Low-density lipoprotein cholesterol
Oral glucose tolerance test
Systolic blood pressure
This work was supported by grants from the Principal Research Project of Capital Medical University (No. 2016JYY130), the Undergraduate Scientific Researching Innovation Project of Capital Medical University (No. XSKY2016143) and the Research Project of Beijing Chao-Yang Hospital for Youth to Xiaomeng Feng.
Availability of data and materials
YX conceived the study; XF wrote the manuscript; XG and ZY collected and read the literature; and YX read and corrected the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study was approved by the Medicine and Pharmacy Ethics Committee of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. Written informed consent was obtained from all patients.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Festa A, Williams K, D’Agostino Jr R, Wagenknecht LE, Haffner SM. The natural course of beta-cell function in nondiabetic and diabetic individuals: the insulin resistance atherosclerosis study. Diabetes. 2006;55(4):1114–20.View ArticlePubMedGoogle Scholar
- Theuma P, Fonseca VA. Inflammation, insulin resistance, and atherosclerosis. Metab Syndr Relat D. 2004;2(2):105–13.View ArticleGoogle Scholar
- Gerstein HC, Santaguida P, Raina P, Morrison KM, Balion C, Hunt D, et al. Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies. Diabetes Res Clin Pract. 2007;78(3):305–12.View ArticlePubMedGoogle Scholar
- Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata diabetes study. Diabetes Care. 1999;22(6):920–4.View ArticlePubMedGoogle Scholar
- Ceriello A. Impaired glucose tolerance and cardiovascular disease: the possible role of post-prandial hyperglycemia. Am Heart J. 2004;147(5):803–7.View ArticlePubMedGoogle Scholar
- Bandeali S, Farmer J. High-density lipoprotein and atherosclerosis: the role of antioxidant activity. Curr Atheroscler Rep. 2012;14(2):101–7.View ArticlePubMedGoogle Scholar
- Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease? Prog Lipid Res. 2012;51(4):314–24.View ArticlePubMedGoogle Scholar
- McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372(9634):224–33.View ArticlePubMedGoogle Scholar
- Rütti S, Ehses JA, Sibler RA, Prazak R, Rohrer L, Georgopoulos S, et al. Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells. Endocrinology. 2009;150(10):4521–30.View ArticlePubMedGoogle Scholar
- Waldman B, Jenkins AJ, Davis TM, Taskinen MR, Scott R, O'Connell RL, et al. HDL-C and HDL-C/ApoA-I predict long-term progression of glycemia in established type 2 diabetes. Diabetes Care. 2014;37(8):2351–8.View ArticlePubMedGoogle Scholar
- Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373(9682):2215–21.View ArticlePubMedPubMed CentralGoogle Scholar
- Abbasi A, Corpeleijn E, Gansevoort RT, Gans RO, Hillege HL, Stolk RP, et al. Role of HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population: the PREVEND study. J Clin Endocrinol Metab. 2013;98(8):E1352–9.View ArticlePubMedGoogle Scholar
- American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2015;38 Suppl:S8–16.View ArticleGoogle Scholar
- Oslakovic C, Krisinger MJ, Andersson A, Jauhiainen M, Ehnholm C, Dahlback B. Anionic phospholipids lose their procoagulant properties when incorporated into high density lipoproteins. J Biol Chem. 2009;284(9):5896–904.View ArticlePubMedGoogle Scholar
- Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res. 2000;41(9):1495–508.PubMedGoogle Scholar
- Di Bartolo BA, Scherer DJ, Nicholls SJ. Inducing apolipoprotein A-I synthesis to reduce cardiovascular risk: from ASSERT to SUSTAIN and beyond. Arch Med Sci. 2016;12(6):1302–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Banach M, Aronow WS, Serban MC, Rysz J, Voroneanu L, Covic A. Lipids, blood pressure and kidney update 2015. Lipids Health Dis. 2015;14:167.View ArticlePubMedPubMed CentralGoogle Scholar
- Dansky HM, Charlton SA, Barlow CB, Tamminen M, Smith JD, Frank JS, et al. Apo A-I inhibits foam cell formation in Apo E-deficient mice after monocyte adherence to endothelium. J Clin Invest. 1999;104(1):31–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, et al. High-dose recombinant apolipoprotein A-I Milano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein E-deficient mice: potential implications for acute plaque stabilization. Circulation. 2001;103(25):3047–50.View ArticlePubMedGoogle Scholar
- Parolini C, Marchesi M, Lorenzon P, Castano M, Balconi E, Miragoli L, et al. Dose-related effects of repeated ETC.-216 (recombinant apolipoprotein A-I Milano/1-palmitoyl-2-oleoyl phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques. In vivo assessment by intravascular ultrasound and magnetic resonance imaging. J Am Coll Cardiol. 2008;51(11):1098–103.View ArticlePubMedGoogle Scholar
- Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant apoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292–300.View ArticlePubMedGoogle Scholar
- Nikolic D, Rizzo M, Mikhailidis DP, Wong NC, Banach M. An evaluation of RVX-208 for the treatment of atherosclerosis. Expert Opin Investig Drugs. 2015;24(10):1389–98.View ArticlePubMedGoogle Scholar
- Włodarczyk M, Wrzosek M, Nowicka G, Jabłonowska-Lietz B. Impact of variants in CETP and apo AI genes on serum HDL cholesterol levels in men and women from the Polish population. Arch Med Sci. 2016;12(6):1188–98.View ArticlePubMedPubMed CentralGoogle Scholar
- Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358(9298):2026–33.View ArticlePubMedGoogle Scholar
- Moss AJ, Goldstein RE, Marder VJ, Sparks CE, Oakes D, Greenberg H, et al. Thrombogenic factors and recurrent coronary events. Circulation. 1999;99(19):2517–22.View ArticlePubMedGoogle Scholar
- van Lennep JE, Westerveld HT, van Lennep HW, Zwinderman AH, Erkelens DW, van der Wall EE. Apolipoprotein concentrations during treatment and recurrent coronary artery disease events. Arterioscler Thromb Vasc Biol. 2000;20(11):2408–13.View ArticlePubMedGoogle Scholar
- Kappert K, Meyborg H, Clemenz M, Graf K, Fleck E, Kintscher U, et al. Insulin facilitates monocyte migration: a possible link to tissue inflammation in insulin-resistance. Biochem Biophys Res Commun. 2008;365(3):503–8.View ArticlePubMedGoogle Scholar
- Tabas I, Seimon T, Arellano J, Li Y, Forcheron F, Cui D, et al. The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis. Novartis Found Symp. 2007;286:99–109.View ArticlePubMedPubMed CentralGoogle Scholar
- Boden G, Song W, Pashko L, Kresge K. In vivo effects of insulin and free fatty acids on matrix metalloproteinases in rat aorta. Diabetes. 2008;57(2):476–83.View ArticlePubMedGoogle Scholar
- Grant PJ. The genetics of atherothrombotic disorders: a clinician’s view. J Thromb Haemost. 2003;1(7):1381–90.View ArticlePubMedGoogle Scholar
- Anfossi G, Russo I, Trovati M. Platelet resistance to the anti-aggregating agents in the insulin resistant states. Curr Diabetes Rev. 2006;2(4):409–30.View ArticlePubMedGoogle Scholar
- Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009;119(15):2103–11.View ArticlePubMedGoogle Scholar
- Stenkula KG, Lindahl M, Petrlova J, Dalla-Riva J, Göransson O, Cushman SW, et al. Single injections of apoA-I acutely improve in vivo glucose tolerance in insulin-resistant mice. Diabetologia. 2014;57(4):797–800.View ArticlePubMedPubMed CentralGoogle Scholar
- McGrath KC, Li XH, Whitworth PT, Kasz R, Tan JT, McLennan SV, et al. High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation. J Lipid Res. 2014;55(3):421–30.View ArticlePubMedPubMed CentralGoogle Scholar
- Pétremand J, Bulat N, Butty AC, Poussin C, Rütti S, Au K, et al. Involvement of 4E-BP1 in the protection induced by HDLs on pancreatic beta-cells. Mol Endocrinol. 2008;23(10):1572–86.View ArticleGoogle Scholar
- Dalla-Riva J, Stenkula KG, Petrlova J, Lagerstedt JO. Discoidal HDL and apoA-I-derived peptides improve glucose uptake in skeletal muscle. J Lipid Res. 2013;54(5):1275–82.View ArticlePubMedPubMed CentralGoogle Scholar
- Han R, Lai R, Ding Q, Wang Z, Luo X, Zhang Y, et al. Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism. Diabetologia. 2007;50(9):1960–8.View ArticlePubMedGoogle Scholar
- Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011;13(3):294–307.View ArticlePubMedGoogle Scholar
- Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation. 2001;104(3):342–5.View ArticlePubMedGoogle Scholar
- Hasegawa Y, Saito T, Ogihara T, Ishigaki Y, Yamada T, Imai J, et al. Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation. 2012;125(9):1122–33.View ArticlePubMedGoogle Scholar
- Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, et al. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med. 2001;7(7):853–7.View ArticlePubMedGoogle Scholar
- Suc I, Escargueil-Blanc I, Troly M, Salvayre R, Nègre-Salvayre A. HDL and ApoA prevent cell death of endothelial cells induced by oxidized LDL. Arterioscler Thromb Vasc Biol. 1997;17(10):2158–66.View ArticlePubMedGoogle Scholar
- Sugano M, Tsuchida K, Makino N. High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis. Biochem Biophys Res Commun. 2000;272(3):872–6.View ArticlePubMedGoogle Scholar
- Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27(3):813–23.View ArticlePubMedGoogle Scholar
- Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes. 2003;27:S53–5.View ArticleGoogle Scholar
- Cockerill GW, Rye KA, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol. 1995;15(11):1987–94.View ArticlePubMedGoogle Scholar
- Yin K, Chen WJ, Zhou ZG, Zhao GJ, Lv YC, Ouyang XP, et al. Apolipoprotein A-I inhibits CD40 proinflammatory signaling via ATP-binding cassette transporter A1-mediated modulation of lipid raft in macrophages. J Atheroscler Thromb. 2012;19(9):823–36.View ArticlePubMedGoogle Scholar
- Yousuf O, Mohanty BD, Martin SS, Joshi PH, Blaha MJ, Nasir K, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013;62(5):397–408.View ArticlePubMedGoogle Scholar
- Tani S, Takahashi A, Nagao K, Hirayama A. Contribution of apolipoprotein A-I to the reduction in high-sensitivity C-reactive protein levels by different statins: comparative study of pitavastatin and atorvastatin. Heart Vessels. 2015;30(6):762–70.View ArticlePubMedGoogle Scholar
- Siebel AL, Heywood SE, Kingwell BA. HDL and glucose metabolism: current evidence and therapeutic potential. Front Pharmacol. 2015;6:258.View ArticlePubMedPubMed CentralGoogle Scholar