Apolipoprotein E and lipoprotein lipase gene polymorphisms interaction on the atherogenic combined expression of hypertriglyceridemia and hyperapobetalipoproteinemia phenotypes.

The combination of hypertriglyceridemia (hyperTG) and hyperapobetalipoproteinemia (hyperapoB) is associated with an increased coronary artery disease (CAD) risk. Apolipoprotein (apo) E and lipoprotein lipase (LPL) genes are involved in the catabolism of triglycerides (TG)-rich apoB-containing lipoproteins (VLDL). Several apoE and LPL gene variants affecting CAD risk, plasma TG or apoB concentrations have an allelic frequency of >5% in the general population. This study examined the combined effect of frequent apoE and LPL gene polymorphisms on the expression of hyperTG and hyperapoB. ApoE (E2, E3, and E4) and LPL (D9N, N291S, G188E, and P207L) were genotyped and fasting lipid profiles were assessed among 1,441 French-Canadian subjects. Multivariate analyses were performed to estimate the relationship between apoE and LPL gene variants and the risk of hyperTG (TG>1.7 mmol/l) and hyperapoB (apoB>0.9 g/l). Compared to apoE3 carriers, the apoE4 allele significantly increased the risk of expressing the "hyperTG/hyperapoB" phenotype [odds ratio (OR)=1.95; p=0.014]. This risk was significantly exacerbated (OR=4.69; p=0.017) by the presence of frequent deleterious LPL gene variants in this population. The apoE2 allele was negatively associated with hyperTG/hyperapoB (OR=0.49; p=0.002) in the absence of a deleterious LPL gene variant. These results suggest that epistasis is a phenomenon to consider while assessing the CAD risk associated with gene variants or the effect of frequent alleles on high-risk lipid profiles.

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects.

BACKGROUND: Abdominal obesity and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) increase cardiovascular risk. The very low-density lipoprotein (VLDL) is a triglyceride (TG)-rich particle. Frequent variations in the genes coding for enzymes and proteins involved in the VLDL catabolism have already been documented. The epistatic effect of such variants on the risk profile associated with abdominal obesity remains to be elucidated. OBJECTIVE: This study aims to assess the effect of combinations of frequent single-nucleotide polymorphisms (SNPs) in the VLDL catabolic pathway on the relation between abdominal obesity and fasting TG. METHOD: Only gene variants in the lipoprotein lipase, apolipoprotein (apo) CIII, hepatic lipase and apo E genes known to be frequent in the general population (allele frequency>5%) were included in this study. The presence of selected SNPs was detected by polymerase chain reaction-restriction fragment length polymorphism in a sample of 640 non-diabetic French Canadians at high cardiovascular risk (405 obese, 235 non-obese). RESULTS: Carrying more than two frequent gene variants involved in the VLDL catabolic pathway significantly increased the risk of hyperTG (odds ratio of TG>1.7 mmol/l=4.15; P=0.001). This effect was proportional to the number of SNPs and genes involved and was significantly amplified by the presence of abdominal obesity defined on the basis of waist circumference. CONCLUSION: When combined with abdominal obesity, epistasis in the VLDL pathway has a deleterious effect on fasting TG and coronary artery disease risk profile according to the TG threshold (1.7 mmol/l) used in medical guidelines for the assessment of the metabolic syndrome and associated risk.

Effects of insulin on regional blood flow and glucose uptake in Wistar and Sprague-Dawley rats.

The euglycemic-hyperinsulinemic clamp technique in conscious Sprague-Dawley and Wistar rats chronically instrumented with intravascular catheters and pulsed Doppler flow probes was used to examine insulin's actions on regional blood flow and glucose metabolism. The effect of insulin on in vivo and in vitro glucose utilization in individual muscles was estimated using [3H]-2-deoxy-D-glucose. We found that in both strains, insulin (4, 32, and 64 mU x kg(-1) x min(-1)) causes similar cardiovascular changes characterized by slight increases in blood pressure (at high dose), vasodilation in renal and hindquarter vascular beds, and vasoconstriction (at high dose) in the superior mesenteric vascular bed. However, at the lowest dose of insulin tested, we found a smaller insulin sensitivity index and a lower insulin-stimulated in vivo glucose uptake in extensor digitorum longus (EDL) muscles of Wistar versus Sprague-Dawley rats. Higher insulin-stimulated glucose transport activity was found in isolated soleus muscle, while greater basal glucose transport was noted in isolated EDL muscle from Sprague-Dawley versus Wistar rats. These results provide further evidence for an insulin blood flow-regulatory effect and suggest that strain characteristics (differences in muscle perfusion, hindquarter composition, or fiber insulin sensitivity) constitute a major determinant in the variation in whole-body insulin sensitivity.

Effect of metformin on the vascular and glucose metabolic actions of insulin in hypertensive rats.

We investigated the long-term effect of metformin treatment on blood pressure, insulin sensitivity, and vascular responses to insulin in conscious spontaneously hypertensive rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and blood flow. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique. Two groups of SHR received metformin (100 or 300 mg x kg(-1) x day(-1)) for 3 wk while another group of SHR and a group of Wistar Kyoto (WKY) rats were left untreated. We found that vasodilation of skeletal muscle and renal vasculatures by insulin is impaired in SHR. Moreover, a reduced insulin sensitivity was detected in vivo and in vitro in isolated soleus and extensor digitorum longus muscles from SHR compared with WKY rats. Three weeks of treatment with metformin improves the whole-body insulin-mediated glucose disposal in SHR but has no blood pressure-lowering effect and no influence on vascular responses to insulin (4 mU x kg(-1) x min(-1)). An improvement in insulin-mediated glucose transport activity was detected in isolated muscles from metformin-treated SHR, but in the absence of insulin no changes in basal glucose transport activity were observed. It is suggested that part of the beneficial effect of metformin on insulin resistance results from a potentiation of the hormone-stimulating effect on glucose transport in peripheral tissues (mainly skeletal muscle). The results argue against a significant antihypertensive or vascular effect of metformin in SHR.

Isradipine and insulin sensitivity in hypertensive rats.

The present study was designed to investigate the effect of a reduction in blood pressure, by using the calcium channel antagonist isradipine, on insulin sensitivity and vascular responses to insulin in conscious spontaneously hypertensive male rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and blood flows. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp technique. Two groups of rats received isradipine at a dose of 0.05 or 0.15 mg. kg-1. h-1, whereas a third group received a continuous infusion of vehicle (15% DMSO). Both doses of isradipine were found to decrease mean blood pressure (-25 +/- 4 mmHg at the dose of 0.05 mg. kg-1. h-1 and -20 +/- 2 mmHg at the dose of 0.15 mg. kg-1. h-1) and to improve insulin sensitivity. Moreover, in the rats treated with the low dose of isradipine, we observed vasodilations in renal, superior mesenteric, and hindquarter vascular beds. In the untreated group, the euglycemic infusion of insulin (4 mU. kg-1. min-1) was found to cause vasoconstrictions in superior mesenteric and hindquarter vascular beds, but no changes in mean blood pressure, heart rate, or renal vascular conductance were found. In contrast, in the isradipine-treated groups, the same dose of insulin was found to produce vasodilations in the renal vascular bed and to abolish the vasoconstrictor responses previously observed. We concluded that short-term treatment with isradipine in SHR can lower blood pressure and improve insulin sensitivity, mainly through hemodynamic factors, as supported by experiments with hydralazine as a positive vasodilator control.