Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease. Feng Ma,Darabi Maryam,Tubeuf Emilie,Canicio Aurélie,Lhomme Marie,Frisdal Eric,Lanfranchi-Lebreton Sandrine,Matheron Lucrèce,Rached Fabiana,Ponnaiah Maharajah,Serrano Carlos V,Santos Raul D,Brites Fernando,Bolbach Gerard,Gautier Emmanuel,Huby Thierry,Carrie Alain,Bruckert Eric,Guerin Maryse,Couvert Philippe,Giral Philippe,Lesnik Philippe,Le Goff Wilfried,Guillas Isabelle,Kontush Anatol European journal of preventive cardiology BACKGROUND:Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk. METHODS:To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase. RESULTS:When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis. CONCLUSIONS:Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis. 10.1177/2047487319894114

Insulin resistance and risk of vascular events, interventions and mortality in type 1 diabetes. European journal of endocrinology OBJECTIVE:To identify determinants associated with insulin resistance and to assess the association between insulin resistance and cardiovascular events, vascular interventions and mortality in people with type 1 diabetes at high risk of cardiovascular disease. DESIGN:Prospective cohort study. METHODS:One hundred and ninety-five people with type 1 diabetes from the Secondary Manifestations of ARTerial disease (SMART) cohort were included. Insulin resistance was quantified by the estimated glucose disposal rate (eGDR) with higher eGDR levels indicating higher insulin sensitivity (i.e. lower eGDR levels indicating higher insulin resistance). Linear regression models were used to evaluate determinants associated with eGDR. The effect of eGDR on cardiovascular events, cardiovascular events or vascular interventions (combined endpoint) and on all-cause mortality was analysed using Cox proportional hazards models adjusted for confounders. RESULTS:In 195 individuals (median follow-up 12.9 years, IQR 6.7-17.0), a total of 25 cardiovascular events, 26 vascular interventions and 27 deaths were observed. High eGDR as a marker for preserved insulin sensitivity was independently associated with a lower risk of cardiovascular events (HR: 0.75; 95% CI: 0.61-0.91), a lower risk of cardiovascular events and vascular interventions (HR: 0.74; 95% CI: 0.63-0.87) and a lower risk of all-cause mortality (HR: 0.81; 95% CI: 0.67-0.98). CONCLUSIONS:Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease. 10.1530/EJE-21-0636

Comparison between indexes of insulin resistance for risk prediction of cardiovascular diseases or development of diabetes. Zethelius Björn,Cederholm Jan Diabetes research and clinical practice AIM:The predictive effect of various insulin resistance indexes for risk of cardiovascular diseases (CVD) or type 2 diabetes (T2DM) is still unclear. METHODS:One thousand and forty-nine 71-years-old male subjects from the Swedish ULSAM study, mean follow-up 9 years. All subjects performed the euglycemic insulin clamp for M/I [glucose disposal/mean insulin], and 75-g oral glucose tolerance test for Ceder-IR: 1/glucose uptake rate/[mean glucose×log mean insulin]; Matsuda-IR: 1/10,000/square root [glucose0×insulin0×glucose120×insulin120]; Belfiore-IR: 1/([glucose0+glucose120]/normal mean glucose×[insulin0+insulin120]/normal mean insulin)+1); and HOMA-IR: [glucose0×insulin0]/22.5. RESULTS:Bland-Altman plots showed best agreement between M/I versus Belfiore-IR and Ceder-IR with mean difference near zero, -0.21 to -0.46, while -0.68 to -0.77 for the other indexes. ISI-Ceder was the strongest predictor for incident nonfatal/fatal ischemic heart disease (CHD) or CVD at Cox regression in all subjects, and for incident T2DM at logistic regression in 1024 subjects with no baseline T2DM, with significantly higher hazard ratios or odds ratios than with all other indexes, also with best model fit, after adjusting for clinical characteristics and the traditional cardiovascular risk factors, including metabolic syndrome for CVD risk. CONCLUSION:Ceder-IR performed strongest as independent predictor for incidences of CHD/CVD and T2DM. 10.1016/j.diabres.2015.09.003

Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. Patel Tushar P,Rawal Komal,Bagchi Ashim K,Akolkar Gauri,Bernardes Nathalia,Dias Danielle da Silva,Gupta Sarita,Singal Pawan K Heart failure reviews Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here. 10.1007/s10741-015-9515-6

The Association between Insulin Resistance and Cardiovascular Disease Risk: A Community-Based Cross-Sectional Study among Taiwanese People Aged over 50 Years. Lu Mei-Chun,Fang Wei-Ching,Li Wen-Cheng,Yeh Wei-Chung,Shieh Ying-Hua,Chen Jau-Yuan International journal of environmental research and public health BACKGROUND AND AIMS:Previous studies have implied that insulin resistance (IR) could represent a major underlying abnormality leading to cardiovascular disease (CVD). The aim of this study was to evaluate the relationships between IR (estimated by the homeostasis model assessment of IR (HOMA-IR) index) and CVD risk among middle-aged and elderly Taiwanese individuals. METHODS:In this cross-sectional, community-based study, a total of 320 participants were interviewed to collect demographical parameters and blood samples. The recruited participants were divided into tertiles according to their levels of HOMA-IR. The Framingham risk score (FRS) was calculated according to the 2008 general CVD risk model from the Framingham Heart Study. RESULTS:The HOMA-IR index was significantly correlated with the FRS, with a Pearson's coefficient of 0.22. In the multiple logistic regression model, a higher HOMA-IR level was significantly associated with a high FRS (FRS ≥ 20%) (highest tertile vs. lowest tertile of HOMA-IR, crude OR = 3.69; 95% CI = 1.79-7.62), even after adjusting for smoking, fasting plasma glucose (FPG), and systolic blood pressure (SBP) (highest tertile vs. lowest tertile of HOMA-IR, adjusted OR = 11.51; 95% CI = 2.55-51.94). The area under the receiver operating characteristic curve for the HOMA-IR index as the predictor of high FRS was 0.627, and the optimal HOMA-IR cutoff value was 1.215 (sensitivity = 83.6%, specificity = 42.9%). CONCLUSIONS:We considered that HOMA-IR is an independent factor but that it cannot be used solely for evaluating the CVD risk due to the low AUC value. Further prospective cohort studies are warranted to better assess the relationship between CVD risk and insulin resistance. 10.3390/ijerph17197195