ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

<p>Abstract</p> <p>Background</p> <p>Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the <it>ANGPTL4 </it>coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D.</p> <p>Methods</p> <p>The association of <it>ANGPTL4 </it>E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels.</p> <p>Results</p> <p>Among non-Hispanic White Look AHEAD participants, <it>ANGPTL4 </it>K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels.</p> <p>Conclusions</p> <p>This is the first study to demonstrate that the <it>ANGPTL4 </it>E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that <it>ANGPTL4 </it>genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.</p

The effect of prior walking on coronary heart disease risk markers in South Asian and European men.

Purpose: Heart disease risk is elevated in South Asians possibly due to impaired postprandial metabolism. Running has been shown to induce greater reductions in postprandial lipaemia in South Asian than European men but the effect of walking in South Asians is unknown. Methods: Fifteen South Asian and 14 White European men aged 19-30 years completed two, 2-d trials in a randomised crossover design. On day 1, participants rested (control) or walked for 60 min at approximately 50% maximum oxygen uptake (exercise). On day 2, participants rested and consumed two high fat meals over a 9h period during which 14 venous blood samples were collected. Results: South Asians exhibited higher postprandial triacylglycerol (geometric mean (95% confidence interval) 2.29(1.82 to 2.89) vs. 1.54(1.21 to 1.96) mmol·L-1·hr-1), glucose (5.49(5.21 to 5.79) vs. 5.05(4.78 to 5.33) mmol·L-1·hr-1), insulin (32.9(25.7 to 42.1) vs. 18.3(14.2 to 23.7) µU·mL-1·hr-1) and interleukin-6 (2.44(1.61 to 3.67) vs. 1.04(0.68 to 1.59) pg·mL-1·hr-1) than Europeans (all ES ≥ 0.72, P≤0.03). Between-group differences in triacylglycerol, glucose and insulin were not significant after controlling for age and percentage body fat. Walking reduced postprandial triacylglycerol (1.79(1.52 to 2.12) vs. 1.97(1.67 to 2.33) mmol·L-1·hr-1) and insulin (21.0(17.0 to 26.0) vs. 28.7(23.2 to 35.4) µU·mL-1·hr-1) (all ES ≥ 0.23. P≤0.01), but group differences were not significant. Conclusions: Healthy South Asians exhibited impaired postprandial metabolism compared with White Europeans, but these differences were diminished after controlling for potential confounders. The small-moderate reduction in postprandial triacylglycerol and insulin after brisk walking was not different between the ethnicities

Angiotensin II receptor blockers and insulin resistance

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Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups

In a randomized, double-blind study (n = 58) with parallel groups, the effects of diltiazem (mean dose 329 mg/day) and atenolol (mean dose 67 mg/day) on carbohydrate and lipoprotein metabolism in hypertensive patients were compared. The mean systolic blood pressure (SBP)/diastolic blood pressure (DBP) reductions in the supine position were similar and satisfactory, 9/11 and 11/9 mmHg during atenolol and diltiazem treatment, respectively. Insulin-mediated glucose uptake, measured with the euglycaemic insulin clamp technique, decreased during atenolol treatment, from 7.1 to 5.6 mg/kg per min (P = 0.05). but not during treatment with diltiazem (initial value 6.8, final value 6.7 mg/kg per min; P greater than 0.8). Treatment differences between groups were statistically significant (P less than 0.05). During atenolol treatment there was a slight but significant increase in plasma glucose in the fasting state (P less than 0.05) and at the end of an intravenous glucose tolerance test (IVGTT; P less than 0.01), and in plasma insulin at the end of IVGTT (P less than 0.05). Despite increased insulin resistance the increase in insulin response was small, suggesting inhibition of insulin release. The insulin peak was decreased by 13% during diltiazem treatment (P less than 0.05). The concentrations of very-low and low-density lipoprotein triglycerides increased, whereas high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol was unaffected during atenolol treatment. In conclusion, there was no difference between the antihypertensive effects of atenolol and diltiazem, but atenolol decreased insulin sensitivity and altered the lipid profile, thus possibly increasing the risk of diabetes mellitus and theoretically reducing the benefits of blood pressure reduction with regard to risk of coronary heart disease

Influences of different antihypertensive treatments on indices of systemic mineral metabolism

A negative calcium balance has previously been described in human hypertension with low levels of plasma ionized calcium (Ca2+) and an increased urinary excretion of calcium. The cause of this disturbance in mineral metabolism is not known, nor is it known if this derangement could be abolished if blood pressure is reduced by antihypertensive treatment. In the present investigation, the effects of antihypertensive monotherapy on serum and fasting urinary electrolytes were studied. For 3 to 6 months, 319 hypertensive patients entered 17 study groups, each group using one of the following antihypertensive drugs: dilevalol, metoprolol, antenolol, pindolol, propranolol, hydrochlorothiazide, bendrofluomethiazide, furosemide, spironolactone, doxazocine, prazocine, diltiazem, verapamil, nifedipine, isradipine, captopril, or lisinopril. Treatment with different beta-blockers, as well as diuretics, reduced the fasting urinary calcium excretion (P < .001). However, while the beta-blockers increased the proportion of the ionized form of calcium in blood (Ca2+) (P < .001), Ca2+ was further decreased by diuretic treatment (P < .05). Angiotensin converting enzyme inhibitors caused no major changes in mineral metabolism while of the calcium antagonists studied only verapamil raised the levels of Ca2+ (P < .01). No significant relationship between the changes in mineral metabolism and the reduction in blood pressure was observed in any of the treatment groups. Of the antihypertensive drugs used in the present study, beta-blockers appeared to reverse the basic abnormality with regard to calcium balance, suggesting that the activity of the sympathetic nerve system is involved in the disturbed calcium metabolism seen in hypertensive patients

Long-term treatment with active vitamin D (alphacalcidol) in middle-aged men with impaired glucose tolerance. Effects on insulin secretion and sensitivity, glucose tolerance and blood pressure

There are specific receptors for the active metabolite of vitamin D on the pancreatic beta cells and severe vitamin D deficiency can inhibit insulin secretion. In the present study 14 middle aged men with impaired glucose tolerance and low glucose-stimulated insulin values received 2 micrograms alphacalcidol daily for 18 months. On treatment there was a transient increase of both the peak and the late insulin response to intravenous glucose while neither intravenous nor oral glucose tolerance were consistently altered. Nor was the peripheral insulin sensitivity, measured by the euglycemic clamp technique, significantly affected. In the untreated state there was a positive relationship (r = 0.77) between the tissue insulin sensitivity and the serum concentrations of 25-hydroxyvitamin D. There was also an inverse relationship (r = 0.61) between systolic blood pressure and the serum levels of 1,25-dihydroxy vitamin D. Although the subjects were normotensive and not overweight, treatment with alphacalcidol tended to lower both systolic (6 +/- 12 mmHg) and diastolic blood pressures (5.8 +/- 9.1 mmHg) and there was a small reduction (0.9 kg) in body weight. In conclusion, subjects with impaired glucose tolerance without vitamin D deficiency do not benefit from vitamin D supplementation, which however has some hypotensive action also in normotensive individuals