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Effects of hyperlipidaemia on glucocorticoid metabolism: results of a randomized controlled trial in healthy young women.
Mai, K, Reinecke, F, Andres, J, Bobbert, T, Kraatz, J, Wudy, SA, Hartmann, MF, Maser-Gluth, C, Pfeiffer, AF, Spranger, J
Clinical endocrinology. 2011;(5):551-7
Abstract
OBJECTIVE It is well established that the hypothalamic-pituitary-adrenal (HPA) axis is altered in obese individuals. Hyperlipidaemia with elevated levels of free fatty acids (FFAs) is also frequently seen in obesity and in the metabolic syndrome. We hypothesized, therefore, that hyperlipidaemia may alter the activity of the HPA axis. PATIENTS AND METHODS The effects of hyperlipidaemia, including increased circulating FFAs, on ACTH secretion and cortisol metabolism were analysed in 13 healthy young women during the early follicular phase of two subsequent cycles. We administered a 20% lipid/heparin (LHI) or a saline/heparin infusion (SHI) using a crossover design in random order for 330 min. A detailed characterization of glucocorticoid metabolism was performed by measurement of plasma ACTH, cortisol and urinary excretion rates of adrenal glucocorticoids and the glucocorticoid metabolites. RESULTS We observed that LHI-induced hyperlipidaemia elevated serum cortisol levels compared to SHI. No changes in plasma ACTH levels, daily urinary excretion rates of adrenal glucocorticoids, glucocorticoid precursors/metabolites and the calculated activities of the 5α-reductase, 3β-hydroxysteroid dehydrogenase (HSD), 11-, 17-, 21-hydroxylase and 11β-HSD 1 or 2 were found. CONCLUSION Our randomized controlled trial suggests that the adrenal sensitivity to ACTH may be enhanced by LHI-induced hyperlipidaemia in normal-weight healthy young women. This effect might contribute to the disturbances of the HPA axis described in women with abdominal obesity and impaired lipid metabolism.
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Exchanging saturated fatty acids for (n-6) polyunsaturated fatty acids in a mixed meal may decrease postprandial lipemia and markers of inflammation and endothelial activity in overweight men.
Masson, CJ, Mensink, RP
The Journal of nutrition. 2011;(5):816-21
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Abstract
Postprandial lipemia, low-grade systemic inflammation, and endothelial activity are related to metabolic disorders. It is well known that dietary fatty acid composition modulates postprandial lipemia, but information on the other metabolic risk markers is limited. We therefore studied the acute effects of a meal rich in SFA compared with those of a meal rich in (n-6) PUFA on postprandial responses in overweight men who are at an increased risk to develop the metabolic syndrome and its comorbidities. In a crossover design, the effects of 50 g butter (rich in SFA) on lipemia and markers for inflammation and endothelial activity were compared with those of 50 g sunflower oil [rich in (n-6) PUFA] during an 8-h postprandial mixed meal tolerance test in 13 overweight men. Postprandial changes in serum TG were comparable between the meals (P = 0.38), except for a reduction in the incremental area under the curve (P = 0.046) in the late postprandial phase after (n-6) PUFA (125 ± 96 mmol⋅min⋅L(-1)) compared with SFA (148 ± 98 mmol⋅min⋅L(-1)). Compared with the SFA meal, the (n-6) PUFA meal decreased plasma IL-6 (P = 0.003), TNFα (P = 0.005), soluble TNF receptors I and II (sTNFr; P = 0.024 and P < 0.001, respectively), and soluble vascular cell adhesion molecule-1 (sVCAM-1; P = 0.030) concentrations. These results indicate that exchanging SFA from butterfat for (n-6) PUFA in a mixed meal may decrease postprandial lipemia and concentrations of IL-6, TNFα, sTNFr-I and -II, and sVCAM-1 in overweight men.
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Long-term efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidaemic patients with diabetes or metabolic syndrome.
Fazio, S, Guyton, JR, Lin, J, Tomassini, JE, Shah, A, Tershakovec, AM
Diabetes, obesity & metabolism. 2010;(11):983-93
Abstract
AIMS: To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended-release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non-DM) or neither (non-DM/non-MetS). METHODS A subgroup analysis of a double-blind, 64-week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2-g dose were included in the analysis. RESULTS E/S+N improved levels of low-density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high-density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high-sensitivity C-reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New-onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N-containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during the 24-64 week extension study, diabetes was diagnosed in five additional patients in the E/S(cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%). Treatment-incident elevations in uric acid levels were increased among subjects assigned to N-containing regimens, but there were no effects on symptomatic gout. CONCLUSION Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels.
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Heart positive: design of a randomized controlled clinical trial of intensive lifestyle intervention, niacin and fenofibrate for HIV lipodystrophy/dyslipidemia.
Samson, SL, Pownall, HJ, Scott, LW, Ballantyne, CM, Smith, EO, Sekhar, RV, Balasubramanyam, A
Contemporary clinical trials. 2006;(6):518-30
Abstract
Dyslipidemia and insulin resistance occur in a large proportion of HIV-infected patients treated with highly active antiretroviral therapy (HAART); anthropomorphic changes, such as lipoatrophy and central obesity, occur in a subset of patients. This cluster of clinical features, which is termed HIV lipodystrophy, places patients at increased risk for cardiovascular disease. Currently, there is no consensus on the appropriate therapy for the management of HIV lipodystrophy for which the underlying defects are enhanced lipolysis, impaired fat oxidation, increased hepatic VLDL-triglyceride synthesis and secretion, and impaired disposal of intestinally-derived lipoprotein-triglycerides. We describe the design of a randomized, placebo-controlled trial to compare the effects of usual care to diet, exercise and lipid-lowering drugs on lipid profiles of patients with HIV lipodystrophy. The trial will randomize 200 patients into five groups. Outcomes of usual care, diet and exercise alone or in combination with niacin, fenofibrate or both medications will be compared after six months. Unique aspects of the design include an interactive Internet Diet Management system to increase ATP-III recommended dietary compliance for metabolic syndrome, and a supervised program of aerobic and resistance exercises. The study is powered to detect a 20% decrease in triglycerides with the lifestyle intervention and an additional 20% improvement with the addition of niacin and/or fenofibrate. Secondary outcomes include assessment of lipid profile changes, LDL and HDL particle size, plasma cholesterol ester transport protein activity, visceral and subcutaneous fat distribution, glucose tolerance, insulin resistance, and leptin and adiponectin levels.
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Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation.
Ibáñez, L, Valls, C, Ferrer, A, Ong, K, Dunger, DB, De Zegher, F
The Journal of clinical endocrinology and metabolism. 2002;(6):2870-4
Abstract
The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m(2); hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated. In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.