Metabolic Response to Omega-3 Fatty Acids and Vitamin E Co-Supplementation in Patients with Fibrocystic Breast Disease: A Randomized, Double-Blind, Placebo-Controlled Trial.
Seyyed Mehdi MirhashemiMehdi SahmaniBehnaz SalehiJavad Zavar RezaMohsen TaghizadehNushin MoussaviBita BadehnooshZatollah Asemi
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There is scarce data on the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with fibrocystic breast disease (FBD). The current study was carried out to determine the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with FBD.A randomized clinical trial was conducted on 56 patients with FBD. Participants were randomly divided into two groups to receive either 1000 mg omega-3 fatty acids plus 400 mg vitamin E (n = 28) or placebo (n = 28) for 12 weeks. Fasting blood samples were taken at the beginning of the study and after 12 weeks of intervention to determine inflammatory factors, biomarkers of oxidative stress, and metabolic profiles.After 12 weeks of intervention, changes in serum high-sensitivity C-reactive protein (-2171.4 ± 3189.1 vs. +696.9 ± 2774.8 ng/mL, P = 0.001) and plasma nitric oxide (+1.8 ± 4.0 vs. -0.1 ± 2.4 µmol/L, P = 0.04) in supplemented women were significantly different from those in the placebo group. In addition, compared to the placebo group, subjects who consumed omega-3 fatty acids plus vitamin E supplements had significantly decreased serum insulin concentrations (-3.2 ± 6.5 vs. -0.2 ± 1.7 µIU/mL, P = 0.01), the homeostasis model of assessment-estimated insulin resistance (-0.8 ± 1.7 vs. -0.02 ± 0.4, P = 0.03), serum triglycerides levels (-11.5 ± 47.3 vs. +10.6 ± 24.3 mg/dL, P = 0.03) and VLDL-cholesterol (-2.3 ± 9.5 vs. +2.1 ± 4.9 mg/dL, P = 0.03), as well as increased quantitative insulin sensitivity check index (+0.01 ± 0.01 vs. +0.001 ± 0.007, P = 0.001) and HDL-cholesterol (+3.4 ± 6.0 vs. -1.3 ± 4.3 mg/dL, P = 0.001).Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks had beneficial effects on inflammatory markers and metabolic profiles in patients with FBD.Cite
Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.
Pioglitazone
Thiazolidinedione
Glucose clamp technique
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Chronic peroxisome proliferator-activated receptor (PPAR)-α activation improves glucose metabolism in rodent models of insulin resistance and diabetes; however, PPAR-α deficiency was also reported to protect against high-fat diet (HFD)-induced insulin resistance. The aim of this study was to clarify the role of PPAR-α in the development of insulin resistance using PPAR-α knockout (KO) mice and wild-type controls (WT). Both WT and PPAR-α KO mice on HFD gained significantly more weight relative to chow-fed groups and displayed an increase in insulin levels and a decrease in adiponectin levels. Hyperinsulinemic-euglycemic clamp performed in the nonfasting state demonstrated that HFD caused a marked reduction in whole body, muscle, and white and brown adipose tissue glucose uptake in both WT and PPAR-α KO mice relative to chow-fed groups. Suppression of endogenous glucose production during the clamp was markedly blunted in both WT and PPAR-α KO HFD-fed mice, indicating liver insulin resistance. The magnitude of HFD-induced changes in the clamp parameters of insulin sensitivity was comparable in PPAR-α KO and WT mice. In conclusion, these data show that PPAR-α deficiency does not alter insulin sensitivity in mice fed normal chow diet and does not protect against HFD-induced insulin resistance as measured by hyperinsulinemic-euglycemic clamp in nonfasted state.
Glucose clamp technique
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Hyperinsulinemia is widely thought to be a compensatory response to insulin resistance, whereas its potentially causal role in the progression of insulin resistance remains to be established. Here, we aimed to examine whether hyperinsulinemia could affect the progression of insulin resistance in Zucker fatty diabetic (ZDF) rats. Male ZDF rats at 8 wk of age were fed a diet ad libitum (AL) or dietary restriction (DR) of either 15 or 30% from AL feeding over 6 wk. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. ZDF rats in the AL group progressively developed hyperglycemia and hyperinsulinemia by 10 wk of age, and then plasma insulin rapidly declined to nearly normal levels by 12 wk of age. Compared with AL group, DR groups showed delayed onset of hyperglycemia and persistent hyperinsulinemia, leading to weight gain and raised plasma triglycerides and free fatty acids by 14 wk of age. Notably, insulin sensitivity was significantly reduced in the DR group rather than the AL group and inversely correlated with plasma levels of insulin and triglyceride but not glucose. Moreover, enhanced lipid deposition and upregulation of genes involved in lipogenesis were detected in liver, skeletal muscle, and adipose tissues of the DR group rather than the AL group. Alternatively, continuous hyperinsulinemia induced by insulin pellet implantation produced a decrease in insulin sensitivity in ZDF rats. These results suggest that chronic hyperinsulinemia may lead to the progression of insulin resistance under DR conditions in association with altered lipid metabolism in peripheral tissues in ZDF rats.
Hyperinsulinemia
Glucose clamp technique
Lipogenesis
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Obesity is associated with both insulin resistance and hyperinsulinemia. Initially hyperinsulinemia compensates for the insulin resistance and thereby maintains normal glucose homeostasis. Obesity is also associated with increased tissue triglyceride (TG) content. To determine whether both insulin resistance and hyperinsulinemia might be secondary to increased tissue TG, we studied correlations between TG content of skeletal muscle, liver, and pancreas and plasma insulin, plasma [insulin] × [glucose], and β-cell function in four rat models with widely varying fat content: obese Zucker diabetic fatty rats, free-feeding lean Wistar rats, hyperleptinemic Wistar rats with profound tissue lipopenia, and rats pair fed to hyperleptinemics. Correlation coefficients >0.9 ( P < 0.05) were obtained among TG of skeletal muscle, liver, and pancreas and among plasma insulin, [insulin] × [glucose] product, and β-cell function as gauged by basal, glucose-stimulated, and arginine-stimulated insulin secretion by the isolated perfused pancreas. Although these correlations cannot prove cause and effect, they are consistent with the hypothesis that the TG content of tissues sets the level of both insulin resistance and insulin production.
Hyperinsulinemia
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Objective To investigate the correlation of orexin A( OXA) with insulin- like growth factor 1( IGF- 1) in besity rat with insulin resistance induced by high- fat diet. Methods Male Sprague- Dawley rats model with insulin resistance induced by high- fat diet was verified by euglycemic insulin clamp technique to determine the insulin resistance.The rats were treated with OXA( 0 to 10- 6M) by hypodermic injection. The serum levels of OXA and IGF- 1 in SD rat were detected by luminescent immunoassay enzymic method. Results After 6 weeks high- fat diet,serum insulin,total cholesterol( TC),triglyeride( TG) and low density lipoprotein( LDL- C) increased significantly in obesity rats with insulin resistance( P 0. 05),the GIR60- 120in obesity rats was decreased significantly,compared with normal rats. After treated with OXA( 10- 8M,10- 7M and 10- 6M),the levels of serum IGF- 1 decreased 25. 0%,43. 5% and 55. 6% in normal rats,respectively,decreased 11. 3%,17. 7% and 27. 4% in obesity rats,respectively. The correlation coefficient between OXA and serum IGF- 1,high density lipoprotein( HDL- C) in insulin resistance rats were- 0. 342 and- 0. 226,P 0. 05.The correlation coefficient between OXA and serum insulin,TC,TG,LDL- C in insulin resistance rats were 0. 303,0. 388,0. 255,0. 253,P 0. 05. Conclusions High- fat diet could induce insulin- resistance and obesity in SD rat. OXA correlated with IGF- 1 in insulin- resistance in SD rat. That OXA down- regulated serum IGF- 1 would involve in insulin- resistance in high- fat diet induced obesity rat.
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The effect of short- and long-term caloric restriction (CR) on insulin resistance in male Fisher-344 rats was studied. The short- and long-term CR rats had not only significantly lower blood glucose and insulin levels, but also lower body and liver weights as compared with ad libitum (AL) rats. The insulin resistance index (IRI) was markedly lower, but the insulin sensitive index (ISI) was significantly higher in CR rats than in AL ones. The results indicate that CR rats can ultilize glucose and adapt themselves to the condition of lower insulin and glucose concentrations. They have higher ISI and lower IRI, which probably result from decreased body fat and increased exercise. Insulin resistance increased with aging, and this phenomenon could be retarted through CR. It is concluded that rats on CR show decreased body and liver weights, lowered glucose and insulin concentrations, lowered insulin resistance, and elevated insulin sensitivity.
Caloric theory
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The expression of musclin gene in skeletal muscle of rats fed with high-fat diet and its correlation to insulin resistance.diabetes mellitus and GLUT4 were explored.The results showed that musclin expressin was up-regulated(1.39±0.36 vs 0.31±0.07,P<0.01)in skeletal muscle of rats fed with high-fat diet, suggesting that this finding may be related with insulin resistance and involvement of GLUT-4 expression(1.27 4± 0.32 vs 1.84±0.24.P<0.01).
Key words:
Insulin resistance; Musclin; Glucose transporter 4; Gene expression
GLUT4
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Hyperinsulinemia
Lipogenesis
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Impaired sensitivity to the antilipolytic action of insulin in adipose tissue (AT) may play a role in determining metabolic dysfunction in polycystic ovary syndrome (PCOS).To test the hypothesis that insulin resistance (IR) in AT is associated with whole-body insulin sensitivity and β-cell function in PCOS.Prospective cross-sectional study.Eighteen participants with PCOS and 18-matched control participants underwent a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT); subgroups underwent single-slice computed tomography scans determining AT distribution and adipocyte glucose transporter type 4 (GLUT-4) expression.IR in AT in basal (by the adipose insulin resistance index [Adipo-IR]) and dynamic (mFSIVGTT-derived indices of insulin-mediated nonesterified fatty acids [NEFA] suppression [NEFAnadir, TIMEnadir, and %NEFAsupp]) states; whole-body insulin-mediated glucose uptake and insulin secretion in basal (by homeostatic model assessment [HOMA]-IR and HOMA-β%) and dynamic (mFSIVGTT-derived insulin sensitivity index [Si], acute insulin response to glucose [AIRg], and disposition index [Di]) states.Participants with PCOS had higher HOMA-IR and HOMA-β%, lower Si and Di, higher longer TIMEnadir, higher Adipo-IR and NEFAnadir, and a trend toward lower GLUT-4, than the control group participants. Adipo-IR was associated with dynamic state IR in AT (NEFAnadir TIMEnadir, and %NEFAsupp), but only in PCOS, and with HOMA-IR and HOMA-β% in both groups. NEFAnadir and TIMEnadir were negatively and %NEFAsupp positively associated with Si only in PCOS, but not with AIRg and Di, or GLUT-4 expression.Women with PCOS demonstrated increased IR in AT, which is closely associated with whole-body IR but not with dynamic state β-cell function or adipocyte GLUT-4 gene expression.
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We studied the effects of genetic background on the phenotype of ob/ob mice, a model of severe obesity, insulin resistance, and diabetes caused by leptin deficiency. Despite a comparable degree of obesity and hyperinsulinemia, C57BL/6J ob/ob mice had much milder hyperglycemia and, surprisingly, normal circulating adiponectin levels despite still-prominent signs of insulin resistance. Hyperinsulinemic-euglycemic clamp revealed relatively less whole-body and muscle insulin resistance in C57BL/6J ob/ob mice, whereas liver insulin resistance tended to be more severe than in FVB/N ob/ob mice. C57BL/6J ob/ob mice had also more rapid clearance of circulating triglycerides and more severe hepatic steatosis. We suggest that strain-related distinction in lipid handling is the most important player in the differences in diabetic phenotype and insulin sensitivity, whereas the impact of circulating adiponectin levels on the overall phenotype of ob/ob mice is less important.
Hyperinsulinemia
Steatosis
Glucose clamp technique
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