phytoestrogens and Insulin-Resistance

Polycystic ovary syndrome (PCOS) is one of the most prevalent polygenic endocrine disorders in reproductive-age women. Genistein is a soy-isolated phytoestrogen and isoflavone with antioxidant, anti-inflammatory, estrogenic, and antineoplastic activity. This systematic review aimed to investigate the therapeutic effects and mechanisms of actions of genistein in PCOS. The present study was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. We searched PubMed, Scopus, Embase, and Google Scholar databases up to February 2022 using relative keywords. Studies published in English evaluated genistein's effects on PCOS, and its related symptoms were considered. Out of 298 records screened, only 13 articles met the inclusion criteria: Nine animal and 4 human studies. The results of the current study indicated that genistein supplementation may effectively improve PCOS-related symptoms by decreasing insulin resistance and anthropometric indices, improving ovarian morphology and regulating reproductive hormones, and reducing oxidative stress and inflammation by influencing biological pathways. According to the current literature, genistein may diminish the dues of PCOS. Therefore, this study shows that genistein can be considered an effective agent. in reducing the complications of PCOS. However, further studies are recommended for a broad conclusion on the exact mechanism of genistein in PCOS patients.

Topics: Animals; Antioxidants; Female; Genistein; Humans; Insulin Resistance; Phytoestrogens; Polycystic Ovary Syndrome

Phytoestrogens might have advantageous effects on diabetes in women. We performed a systematic review and meta-analysis to determine the effect of phytoestrogens on glucose homeostasis and the risk of type 2 diabetes (T2D) among women. Randomized controlled trials (RCTs) and prospective observational studies that assessed associations of phytoestrogens (supplementation, dietary intake, or biomarkers) with fasting glucose or insulin, homeostatic model assessment of insulin resistance (HOMA-IR), or with the risk of T2D were included. We identified 18 RCTs (n = 1687 individuals) investigating the effect of phytoestrogen supplementation on glucose homeostasis and 9 prospective population-based studies (n = 212,796 individuals) examining the association between phytoestrogen intake and the risk of T2D. Compared with placebo, phytoestrogen supplementation resulted in improvements in fasting glucose and HOMA-IR: the pooled mean differences of changes were -0.12 mmol/L (95% CI: -0.20, -0.03 mmol/L) and -0.24 mmol/L (95% CI: -0.45, -0.03 mmol/L), respectively. Although there was no significant decrease in insulin concentrations with overall phytoestrogen supplementation, the pooled mean difference in changes was -0.99 pmol/L (95% CI: -4.65, 2.68 pmol/L). However, the results of RCTs varied by type of phytoestrogens: soy-derived isoflavones and genistein improved glucose homeostasis, whereas isoflavone mix and daidzein had no effect or were associated with an adverse glycemic profile. Higher dietary phytoestrogen intake was associated with a 10% lower risk of developing T2D in observational studies (pooled RR: 0.90; 95% CI: 0.85, 0.96; for the highest compared with the lowest quantiles). Results were similar when the analyses were restricted to only medium- and high-quality studies. Overall, phytoestrogens may have a positive influence on glycemia and could be used for diabetes prevention in women. However, for some individual types of phytoestrogens, such as mixed isoflavones, caution is needed in recommending their use in women, because their use could lead to an adverse glycemic profile in women.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Supplements; Fasting; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Middle Aged; Observational Studies as Topic; Phytoestrogens; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors

The aim of this meta-analysis was to investigate whether soy isoflavones, a type of phytoestrogen, would affect glucose homeostasis in menopausal women.. Studies concerning about the relationship between soy isoflavone treatment and glucose metabolism were searched on MEDLINE and WEB OF SCIENCE (updated through April 2015) and EMBASE (1990-April 2015). Seventeen randomized controlled trials (RCTs) with a total number of 1529 menopausal women were identified for meta-analysis. Soy isoflavones were found to show great significance for the improvement of glucose metabolism, though marked heterogeneity was found between studies. The overall results showed that the average difference in fasting blood glucose values between women assigned to soy isoflavones and women in placebo groups was -0.22 mmol/L (95% CI: -0.38 to -0.07 mmol/L) under a random-effects model. In addition, the effect of soy isoflavones on insulin was also significant: -0.43 μIU/mL (95% CI: -0.71 to -0.14 μIU/mL), as was the effect on homeostasis model assessment insulin resistance (HOMA-IR): -0.52 (95% CI: -0.76 to -0.28).. Although the results displayed a significant tendency in favor of soy isoflavones, it appears that genistein alone played an important role in improving glucose metabolism due to its low heterogeneity.

Topics: Blood Glucose; Carbohydrate Metabolism; Female; Genistein; Glycine max; Humans; Insulin; Insulin Resistance; Isoflavones; Phytoestrogens; Postmenopause; Randomized Controlled Trials as Topic; Sensitivity and Specificity

Evidence is emerging that dietary phytoestrogens play a beneficial role in obesity and diabetes. Nutritional intervention studies performed in animals and humans suggest that the ingestion of soy protein associated with isoflavones and flaxseed rich in lignans improves glucose control and insulin resistance. In animal models of obesity and diabetes, soy protein has been shown to reduce serum insulin and insulin resistance. In studies of human subjects with or without diabetes, soy protein also appears to moderate hyperglycemia and reduce body weight, hyperlipidemia, and hyperinsulinemia, supporting its beneficial effects on obesity and diabetes. However, most of these clinical trials were relatively short and involved a small number of patients. Furthermore, it is not clear whether the beneficial effects of soy protein and flaxseed are due to isoflavones (daidzein and genistein), lignans (matairesinol and secoisolariciresinol), or some other component. Isoflavones and lignans appear to act through various mechanisms that modulate pancreatic insulin secretion or through antioxidative actions. They may also act via estrogen receptor-mediated mechanisms. Some of these actions have been shown in vitro, but the relevance of these studies to in vivo disease is not known. The diversity of cellular actions of isoflavones and lignans supports their possible beneficial effects on various chronic diseases. Further investigations are needed to evaluate the long-term effects of phytoestrogens on obesity and diabetes mellitus and their associated possible complications.

Topics: Blood Glucose; Diabetes Mellitus; Diet; Estrogens, Non-Steroidal; Humans; Insulin; Insulin Resistance; Isoflavones; Obesity; Phytoestrogens; Phytotherapy; Plant Preparations; Soybean Proteins

The aim of this study was to determine and compare the effect of treatment with transdermal oestrogen and phytoestrogen on insulin sensitivity and sex hormone-binding globulin (SHBG) levels in healthy postmenopausal women.. Forty-three healthy postmenopausal women aged 68 ± 7 (mean ± SD) years who were not receiving hormonal replacement therapy completed a 3 month randomized drug therapy study. The participants were randomized to one of four groups: 0.05 mg or 0.1 mg transdermal oestrogen/day, or 40 or 80 mg oral phytoestrogen (Promensil)/day insulin sensitivity was indirectly measured using the quantitative insulin sensitivity check index (QUICKI). SHBG, total testosterone, oestradiol, and fasting glucose and insulin levels for calculation of insulin sensitivity were obtained at baseline and at monthly intervals during the 3 months of therapy.. In healthy nondiabetic postmenopausal women, the rate of change in QUICKI was significantly different between the red clover based phytoestrogen and transdermal oestrogen groups, so that after three months of therapy, QUICKI with red clover based phytoestrogen therapy was lower than that in the transdermal oestrogen group, p = 0.01. Red clover based phytoestrogen therapy was not associated with any changes in SHBG levels whereas transdermal estrogen therapy significantly increased SHBG levels, p = 0.05.. In contrast to transdermal oestrogen therapy, oral phytoestrogen therapy does not decrease androgenicity and is associated with a decrease in insulin sensitivity. These effects are similar to those of raloxifene and consistent with phytoestrogen's selective oestrogen receptor modulator properties.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Aged, 80 and over; Androgens; Biomarkers; Blood Glucose; Estradiol; Female; Humans; Insulin; Insulin Resistance; Isoflavones; Middle Aged; Phytoestrogens; Postmenopause; Sex Hormone-Binding Globulin; Testosterone; United Kingdom

There is concern whether soy phytoestrogens may affect thyroid function. If true, soy phytoestrogens may be expected to have a greater impact in subjects with subclinical hypothyroidism.. The primary aim was to determine the effect of soy phytoestrogen supplementation on thyroid function, with a secondary aim of assessing the effects on cardiovascular risk indices in patients with subclinical hypothyroidism.. We conducted a randomized, double-blind, crossover study in a tertiary care setting.. Sixty patients with subclinical hypothyroidism participated in the study.. Patients were randomly assigned to either low-dose phytoestrogen (30 g soy protein with 2 mg phytoestrogens, representative of a Western diet) or high-dose phytoestrogen (30 g soy protein with 16 mg phytoestrogens, representative of a vegetarian diet) supplementation for 8 wk, then crossed over after an 8-wk washout period.. The primary outcome was progression to overt hypothyroidism, with secondary outcome measures of blood pressure, insulin resistance, lipids, and highly sensitive C-reactive protein (hsCRP).. Six female patients in the study progressed into overt hypothyroidism with a standardized rate ratio of 3.6 (95% confidence interval, 1.9, 6.2) after 16-mg phytoestrogen supplementation. Both systolic and diastolic blood pressure decreased with 16 mg phytoestrogens, whereas systolic pressure alone decreased with 2 mg phytoestrogens. Insulin resistance (homeostasis model assessment of insulin resistance, 3.5 ± 0.09 vs. 2.6 ± 0.08; P < 0.02) and hsCRP (4.9 ± 0.04 vs. 3.9 ± 0.03; P < 0.01) decreased with 16 mg phytoestrogens. Lipid profile remained unchanged.. There is a 3-fold increased risk of developing overt hypothyroidism with dietary supplementation of 16 mg soy phytoestrogens with subclinical hypothyroidism. However, 16-mg soy phytoestrogen supplementation significantly reduces the insulin resistance, hsCRP, and blood pressure in these patients.

Topics: Adult; Aged; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cross-Over Studies; Dietary Supplements; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycine max; Humans; Hypothyroidism; Insulin Resistance; Isoflavones; Lipids; Male; Middle Aged; Phytoestrogens; Risk Factors; Thyroid Function Tests; Thyroid Gland; Thyroxine; Treatment Outcome

The wide family of the phytoestrogens has become an alternative to the classical hormonal therapy in menopause; nevertheless, some findings are still conflicting.. To examine the effect of genistein administration on metabolic parameters and vascular reactivity considering the basal endocrine status of the patients.. A randomized placebo controlled study was conducted at a university hospital.. Fifty postmenopausal women participated.. Thirty subjects (group A) were randomized to receive 54 mg/d genistein while 20 subjects (group B) were treated with the placebo for 24 wk. In group A, we distinguish two subgroups: 14 normoinsulinemic and 12 hyperinsulinemic patients.. Anthropometric measures, hormonal and lipid assays, oral glucose tolerance test with glycemic, insulin, and C-peptide evaluation, indexes of insulin sensitivity and endothelial function, and euglycemic-hyperinsulinemic clamps were performed.. The insulin basal values significantly decreased in group A, whereas the homeostasis model index of insulin sensitivity and the fasting glucose levels significantly improved compared with placebo group. The genistein administration decreased fasting glucose and area under the curve glucose levels in the normoinsulinemic patients after treatment. In the hyperinsulinemic patients, a significant reduction in fasting insulin, fasting C-peptide, and area under the curve insulin levels as well as an increase in fractional hepatic insulin extraction was shown. In these patients, high-density lipoprotein cholesterol levels were significantly improved. The endothelium-dependent and -independent dilatation improved in the treated group. Normoinsulinemic patients showed both a significantly enhanced flow-mediated and nitrate-mediated dilatation, whereas no significant changes were found in the hyperinsulinemic group.. The glycoinsulinemic metabolism and the endothelial function were significantly influenced by genistein. In particular, normoinsulinemic patients showed an improvement in glycemic and vascular reactivity indexes. Conversely, an improvement in the insulin sensitivity indexes was noted in hyperinsulinemic patients.

Topics: Biomarkers; Blood Glucose; Body Mass Index; Brachial Artery; Cardiovascular Diseases; Endothelium, Vascular; Female; Genistein; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Middle Aged; Phytoestrogens; Placebos; Postmenopause; Regional Blood Flow; Risk Factors

Genistein is an isoflavone phytoestrogen that has been shown to improve obesity; however, the underlying molecular mechanisms involved therein have not been clearly elucidated. In this study, we administered genistein to high-fat diet-induced obese mice to investigate its effect on hepatic gluconeogenesis. The results showed that genistein treatment significantly inhibited body weight gain, hyperglycemia, and adipose and hepatic lipid deposition in high-fat diet-induced obese mice. Glucose tolerance test (GTT), insulin tolerance test (ITT) and pyruvate tolerance test (PTT) showed that genistein treatment significantly inhibited gluconeogenesis and improved insulin resistance in obese mice. In addition, this study also found that genistein could promote the expression of miR-451 in vitro and in vivo, and the dual-luciferase reporter system showed that

Topics: Animals; Diet, High-Fat; Genistein; Gluconeogenesis; Insulin Resistance; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Obesity; Phytoestrogens

Genistein, a naturally occurring phytoestrogen and a member of the large class of compounds known as isoflavones, exerts protective effects in several diseases. Recent studies indicate that genistein plays a critical role in controlling body weight, obesity-associated insulin resistance, and metabolic disorders, but its target organs in reversing obesity and related pathological conditions remain unclear. In this study, we showed that mice supplemented with 0.2% genistein in a high-fat diet for 12 weeks showed enhanced metabolic homeostasis, including reduced obesity, improved glucose uptake and insulin sensitivity, and alleviated hepatic steatosis. We also observed a beiging phenomenon in the white adipose tissue and reversal of brown adipose tissue whitening in these mice. These changes led to enhanced resistance to cold stress. Altogether, our data suggest that the improved metabolic profile in mice treated with genistein is likely a result of enhanced adipose tissue function.

Topics: Adipocytes, White; Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Body Weight; Cell Enlargement; Cold-Shock Response; Diet, High-Fat; Eating; Energy Metabolism; Genistein; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Phytoestrogens; Protective Agents

Obesity and type 2 diabetes mellitus, correlate with increased tissue concentration of sphingolipids, which directly interfere with insulin signaling pathway. Phytoestrogens are a group of plant-derived compounds that have been studied in the case of metabolic disorders treatment. Therefore, the aim of this study was to ascertain whether enterolactone (ENL), a commonly known phytoestrogen, may affect sphingolipid metabolism and decrease hepatic insulin resistance development in a lipid overload state.. The study was conducted on HepG2 cells incubated with ENL and/or palmitic acid (PA) for 16 h. Intra- and extracellular sphingolipid concentrations were assessed by high performance liquid chromatography. The expression of sphingolipid pathway enzymes, apoptosis and insulin signaling pathway proteins and glucose metabolism regulators were evaluated by Western Blot.. In HepG2 cells, a considerable augmentation of intracellular ceramide and sphingosine concentration in ENL with PA group were indicated with simultaneous increase in extracellular ceramide concentration. The ENL treatment increased expression of selected enzymes from de novo ceramide synthesis pathway with lower expression of ceramide transfer protein. We also observed a decreased expression of insulin-stimulated phosphorylation of AKT and AMPK after exposure to ENL with PA. Our research demonstrated that ENL with PA resulted in an increased expression of caspase-3.. Enterolactone, in a higher fatty acids availability, led to the development of hepatic IR in HepG2 cells. This phenomenon may be the result of elevated intracellular ceramide accumulation caused by increased de novo synthesis pathway what led to enhanced apoptosis of HepG2 cells.

Topics: 4-Butyrolactone; Ceramides; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Lignans; Lipid Metabolism; Liver; Phytoestrogens; Signal Transduction; Sphingolipids

The aim of this study was to compare the effect of synthetic estrogen (E2) with a phytoestrogen and genistein in ameliorating type 2 diabetes mellitus (T2D)-mediated testicular dysfunction in mice. The streptozotocin (STZ)-induced type 2 diabetic mice were treated exogenously with either E2 or genistein for 2 durations and compared their effects on testicular activities, serum glucose, and insulin level. Type 2 diabetic mice treated with E2 for only short term (14 days) improved regressive changes in the testicular histology by increasing testosterone synthesis and improving insulin sensitivity, whereas those treated for longer duration (28 days) failed to improve testicular dysfunctions. On the other hand, genistein treated for both short- and long term was useful in improving T2D-induced adverse effects on testicular functions. This study further suggests that treatment with genistein improves spermatogenesis in type 2 diabetic mice by increasing insulin-induced formation of lactate and antioxidative enzymes, which contributes to prevent germ cell apoptosis. Thus, genistein can be used to ameliorate T2D-induced testicular dysfunction.

Topics: Animals; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Estradiol; Genistein; Insulin; Insulin Resistance; Lipid Peroxidation; Male; Mice; Oxidative Stress; Phytoestrogens; Superoxide Dismutase; Testis; Testosterone

Genistein, a natural food compound mainly present in soybeans, is considered a potent antioxidant and to improve glucose homeostasis. However, its mechanism of action remains poorly understood. Here, we analyzed whether genistein could antagonize the progression of the hyperinsulinemic normoglycemic state (pre-diabetes) toward full-blown T2DM in Zucker Diabetic Fatty (ZDF) rats by decreasing mitochondrial oxidative stress and improving skeletal muscle oxidative capacity. Rats were assigned to three groups: (1) lean control (CNTL), (2) fa/fa CNTL, and (3) fa/fa genistein (GEN). GEN animals were subjected to a 0.02% (w/w) genistein-enriched diet for 8 weeks, whereas CNTL rats received a standard diet. We show that genistein did not affect the overall response to a glucose challenge in ZDF rats. In fact, genistein may exacerbate glucose intolerance as fasting glucose levels were significantly higher in fa/fa GEN (17.6 ± 0.7 mM) compared with fa/fa CNTL animals (14.9 ± 1.4 mM). Oxidative stress, established by electron spin resonance (ESR) spectroscopy, carbonylated protein content and UCP3 levels, remained unchanged upon dietary genistein supplementation. Furthermore, respirometry measurements revealed no effects of genistein on mitochondrial function. In conclusion, dietary genistein supplementation did not improve glucose homeostasis, alleviate oxidative stress, or augment skeletal muscle metabolism in ZDF rats.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet; Genistein; Glucose; Glucose Tolerance Test; Homeostasis; Insulin Resistance; Mitochondria, Muscle; Muscle, Skeletal; Oxidation-Reduction; Oxidative Stress; Phytoestrogens; Rats, Zucker

Estrogen deficiency after menopause accelerates the redox imbalance and insulin signaling, leading to oxidative stress (OS) and insulin resistance (IR). The molecular mechanisms by which the loss of ovarian hormone leads to OS and IR remain unclear. In the present study we found that rats when subjected to ovariectomy (OVX) resulted in reduction of whole blood antioxidants and elevation of oxidant markers. The expression of anti-oxidant enzymes, superoxide dismutase (SOD1) and glutathione peroxidase (GPX1) was suppressed whereas the pro-oxidative enzyme NADPH oxidase (NOX4) and mitogen activated protein (MAP) kinases ERK 1/2 and p38 were increased at different tissues. Treatment with soy (SIF, 150 mg/kg BW for 12 weeks) extract markedly reversed these metabolic changes and improved OS. Ovariectomized rats also displayed glucose intolerance (GI) and IR as evident from the impaired glucose tolerance test, and reduced expression of adipose and hepatic insulin receptor beta (IRβ) and adipose tissue GLUT4. Treatment with SIF reversed the ovariectomy induced GI and IR. On the other hand, all these metabolic changes were further augmented when ovariectomy was followed by a high fat diet, and these changes were also reversed by SIF. Taken together, these findings emphasized the antioxidant property and anti-diabetic effects of soy isoflavones suggesting the use of this natural phytoestrogen as a strategy for relieving oxidative stress and insulin resistance in postmenopausal women.

Topics: Adipose Tissue; Animals; Antioxidants; Diet, High-Fat; Female; Glucose Transporter Type 4; Glycine max; Insulin; Insulin Resistance; Isoflavones; Liver; Ovariectomy; Oxidative Stress; Phytoestrogens; Rats; Rats, Wistar

Consumption of foods that modulate inflammatory stress in genetically-prone individuals may influence development of cardiometabolic diseases. Isoflavones in soy-derived foods function as phytoestrogens, have antioxidant and anti-inflammatory activity, inhibit protein-tyrosine kinase activity, and may be atheroprotective. We examined the relationship between soy food consumption and inflammatory responses to endotoxemia, postprandial responses to oral lipid tolerance test (OLTT), and insulin sensitivity from frequently sampled intravenous tolerance tests (FSIGTT).. We administered low-dose endotoxin (LPS 1 ng/kg) to induce transient endotoxemia in young, healthy volunteers (N = 215) of African (AA), and European (EA) ancestry as part of the GENE Study. We further supported these findings in two independent samples: the MECHE Study and NHANES. Soy food consumption was a significant predictor of peak cytokine response following LPS. Individuals with moderate-high (>1.48 mg/day, N = 65) vs. low-no (<1.48 mg/day, N = 150) isoflavone consumption had significantly higher tumor necrosis factor alpha (TNFα) post-LPS (AUC, P = 0.009). Further, high-isoflavone consumers were protected against inflammation-induced decline in insulin sensitivity (SI) in GENE. We observed significant differences by soy consumption in the interferon gamma (IFNγ) response to OLTT, and the insulin response to OGTT in MECHE, as well as significantly lower fasting insulin, and 2-hour glucose post-OGTT in EA NHANES subjects.. We demonstrate that soy consumption may influence inflammatory and metabolic responses. In research of nutritional exposures, measuring evoked phenotypes may be more informative than describing resting characteristics. The GENE Study was registered under NCT00953667 and the MECHE Study under NCT01172951, both at clinicaltrials.gov.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Antioxidants; Black or African American; Blood Glucose; Body Mass Index; Cardiovascular Diseases; Female; Healthy Volunteers; Homeostasis; Humans; Inflammation; Insulin Resistance; Isoflavones; Linear Models; Lipopolysaccharides; Male; Middle Aged; Nutrition Surveys; Phytoestrogens; Protein-Tyrosine Kinases; Randomized Controlled Trials as Topic; Soy Foods; Tumor Necrosis Factor-alpha; White People; Young Adult

Genistein is an isoflavone phytoestrogen found in a number of plants such as soybeans and there is accumulating evidence that it has beneficial effects on the regulation of glucose homeostasis. In this study we evaluated the effect of genistein on glucose homeostasis and its underlying mechanisms in normal and insulin-resistant conditions.. To induce insulin resistance, mice or differentiated 3T3-L1 adipocytes were treated with macrophage-derived conditioned medium. A glucose tolerance test was used to investigate the effect of genistein. Insulin signalling activation, glucose transporter-4 (GLUT4) translocation and AMP-activated PK (AMPK) activation were detected by Western blot analysis or elisa.. Genistein impaired glucose tolerance and attenuated insulin sensitivity in normal mice by inhibiting the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1) at tyrosine residues, leading to inhibition of insulin-mediated GLUT4 translocation in adipocytes. Mac-CM, an inflammatory stimulus induced glucose intolerance accompanied by impaired insulin sensitivity; genistein reversed these changes by restoring the disturbed IRS1 function, leading to an improvement in GLUT4 translocation. In addition, genistein increased AMPK activity under both normal and inflammatory conditions; this was shown to contribute to the anti-inflammatory effect of genistein, which leads to an improvement in insulin signalling and the amelioration of insulin resistance.. Genistein showed opposite effects on insulin sensitivity under normal and inflammatory conditions in adipose tissue and this action was derived from its negative or positive regulation of IRS1 function. Its up-regulation of AMPK activity contributes to the inhibition of inflammation implicated in insulin resistance.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Genistein; Glucose; Glucose Tolerance Test; Glucose Transporter Type 4; Homeostasis; Inflammation; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred ICR; Phosphorylation; Phytoestrogens; Up-Regulation

To determine whether daidzein improves insulin resistance by modifying weight gain, visceral fat accumulation, blood lipids and serum cytokines levels in ovariectomized Sprague-Dawley rats.. Twenty-eight 12-week-old female rats were divided into three groups: the sham-operated group (SHAM) (n =10), the ovariectomized group receiving daidzein therapy (DAID) (n =10), and the ovariectomized control group (Control) (n =8). The rats in the DAID group received 50 mg/kg daidzein via gavage daily. Weight and food intake were recorded every 2 weeks. All of the animals were euthanized 12 weeks after ovariectomy, after which their fasting insulin, glucose, blood lipids, estradiol, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), adiponectin and leptin levels were measured.. After 12 weeks, the ovariectomized rats demonstrated an increase in their body weight and visceral fat; compared to the SHAM rats, the ovariectomized rats also experienced a significant increase in their serum IL-6 levels and insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR) (p <0.05). Daidzein therapy decreased weight gain, visceral fat, the HOMA-IR index and IL-6 levels that were induced by ovariectomy. Rats which had received daidzein therapy had lower levels of TNF-α, leptin and blood lipids (except for high density lipoprotein cholesterol) than the other two groups. IL-6 levels positively correlated with the HOMA-IR index in all of the rats after adjustment for body weight (r =0.495; p =0.016).. We conclude that daidzein can improve insulin resistance induced by ovariectomy by decreasing weight gain, visceral fat accumulation, blood lipids, TNF-α, leptin and IL-6 levels.

Topics: Analysis of Variance; Animals; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Female; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Isoflavones; Leptin; Ovariectomy; Phytoestrogens; Rats; Rats, Sprague-Dawley; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain

Curcuma comosa Roxb. (C. comosa) is an indigenous medicinal herb that has been used in Thailand as a dietary supplement to relieve postmenopausal symptoms. Recently, a novel phytoestrogen, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol or compound 049, has been isolated and no study thus far has investigated the role of C. comosa in preventing metabolic alterations occurring in estrogen-deprived state. The present study investigated the long-term effects (12 weeks) of C. comosa hexane extract and compound 049 on insulin resistance in prolonged estrogen-deprived rats.. Female Sprague-Dawley rats were ovariectomized (OVX) and treated with C. comosa hexane extract (125 mg, 250 mg, or 500 mg/kg body weight (BW)) and compound 049 (50 mg/kg BW) intraperitoneally three times per week for 12 weeks. Body weight, food intake, visceral fat weight, uterine weight, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity, and GLUT-4 protein expression were determined.. Prolonged ovariectomy resulted in dyslipidemia, impaired glucose tolerance and insulin-stimulated skeletal muscle glucose transport, as compared to SHAM. Treatment with C. comosa hexane extract and compound 049, three times per week for 12 weeks, markedly reduced serum total cholesterol and low-density lipoprotein levels, improved insulin sensitivity and partially restored uterine weights in ovariectomized rats. In addition, compound 049 or high doses of C. comosa hexane extract enhanced insulin-mediated glucose uptake in skeletal muscle and increased muscle GLUT-4 protein levels.. Treatment with C. comosa and its diarylheptanoid derivative improved glucose and lipid metabolism in estrogen-deprived rats, supporting the traditional use of this natural phytoestrogen as a strategy for relieving insulin resistance and its related metabolic defects in postmenopausal women.

Topics: Animals; Biological Transport; Cholesterol; Cholesterol, LDL; Curcuma; Diarylheptanoids; Dyslipidemias; Estrogens; Female; Glucose; Glucose Intolerance; Glucose Transporter Type 4; Heptanol; Insulin; Insulin Resistance; Muscle, Skeletal; Organ Size; Ovariectomy; Phytoestrogens; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Uterus

Postmenopausal women are at higher risk for obesity and insulin resistance due to the decline of estrogen, but genistein, a phytoestrogen, may reduce the risks of these diet-related diseases. In this study, we hypothesized that supplemental genistein has beneficial effects on insulin resistance in an ovariectomized rat model by modulating lipid metabolism. Three weeks after a sham surgery (sham) or an ovariectomy (OVX), ovariectomized Sprague-Dawley rats were placed on a diet containing 0 (OVX group) or 0.1% genistein for 4 weeks. The sham rats were fed a high-fat diet containing 0% genistein and served as the control group (sham group). The ovariectomized rats showed increases in body weight and insulin resistance index, but genistein reduced insulin resistance index and the activity of hepatic fatty acid synthetase. Genistein was also associated with increased activity of succinate dehydrogenase and carnitine palmitoyltransferase and the rate of β-oxidation in the fat tissue of rats. The ovariectomized rats given genistein had smaller-sized adipocytes. Using gene-set enrichment analysis (GSEA) of microarray data, we found that a number of gene sets of fatty acid metabolism, insulin resistance, and oxidative stress were differentially expressed by OVX and reversed by genistein. This systemic approach of GSEA enables the identification of such consensus between the gene expression changes and phenotypic changes caused by OVX and genistein supplementation. Genistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance.

Topics: Adipose Tissue; Animals; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Fatty Acid Synthases; Female; Gene Expression; Genistein; Glycine max; Insulin Resistance; Lipid Metabolism; Liver; Microarray Analysis; Obesity; Ovariectomy; Oxidation-Reduction; Oxidative Stress; Phytoestrogens; Phytotherapy; Plant Extracts; Postmenopause; Rats; Rats, Sprague-Dawley; Succinate Dehydrogenase; Weight Gain

Globally, non-alcoholic fatty liver disease (NAFLD) continues to rise and isoflavones exert antisteatotic effects by the regulation of hepatic lipogenesis/insulin resistance or adiposity/a variety of adipocytokines are related to hepatic steatosis. However, there is very little information regarding the potential effects of daidzein, the secondary abundant isoflavone, on NAFLD. Here, we have assessed the hepatic global transcription profiles, adipocytokines and adiposity in mice with high fat-induced NAFLD and their alteration by daidzein supplementation.. C57BL/6J mice were fed with normal fat (16% fat of total energy), high fat (HF; 36% fat of total energy) and HF supplemented with daidzein (0.1, 0.5, 1 and 2 g per kg diet) for 12 weeks.. Daidzein supplementation (≥ 0.5 g per kg diet) reduced hepatic lipid concentrations and alleviated hepatic steatosis. The hepatic microarray showed that daidzein supplementation (1 g per kg diet) downregulated carbohydrate responsive element binding protein, a determinant of de novo lipogenesis, its upstream gene liver X receptor β and its target genes encoding for lipogenic enzymes, thereby preventing hepatic steatosis and insulin resistance. These results were confirmed by lower insulin and blood glucose levels as well as homeostasis model assessment insulin resistance scores. In addition, daidzein supplementation inhibited adiposity by the upregulation of genes involved in fatty acid β-oxidation and the antiadipogeneis, and moreover augmented antisteatohepatitic leptin and adiponectin mRNA levels, whereas it reduced the mRNA or concentration of steatotic tumor necrosis factor α and ghrelin.. These findings show that daidzein might alleviate NAFLD through the direct regulation of hepatic de novo lipogenesis and insulin signaling, and the indirect control of adiposity and adipocytokines by the alteration of adipocyte metabolism.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Body Weight; Diet; Fatty Liver; Gene Expression Profiling; Insulin; Insulin Resistance; Isoflavones; Lipogenesis; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Reverse Transcriptase Polymerase Chain Reaction

This study investigated the effects and molecular mechanisms of genistein in improving insulin resistance induced by free fatty acids (FFAs) in HepG2 hepatocytes. A model of insulin resistance in HepG2 cells was established by adding palmitic acid (0.5 mmol/L) to the culture medium and the cells were treated by genistein. Glucose consumption of HepG2 cells was determined by glucose oxidase method. The levels of c-jun N-terminal kinase (JNK) phosphorylation, insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation, JNK, IRS-1, phosphatidylinositol-3-kinase p85 (PI-3K p85) and glucose transporter 1 (GLUT1) proteins were detected by Western blotting. The results showed that after the treatment with palmitic acid for 24 h, the insulin-stimulated glucose transport in HepG2 cells was inhibited, and the glucose consumption was substantially reduced. Meanwhile, the expressions of IRS-1, PI-3K p85 protein and GLUT1 were obviously reduced, while the levels of JNK phosphorylation and IRS-1 Ser307 phosphorylation and the expression of JNK protein were significantly increased, as compared with cells of normal control. However, the aforementioned indices, which indicated the existence of insulin resistance, were reversed by genistein at 1-4 μmol/L in a dose-dependent manner. It was concluded that insulin resistance induced by FFAs in HepG2 hepatocytes could be improved by genistein. Genistein might reverse FFAs-induced insulin resistance in HepG2 cells by targeting JNK.

Topics: Fatty Acids, Nonesterified; Genistein; Hep G2 Cells; Hepatocytes; Humans; Insulin Resistance; MAP Kinase Kinase 4; Phytoestrogens

Aging is characterized by decline in metabolic function and insulin resistance, and both seem to be in the basis of neurodegenerative diseases and cognitive dysfunction. Estrogens prevent age-related changes, and phytoestrogens influence learning and memory. Our hypothesis was that estradiol and genistein, using rapid-action mechanisms, are able to modify insulin sensitivity, process of learning, and spatial memory. Young and aged ovariectomized rats received acute treatment with estradiol or genistein. Aged animals were more insulin-resistant than young. In each age, estradiol and genistein-treated animals were less insulin-resistant than the others, except in the case of young animals treated with high doses of genistein. In aged rats, no differences between groups were found in spatial memory test, showing a poor performance in the water maze task. However, young females treated with estradiol or high doses of genistein performed well in spatial memory task like the control group. Only rats treated with high doses of genistein showed an optimal spatial memory similar to the control group. Conversely, acute treatment with high doses of phytoestrogens improved spatial memory consolidation only in young rats, supporting the critical period hypothesis for the beneficial effects of estrogens on memory. Therefore, genistein treatment seems to be suitable treatment in aged rats in order to prevent insulin resistance but not memory decline associated with aging. Acute genistein treatment is not effective to restore insulin resistance associated to the early loss of ovarian function, although it can be useful to improve memory deficits in this condition.

Topics: Aging; Analysis of Variance; Animals; Drug Therapy, Combination; Estradiol; Estrogen Replacement Therapy; Estrogens; Female; Genistein; Insulin Resistance; Maze Learning; Memory; Ovariectomy; Phytoestrogens; Rats; Rats, Wistar; Space Perception

There has been a growing interest in lignans, a class of phyto-oestrogens, because of their potentially favourable effects on human health. The aim of the present study was to compare the metabolic profile of post-menopausal women consuming various amounts of dietary lignans. Phyto-oestrogen intake was assessed using a 3-d dietary record analysed with a Canadian food phyto-oestrogen content data table in 115 post-menopausal women (age 56.8 (SD 4.4) years and BMI 28.5 (SD 5.9) kg/m(2)). Plasma enterolactone (ENL), the major biologically active metabolite of dietary lignans, was determined by time-resolved fluoroimmunoassay. Anthropometrics, abdominal adipose tissue areas (computed tomography), body composition (hydrostatic weighing) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) were measured in all women. Women in the high dietary lignan intake subgroup (n 29) had a significantly lower BMI and total body fat mass, as well as a better glucose disposal rate (GDR; P < 0.05), compared with women in the low lignan intake subgroup (n 28). The majority of women with the highest dietary lignan intake were also in the highest quartile of plasma ENL (59 %). Women in the highest ENL quartile had a significantly lower BMI (26.1 (SD 4.4) v. 30.4 (SD 6.9) kg/m(2), P < 0.05), total body fat mass (24.8 (SD 9.8) v. 33.3 (SD 13.3) kg, P < 0.05), 2 h postload glycaemia (5.5 (SD 0.9) v. 5.7 (sd 0.8) nmol/l, P < 0.05) and a higher GDR (8.3 (SD 2.7) v. 5.5 (SD 2.8), P < 0.01) compared with women in the lowest ENL quartile. In conclusion, women with the highest ENL concentrations had a better metabolic profile including higher insulin sensitivity and lower adiposity measures.

Topics: 4-Butyrolactone; Adiposity; Aged; Analysis of Variance; Biomarkers; Body Composition; Body Mass Index; Diet; Diet Records; Female; Fluoroimmunoassay; Humans; Insulin Resistance; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Statistics, Nonparametric

Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes.. The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters.. Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system.. Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density.. Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain.

Topics: Adipose Tissue; Animal Feed; Animals; Blood Pressure; Body Composition; Gene Expression Regulation, Developmental; Glucose; Glucose Tolerance Test; Glycine max; Homeostasis; Insulin Resistance; Lipid Metabolism; Lipids; Male; Mice; Phytoestrogens

The high fructose-fed rat is widely used as a model of insulin resistance. Genistein, a soy isoflavone, has been shown to improve insulin sensitivity in this model. The present study investigated whether genistein could prevent fatty liver disease in this model.. Male Wistar rats were fed a diet containing starch (control) or 60% fructose (insulin-resistant model). Fifteen days later, rats in each dietary group were divided into two groups and were treated with either genistein (1 mg/kg per day) in dimethylsulfoxide (DMSO) or 30% DMSO alone. After 60 days, markers of liver injury, oxidative stress, interleukin (IL)-6, tumor necrosis factor (TNF)-α, lipids, lipoprotein profile, nitrite, and nitrosothiol in the plasma and liver were quantified. Liver sections were examined for 3-nitrotyrosine (3-NT) expression and pathological lesions.. Fructose-fed rats displayed hyperlipidemia, significant changes in plasma lipoprotein profile, and increases in IL-6 and TNF-α levels compared with control. In addition, the accumulation of lipids, liver injury, a decline in liver function, inactivation of the glyoxalase system, depletion of antioxidants, and increased 3-NT expression were observed in the fructose-fed group. Administration of genistein to fructose-fed rats significantly reduced these biochemical and histological abnormalities.. Genistein activates the antioxidant profile, decreases IL-6 and TNF-α concentrations, prevents oxidative damage, and ameliorates fatty liver in insulin-resistant rats.

Topics: Animals; Ascorbic Acid; Body Weight; Cholesterol; Fatty Liver; Genistein; Glutathione Peroxidase; Glutathione Reductase; Insulin; Insulin Resistance; Interleukin-6; Liver; Liver Function Tests; Male; Non-alcoholic Fatty Liver Disease; Organ Size; Phospholipids; Phytoestrogens; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vitamin E