Article

One-year effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome

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Abstract

Objective: To evaluate the 12-month effect of myo-inositol treatment on some biochemical parameters of women affected by metabolic syndrome. Methods: Eighty outpatient postmenopausal women, affected by metabolic syndrome, were enrolled in a 12-month study. All women were treated with a low-energy diet, and then they were randomly assigned to myo-inositol 2 g b.i.d. (n = 40) or placebo (n = 40). All the women were evaluated for serum glucose, insulin, HOMA-IR (Homeostasis Model Assessment-Insulin Resistance), triglycerides, total and high density lipoprotein cholesterol, body mass index (BMI), waist circumference and blood pressure at baseline and after 12 months of treatment. Results: With the exception of BMI and waist circumference, after 12 months of treatment, all the parameters studied showed a significant improvement in the myo-inositol group compared to the control group. At the end of the study, in the myo-inositol group, the number of women without metabolic syndrome was eight (20%) whereas, in the control group, only one woman no longer had the metabolic syndrome after 12 months of diet. Conclusions: Myo-inositol might be considered one of the insulin-sensitizing substances in the treatment of metabolic syndrome.

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... The studies summarized in Table 2 investigated the role of MI or MI plus DCI in ameliorating the InsR-related features of MetS [58][59][60][61]. Three studies [58][59][60] used as an intervention 4 gr MI/day, one of them included additional lipoic acid [60], while another study [61] used the combination of 2 gr MI with 800 mg of DCI plus 10 mg of manganese (Mn) and 400 mcg of folic acid (FA). ...
... The studies summarized in Table 2 investigated the role of MI or MI plus DCI in ameliorating the InsR-related features of MetS [58][59][60][61]. Three studies [58][59][60] used as an intervention 4 gr MI/day, one of them included additional lipoic acid [60], while another study [61] used the combination of 2 gr MI with 800 mg of DCI plus 10 mg of manganese (Mn) and 400 mcg of folic acid (FA). All studies included a placebo group, and three of them had all groups on a hypocaloric diet. ...
... All studies included a placebo group, and three of them had all groups on a hypocaloric diet. The first three studies [58][59][60] showed a significant reduction of HOMA-IR, fasting insulin, and fasting glucose compared to controls (placebo plus diet). Furthermore, there was a significant improvement in the level of triglycerides, HDL, total cholesterol, and a reduction of diastolic blood pressure in all these studies [60][61]. ...
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The incidence of metabolic syndrome (MetS), type II diabetes (T2D) and polycystic ovarian syndrome (PCOS) has been progressively increasing. Insulin resistance (InsR) seems to play a key role in a majority of phenotypes of these conditions, altering metabolic homeostasis, within muscle, liver, adipose and other tissues. Hyperinsulinemia is often associated with InsR and causes hormonal imbalances especially within ovaries and adrenals. Inositol is a polyalcohol, naturally occurring as nine stereoisomers, including D-chiro-inositol (DCI) and myo-inositol (MI), which have prominent roles in the metabolism of glucose and free fatty acids. MI and DCI have been classified as insulin-sensitizers and seem to adequately counteract several InsR-related metabolic alterations with a safe nutraceutical profile. Based on our analysis of selected studies that investigated MI and/or DCI, we conclude that supplementation with MI and/or DCI complement each other in their metabolic actions and act in synergy with other insulin sensitizing drugs and/or nutraceuticals. Nevertheless, considering the possible severe bias due to different methodologies across published studies, we conclude that there is a need for further studies on larger cohorts and with greater statistical power. These should further clarify outcomes and suitable therapeutic dosages of MI and DCI, possibly based on each patient's clinical status.
... The characteristics of the included studies are summarized in Table 1. Studies were published between 1995 [19] and 2012 [9,20], and all studies used parallel design. Four studies were conducted in Italy [9,10,12,20], two studies were conducted in Venezuela [19,21], and one study in republic of Korea [13]. ...
... Studies were published between 1995 [19] and 2012 [9,20], and all studies used parallel design. Four studies were conducted in Italy [9,10,12,20], two studies were conducted in Venezuela [19,21], and one study in republic of Korea [13]. All studies involved both genders. ...
... In total, 322 participants were included (168 in the intervention and 154 in the control group). Most studies were enrolled participants with polycystic ovary syndrome (PCO) [9,12,19,21] and others were conducted on postmenopausal women with metabolic syndrome [10,20]and type 2 diabetes [13]. Dose of inositol supplementation in studies varied between 600 [21]and 4000 [10,12,20]mg/day and intervention duration ranged from 6 to 8 [19,21] to 52 [20]weeks. ...
Article
Background & Aims Potential effects of inositol supplementation on blood pressure (BP) have been examined in several interventional studies. Nevertheless, findings in this context are controversial. Therefore, the current systematic review and meta-analysis aimed to comprehensively assess the impact of inositol supplementation on BP. Methods Five online databases including Web of Science, Scopus, Embase, Cochrane, Google Scholar, and PubMed were systematically searched from inception to March 2020. We included all randomized clinical trials (RCTs) evaluating the effects of inositol supplementation on systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) in humans. Results The random-effects meta-analysis of 7 eligible RCTs demonstrated the significant decline in both SBP (WMD − 5.69 mmHg; 95% CI − 7.35 to − 4.02, P <0.001) and DBP (WMD − 7.12 mmHg; 95% CI − 10.18 to − 4.05, P <0.001) following supplementation with inositol. Subgroup analysis showed that studies performed in individuals with metabolic syndrome with a longer duration (>8 weeks) and a dose of 4000 mg resulted in a more effective reduction in SBP and DBP with acceptable homogeneity. Conclusions The current meta-analysis, indicated that supplementation with inositol significantly decrease SBP and DBP. Further large-scale RCTs with better design are needed to confirm these findings.
... Findings from previous studies suggest that increased consumption of myo-inositol has the potential to target key pathways implicated in AAA progression [16][17][18][19]. Myoinositol can be ingested from a number of foods and is found in high concentrations in vegetables, nuts, whole grains and fresh fruits [20]. ...
... Dietary supplementation with myo-inositol has previously been examined in a number of patient groups, including women with polycystic ovary syndrome and gestational diabetes, as well as patients with depression, with favourable results [16,17,19,45,46]. Administration of doses of~4 g per day has been reported to reduce circulating concentrations of pro-inflammatory cytokines such as resistin, as well as to favourably modify circulating lipids by reducing triglycerides and raising high-density lipoprotein (HDL) cholesterol and phosphatidylcholine plasmalogen lipids [16][17][18][19]. ...
... Dietary supplementation with myo-inositol has previously been examined in a number of patient groups, including women with polycystic ovary syndrome and gestational diabetes, as well as patients with depression, with favourable results [16,17,19,45,46]. Administration of doses of~4 g per day has been reported to reduce circulating concentrations of pro-inflammatory cytokines such as resistin, as well as to favourably modify circulating lipids by reducing triglycerides and raising high-density lipoprotein (HDL) cholesterol and phosphatidylcholine plasmalogen lipids [16][17][18][19]. It has previously been reported that patients with AAA have a distinct circulating pro-inflammatory and lipid profile [47][48][49][50]. ...
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Background An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta and is associated with a risk of fatal rupture. Experimental studies suggest that myo-inositol may exert beneficial effects on AAAs through favourable changes to biological pathways implicated in AAA pathology. The aim of the Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) trial is to assess if myo-inositol will reduce AAA growth. Methods/design IMAGEN is a multi-centre, prospective, parallel-group, randomised, double-blind, placebo-controlled trial. A total of 164 participants with an AAA measuring ≥ 30 mm will be randomised to either 2 g of myo-inositol or identical placebo twice daily for 12 months. The primary outcome measure will be AAA growth estimated by increase in total infrarenal aortic volume measured on computed tomographic scans. Secondary outcome measures will include AAA diameter assessed by computed tomography and ultrasound, AAA peak wall stress and peak wall rupture index, serum lipids, circulating AAA biomarkers, circulating RNAs and health-related quality of life. All analysis will be based on the intention-to-treat principle at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to dietary allocation. Discussion Currently, there is no known medical therapy to limit AAA progression. The IMAGEN trial will be the first randomised trial, to our knowledge, to assess the value of myo-inositol in limiting AAA growth. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12615001209583. Registered on 6 November 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2304-x) contains supplementary material, which is available to authorized users.
... Inositol has been mainly used as a supplement in treating several pathologies such as metabolic syndrome [72,73], GDM [74][75][76][77][78][79][80][81], T2D [82], and PCOS [83,84]. ...
... Myo-inositol decreased diastolic blood pressure (−11%), HOMA index (−75%), and serum triglycerides (−20%); furthermore, the treatment increased high-density lipoprotein cholesterol (+22%). e authors stated that myo-inositol administration may be a therapeutic opportunity for treating metabolic syndrome in postmenopausal women [72]. ...
... Endocrine outcomes were assessed by all the reviews with benefits reported in testosterone, dehydroepiandrosterone (DHEA), or androstenedione levels. Metabolic outcomes were assessed by all the reviews with important results: reduced insulin levels [47,72,85], reduced glucose levels and HOMA-IR, and improved blood pressure, triglycerides, and high-density lipoprotein [86]. e effectiveness of myo-inositol for PCOS was investigated by a systematic review and meta-analysis of RCTs [87]. ...
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Aims. Despite the very clear association between polycystic ovary syndrome (PCOS) and dysglycemia, few studies have explored the continuum of glycemic alterations leading from minor glucose abnormalities to overt diabetes. The purpose of this review is to trace the natural history of glycemic alteration in women with PCOS. Methods. We performed a literature review without time limit until August 2019. Inclusion criteria were studies addressing the association between impaired glucose tolerance or impaired fasting glucose or type 2 diabetes (T2D) and PCOS with at least an English abstract. The exclusion criteria were no PCOS or impaired glucose tolerance or impaired fasting glucose or T2D as outcome. The outcomes of interest were the onset of impaired glucose tolerance, impaired fasting glucose, T2D, and the progression from impaired glucose tolerance or impaired fasting glucose to T2D. Results. Healthy diet and physical activity are the first-line therapy for PCOS. Treatment with metformin was associated with significant lower 2-hour postload glucose levels and with reduction in fasting glucose when compared to placebo. Thiazolidinediones were more effective in reducing fasting glucose levels compared to placebo. Metformin and pioglitazone treatments showed similar effects on fasting glucose levels. The sodium-glucose cotransporter-2 inhibitor empagliflozin did not show differences in metabolic parameters when compared to metformin. The combination therapy with metformin plus the glucagon-like peptide-1 receptor agonist liraglutide was associated with significant improvements in basal and postload glucose levels compared with only liraglutide. Likewise, a combination therapy with the dipeptidyl peptidase-4 inhibitor saxagliptin and metformin demonstrated superiority versus metformin in fasting glucose and oral glucose tolerance test normalization. Myo-inositol supplementation was associated with lower insulin levels, glucose levels, and insulin resistance when compared with placebo, metformin, or estrogen treatments. Conclusions. The use of insulin-sensitizing agents, such as metformin and inositols, along with lifestyle interventions may improve the metabolic profile in PCOS women. 1. Introduction Diabetes mellitus is a worldwide epidemic. Its prevalence and incidence are steeply growing with an estimated 425 million of people currently having diabetes [1]. The great social burden of the disease is worsened by the huge number of people with prediabetes (i.e., impaired fasting glucose and/or impaired glucose tolerance) who are at high risk of developing it. In addition, one in two adults with diabetes (about 212 million of people) is undiagnosed. Several risk factors for the development of the disease have been well recognized. Some risk factors are gender specific, such as gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS). PCOS is defined by its reproductive features of hyperandrogenism, chronic oligoanovulation, and/or polycystic ovarian morphology [2]. Its prevalence is 5–15%, depending on the diagnostic criteria applied [3]. PCOS is associated with metabolic abnormalities, including insulin resistance (IR) and β-cell dysfunction [2]. The result of IR is hyperinsulinemia, which has a central role in the pathogenesis of androgen excess in PCOS. Indeed, insulin acts as a cogonadotropin to increase luteinizing hormone (LH)-induced androgen synthesis in theca cells [4] and can enhance gonadotropin-releasing hormone (GnRH)-mediated gonadotropin secretion [5]. Insulin also reduces hepatic sex hormone binding globulin (SHBG) synthesis, thereby increasing the levels of bioavailable androgens [6]. The defect of insulin action was quantified in PCOS using the euglycemic clamp [7]. Insulin action was reduced by 35–40% in both lean and obese women with PCOS compared to control women of similar age and body composition [8]. Recent studies in daughters of women affected by PCOS have found evidence for pancreatic β-cell dysfunction prior to menarche [9]. Genetic analyses showed that metabolic abnormalities such as obesity and IR contribute to the pathogenesis of PCOS [10]. Women with PCOS have a higher cardiometabolic risk compared with women without ovarian problems [11]. In women with PCOS, dysglycemia typically consists of impaired glucose tolerance [12], its prevalence being of almost 30% in both adult women [13] and affected adolescents [14]. For this reason, PCOS is associated with a two times increased risk for type 2 diabetes (T2D) [15]. Despite the very clear association between PCOS and dysglycemia, few studies have explored the continuum of glycemic alterations leading from minor glucose abnormalities to overt diabetes. The purpose of this review is to summarize the effect of lifestyle and pharmacological management on glycemic alterations of women with PCOS. 2. Materials and Methods We searched the online databases of PubMed/Medline, Scopus, Web of Science, Science Direct, Embase, CINAHL, EBSCO, and Google Scholar search engine using MeSH keywords of “impaired glucose tolerance” or “IGT,” “impaired fasting glucose” or “IFG,” “type 2 diabetes” or “T2D,” and “polycystic ovary syndrome” or “PCOS” or “PCO syndrome” without time limit until August 2019. All the reference lists of the retrieved articles were reviewed. All steps of the study were independently performed by two researchers and any disagreement between researchers was resolved by a third researcher. Inclusion criteria were studies addressing the association between impaired glucose tolerance or impaired fasting glucose or T2D and PCOS with at least an English abstract with a special focus on the available PCOS treatment. The exclusion criteria were as follows: no PCOS or impaired glucose tolerance or impaired fasting glucose or T2D as outcome, conference presentations, and letters to the editors. The outcomes of interest were the onset of impaired glucose tolerance, impaired fasting glucose, T2D, and the progression from impaired glucose tolerance or impaired fasting glucose to T2D with a special focus on the available PCOS treatment. 3. Results and Discussion 3.1. Pathogenesis of Prediabetes and Type 2 Diabetes Several risk factors have been hypothesized having a causal role in the pathogenesis of prediabetes and T2D of women with PCOS. Classical risk factors such as genetic background, obesity, and familiarity for diabetes and PCOS-specific risk factors have been described. The role of obesity does not impact independently on the onset of prediabetes and T2D because it was shown that also lean women with PCOS have a high risk of glucose alterations. However, obesity surely represents a strong additional risk factor. Among the PCOS-specific factors, IR and hyperandrogenism have been reported. Subjects with hyperandrogenism have a higher level of IR compared with those without hyperandrogenism [16]. Treatment with antiandrogens improves insulin sensitivity; therefore hyperandrogenism could contribute to the pathogenesis of prediabetes and T2D through mechanism of sustaining higher level of IR. However, hyperandrogenism in PCOS could worsen glucose tolerance by stimulating low-grade inflammation [17, 18]. Even if IR is not a feature always present in patients with PCOS, it is considered one of the key elements underlying the pathogenesis of the syndrome. It is the main factor associated with the development of T2D in those women. Reported prevalence of IR in women with PCOS varies from 44% to 70% [19] mostly because of different methods used to assess it [20]. IR is the typical condition of subjects with T2D. Women with PCOS share with people with T2D the same impaired glucose pattern consisting of a prevalent disturbance of fasting blood glucose. Higher levels of IR stress the pancreatic beta cell function, resulting in earlier functional depletion of insulin secretion capacity and higher risk of developing prediabetes and T2D. The other key element characterizing PCOS is hyperandrogenism. The relation between hyperandrogenism and IR is a chicken and egg problem. On one side, androgens may have a direct role in the inhibition of hepatic and peripheral insulin action by reducing amount and efficiency of the glucose transporter type 4 (GLUT4), especially in adipose tissue and muscles [21]. Moreover, androgens in association with increased free fatty acids (FFA) levels (a common feature in women with PCOS) reduce insulin excretion in the liver and insulin-dependent glucose uptake in skeletal muscles contributing to IR and compensatory hyperinsulinemia [22]. On the other side, it is well demonstrated that insulin has a direct role in ovarian steroidogenesis and in the ovulation control. Insulin in fact directly stimulates androgen production from ovaries, enhancing the activity of CYP17α and other steroidogenic enzymes with increased androgen production. It also inhibits the hepatic synthesis of SHBG and the secretion of the insulin-like growth factor-binding protein (IGFBP-1) resulting in elevated levels of free IGF and androgens. Furthermore, at pituitary level, insulin stimulates LH secretion, which, in association with insulin itself, acts synergistically on theca cells, increasing androgen biosynthesis [4, 23]. As shown by Dunaif et al., IR associated with PCOS, seems to be determined also by alterations at the level of the insulin receptor signalling. They observed that insulin receptors isolated from fibroblast cultured and skeletal muscle of women with PCOS presented increased insulin-independent autophosphorylation which is associated with reduced receptor activity [24, 25] and can lead to IR. However, other abnormalities have been observed also in downstream pathways, such as the serine phosphorylation of the insulin receptor substrates which inhibits its binding with PI3K and prevents the propagation of the signal downstream [26, 27]. Because of this central role of IR and compensatory hyperinsulinemia in the pathogenesis of the disease, it appears clear how insulin sensitizers represent possible therapeutic agents. Alternative mechanisms of the pathogenesis of prediabetes and T2D in subjects with PCOS are muscle mitochondrial dysfunction [28] and the gut microbiome [29]. The latter hypothesis is sustained by the presence of specific taxa of gut microorganisms that are associated with lower androgen levels. The following sections and Table 1 report existing evidence of the effect of different treatments on impaired glucose tolerance and impaired fasting glucose in women with PCOS. No treatment was effective in restoring normal glucose tolerance or reverse to impaired glucose tolerance or to impaired fasting glucose when T2D was already diagnosed. Intervention Impaired glucose tolerance (IGT) Impaired fasting glucose (IFG) Lifestyle modifications Improved (28, 29, 33, 34) Improved (28, 29, 33, 34) Metformin (i) Improvement in 2-hour glucose levels at the OGTT (46, 47) Reduction in fasting glucose levels compared to placebo (42) (ii) Reversion from IGT to normal glucose tolerance (47) Thiazolidinediones Reversion from IGT to normal glucose tolerance (60) Reduction in fasting glucose levels compared to placebo (58) SGLT2i Neutral effect (61) Neutral effect (61) GLP-1 RA Improved with the combination of liraglutide and metformin (62) Improved with the combination of liraglutide and metformin (62) DPP4i Improved with the combination of saxagliptin and metformin (63) Improved with the combination of saxagliptin and metformin (63) Inositol Improved (78) Improved (78) SGLT2i, sodium-glucose cotransporter-2 inhibitors; GLP-1 RA, glucagon-like peptide-1 receptor agonists; DPP4i, dipeptidyl peptidase-4 inhibitors; OGTT, oral glucose tolerance test.
... The flow chart of step by step details for study identification and selection is illustrated in Fig. 1. Eight studies were used double-blind design [16][17][18][19][20][21][22][23], four were randomized placebo-controlled trial design [11,[24][25][26], and two were randomized controlled trial design [27,28]. Seven trials evaluated the effects of inositol on lipid profiles among patients with PCOS [16,19,20,22,23,27,28] and others were evaluated the effects of inositol on other metabolic diseases [11,17,18,21,[24][25][26]. Twelve studies have reported the effects of inositol on triglycerides, 11 on total cholesterol, five on LDL-cholesterol, and ten on HDL-cholesterol levels. ...
... Eight studies were used double-blind design [16][17][18][19][20][21][22][23], four were randomized placebo-controlled trial design [11,[24][25][26], and two were randomized controlled trial design [27,28]. Seven trials evaluated the effects of inositol on lipid profiles among patients with PCOS [16,19,20,22,23,27,28] and others were evaluated the effects of inositol on other metabolic diseases [11,17,18,21,[24][25][26]. Twelve studies have reported the effects of inositol on triglycerides, 11 on total cholesterol, five on LDL-cholesterol, and ten on HDL-cholesterol levels. ...
Article
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Background: Several studies have evaluated the effect of inositol supplementation on lipid profiles among population with metabolic diseases; however, the findings are controversial. This review of randomized controlled trials (RCTs) was performed to summarize the evidence of the effects of inositol supplementation on lipid profiles among population with metabolic diseases. Methods: Relevant RCTs studies were searched in Cochrane Library, EMBASE, MEDLINE, and Web of Science until October 2017. Two researchers assessed study eligibility, extracted data, and evaluated risk of bias of included primary studies, independently. To check for the heterogeneity among included studies Q-test and I2 statistics were used. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as summary of the effect size. Results: Overall, 14 RCTs were included into meta-analysis. Pooled results showed that inositol supplementation among patients with metabolic diseases significantly decreased triglycerides (SMD − 1.24; 95% CI, − 1.84, − 0.64; P < 0.001), total- (SMD − 1.09; 95% CI, − 1.83, − 0.55; P < 0.001), and LDL-cholesterol levels (SMD − 1.31; 95% CI, − 2.23, − 0.39; P = 0.005). There was no effect of inositol supplementation on HDL-cholesterol levels (SMD 0.20; 95% CI, − 0.27, 0.67; P = 0.40). Conclusions: Inositol supplementation may result in reduction in triglycerides, total- and LDL-cholesterol levels, but did not affect HDL-cholesterol levels among patients with metabolic diseases. Additional prospective studies regarding the effect of inositol supplementation on lipid profiles in patients with metabolic diseases are necessary. Keywords: Inositol, Lipid profiles, Metabolic diseases, Meta-analysis
... In view of its recognized insulin-sensitizing activity, MI has been used to prevent and/or treat a number of metabolic disorders related to IR, such as the metabolic syndrome (4,5), gestational diabetes mellitus (6,7,8,9,10) and the polycystic ovary syndrome (PCOS) (11,12,13). ...
... The remaining 18 articles were assessed for eligibility, and 9 articles which met the criteria were finally included in the meta-analysis. Studies were excluded for several reasons including (a) data of the outcome were unavailable or not expressed in the numerical form (39), (b) patients were treated with MI combined with other molecules such as multivitamin complex (40), lactoferrin and bromelin (41) or oral contraceptives pills (OCPs) (42), (c) menopausal women with metabolic syndrome (4,5) and (d) the study was a non-randomized design (43,44,45). ...
Article
Full-text available
Myo-inositol (MI) supplementation in women with polycystic ovary syndrome (PCOS) has been evaluated over the last years. Many hormonal and reproductive impairments associated with this disorder seem relieved by the supplement. The objective of the meta-analysis was to assess the effects of MI alone or combined with d-chiro-inositol (DCI) on the endocrine and metabolic abnormalities of women with PCOS. Literature was retrieved from selected databases, MEDLINE, EMBASE, PubMed and Research Gate (up to November 2016). Only randomized controlled trials (RCTs) investigating the effects of MI alone or combined with dCI were reviewed. Nine RCTs involving 247 cases and 249 controls were included. Significant decreases in fasting insulin (SMD = −1.021 µU/mL, 95% CI: −1.791 to −0.251, P = 0.009) and homeostasis model assessment (HOMA) index (SMD = −0.585, 95% CI: −1.145 to −0.025, P = 0.041) were identified after MI supplementation. The trial sequential analysis of insulin meta-analysis illustrates that the cumulative z-curve crossed the monitoring boundary, providing firm evidence of the intervention effect. A slight trend toward a reduction of testosterone concentration by MI with respect to controls was found (SMD = −0.49, 95% CI: −1.072 to 0.092, P = 0.099), whereas androstenedione levels remained unaffected. Throughout a subgroup's meta-analysis, a significant increase in serum SHBG was observed only in those studies where MI was administered for at least 24 weeks (SMD = 0.425 nmol/L, 95% CI: 0.050-0.801, P = 0.026). These results highlight the beneficial effect of MI in improving the metabolic profile of women with PCOS, concomitantly reducing their hyperandrogenism.
... In view of its recognized insulin-sensitizing activity, MI has been used to prevent and/or treat a number of metabolic disorders related to IR, such as the metabolic syndrome (4,5), gestational diabetes mellitus (6,7,8,9,10) and the polycystic ovary syndrome (PCOS) (11,12,13). ...
... The remaining 18 articles were assessed for eligibility, and 9 articles which met the criteria were finally included in the meta-analysis. Studies were excluded for several reasons including (a) data of the outcome were unavailable or not expressed in the numerical form (39), (b) patients were treated with MI combined with other molecules such as multivitamin complex (40), lactoferrin and bromelin (41) or oral contraceptives pills (OCPs) (42), (c) menopausal women with metabolic syndrome (4,5) and (d) the study was a non-randomized design (43,44,45). ...
Article
Full-text available
Myo-inositol (MI) supplementation in women with polycystic ovary syndrome (PCOS) has been evaluated over the last years. Many hormonal and reproductive impairments associated with this disorder seem relieved by the supplement. The objective of the meta-analysis was to assess the effects of MI alone or combined with d-chiro-inositol (DCI) on the endocrine and metabolic abnormalities of women with PCOS. Literature was retrieved from selected databases, MEDLINE, EMBASE, PubMed and Research Gate (up to November 2016). Only randomized controlled trials (RCTs) investigating the effects of MI alone or combined with DCI were reviewed. Nine RCTs involving 247 cases and 249 controls were included. Significant decreases in fasting insulin (SMD = −1.021 µU/mL, 95% CI: −1.791 to −0.251, P = 0.009) and homeostasis model assessment (HOMA) index (SMD = −0.585, 95% CI: −1.145 to −0.025, P = 0.041) were identified after MI supplementation. The trial sequential analysis of insulin meta-analysis illustrates that the cumulative z-curve crossed the monitoring boundary, providing firm evidence of the intervention effect. A slight trend toward a reduction of testosterone concentration by MI with respect to controls was found (SMD = −0.49, 95% CI: −1.072 to 0.092, P = 0.099), whereas androstenedione levels remained unaffected. Throughout a subgroup’s meta-analysis, a significant increase in serum SHBG was observed only in those studies where MI was administered for at least 24 weeks (SMD = 0.425 nmol/L, 95% CI: 0.050–0.801, P = 0.026). These results highlight the beneficial effect of MI in improving the metabolic profile of women with PCOS, concomitantly reducing their hyperandrogenism.
... Several small clinical trials suggest that inositol supplementation could be a useful intervention or preventive measure for the insulin-related and metabolic abnormalities in PCOS, GDM and type 2 diabetes (Noventa et al. 2016;Croze and Soulage 2013;Crawford et al. 2015;Papaleo et al. 2007;D'anna et al. 2012;Gateva, Unfer, and Kamenov 2018;Colazingari et al. 2013;Bizzarri and Carlomagno 2014;Unfer and Porcaro 2014;Muscogiuri et al. 2016;Lubin et al. 2016;Brown, Crawford Tineke, and Alsweiler 2015;Farren et al. 2017;Malvasi et al. 2014;Pintaudi, Di Vieste, and Bonomo 2016;D'Anna et al., 2013;Matarrelli et al. 2013;Werner et al. 2016;DʼAnna et al. 2015;D'Anna et al., 2013;Cogram et al. 2002;Cavalli et al. 2011). Inositol supplementation appears to decrease glycemia and improve insulin sensitivity, but effects vary depending on the inositol isomer used, the dose and the population studied Dʼ Anna et al. 2015;D'Anna et al., 2013;Kim et al. 2005;Santamaria et al. 2012;Giordano et al. 2011;Artini et al. 2013;Genazzani et al. 2012;Santamaria, Di Benedetto, et al. 2016;Corrado et al. 2011;Fraticelli et al. 2018). Other small clinical trials have also suggested that inositol supplementation might reduce plasma triglycerides and total and LDL-cholesterol levels among patients with diabetes mellitus, hyperinsulinemia, metabolic syndrome and PCOS (Tabrizi et al. 2018), thereby highlighting a natural compound that could address the increased risk of atherosclerotic and cardiovascular diseases associated with these conditions. ...
... The pharmacological effects of inositol likely depend on the inositol isomer, the dose, and the population studied. For example, daily inositol supplementation resulted in decreased insulin resistance as assessed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in postmenopausal women with metabolic syndrome [4000 mg myo-inositol (Santamaria et al. 2012;Giordano et al. 2011)], in non-pregnant women (Taguchi et al. 1997) GC Adult rat Serum: 80 (10) (Kennington 1992) GC Adult rat Serum: 48.6 (4.9) GC Adult rat Serum: 71.0 (0.6) (Bersudsky et al. 1999 ...
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Inositols, a group of 6-carbon polyols, are highly bioactive molecules derived from diet and endogenous synthesis. Inositols and their derivatives are involved in glucose and lipid metabolism and participate in insulin-signaling, with perturbations in inositol processing being associated with conditions involving insulin resistance, dysglycemia and dyslipidemia such as polycystic ovary syndrome and diabetes. Pregnancy is similarly characterized by substantial and complex changes in glycemic and lipidomic regulation as part of maternal adaptation and is also associated with physiological alterations in inositol processing. Disruptions in maternal adaptation are postulated to have a critical pathophysiological role in pregnancy complications such as gestational diabetes and pre-eclampsia. Inositol supplementation has shown promise as an intervention for the alleviation of symptoms in conditions of insulin resistance and for gestational diabetes prevention. However, the mechanisms behind these affects are not fully understood. In this review, we explore the role of inositols in conditions of insulin dysregulation and in pregnancy, and identify priority areas for research. We particularly examine the role and function of inositols within the maternal-placental-fetal axis in both uncomplicated and pathological pregnancies. We also discuss how inositols may mediate maternal-placental-fetal cross-talk, and regulate fetal growth and development, and suggest that inositols play a vital role in promoting healthy pregnancy.
... These findings boosted investigation on the involvement of inositol in different physiological conditions, comprising fertility [9], oogenesis [10], embryogenesis [11,12] regenerative processes [13], and fat metabolism [14]. ...
... Indeed, some preliminary clinical reports provided compelling evidence supporting the beneficial effects obtained with inositol in insulin-resistant patients. Inositol reduces glycemia levels and hyperinsulinemia, while buffering negative effects of sustained insulin stimulation upon the adipose tissue and the endocrine system [14,88]. As such, myoIns has become a reliable treatment option for insulin-resistant PCOS patients [89,90]. ...
Article
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In the past decades, both the importance of inositol for human health and the complex interaction between glucose and inositol have been the subject of increasing consideration. Glucose has been shown to interfere with cellular transmembrane transport of inositol, inhibiting, among others, its intestinal absorption. Moreover, intracellular glucose is required for de novo biosynthesis of inositol through the inositol-3-phosphate synthase 1 pathway, while a few glucose-related metabolites, like sorbitol, reduce intracellular levels of inositol. Furthermore, inositol, via its major isomers myo -inositol and D- chiro -inositol, and probably some of its phosphate intermediate metabolites and correlated enzymes (like inositol hexakisphosphate kinase) participate in both insulin signaling and glucose metabolism by influencing distinct pathways. Indeed, clinical data support the beneficial effects exerted by inositol by reducing glycaemia levels and hyperinsulinemia and buffering negative effects of sustained insulin stimulation upon the adipose tissue and the endocrine system. Due to these multiple effects, myoIns has become a reliable treatment option, as opposed to hormonal stimulation, for insulin-resistant PCOS patients.
... A fertile man does not have high levels of semen ROS instead [10,11]. ROS are needed for capacitation, acrosome reaction, and ultimately fertilization [12]. However, their uncontrolled production is dangerous for a variety of biomolecules such as lipids, amino acids, carbohydrates, protein, and DNA. ...
... To date, this is the first in vivo study that focuses on this topic. Nevertheless, several evidences of MI clinical efficacy in women with PCOS [33][34][35] and in postmenopausal women with MS are available in literature [12,14]. ...
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This prospective longitudinal study investigated the effects of a dietary supplement in patients affected by reduced sperm motility (asthenospermic males) with metabolic syndrome. The product tested was Andrositol®, which contains myoinositol (MI) as principal compound, in association with other molecules, and the parameters evaluated were semen characteristics as well as hormone and metabolic profiles. The inclusion criteria were subjects aged over 18 years, with asthenospermia and metabolic syndrome. The exclusion criteria were presence of cryptorchidism, varicocele, and prostatitis. For this study, 45 males who had such features were enrolled. Their selection was made according to the 2010 World Health Organization (WHO) criteria (5th Edition) for the Evaluation of Human Semen. Hormone and metabolic profiles and semen parameters were assessed at the beginning of the study and after three months of treatment with Andrositol. The differences between the values before and after the supplementation were found statistically significant. Andrositol normalized the metabolic profile of these patients, improving their insulin sensitivity. Moreover, testosterone levels were increased and the semen characteristics, such as sperm concentration, motility, and morphology, highly improved. In conclusion, the association of MI with other molecules (micronutrients and vitamins) could be an effective therapy for metabolic disorders, as well as hormonal and spermatic changes responsible for male infertility.
... To date, a handful of randomized trials have assessed the impact of inositol regimens on the incidence of GDM. Of those, two studies that recruited overweight pregnant women observed > 50% reduction in the incidence of GDM [17,19], and one study that included obese women observed nearly 60% reduction [20]. Women with polycystic ovarian syndrome may also benefit from inositol supplementation during pregnancy as the incidence of GDM seems to be reduced by more than 60% according to the findings of another study [18]. ...
... Post-menopausal metabolic syndrome is another insulin-resistant syndrome with a good response to myo-inositol administration. In fact, it has been demonstrated that myo-inositol may decrease insulin resistance by approximately 70% in post-menopausal women with metabolic syndrome [19,35]. Another common disorder in which insulin resistance constitutes a crucial factor is type 2 diabetes mellitus (T2DM). ...
Article
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Background: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance with onset or first recognition during pregnancy, which is characterized by an increased insulin resistance. Gestational diabetes mellitus is associated with pregnancy-related maternal and fetal morbidity (both antenatal and perinatal). Myo-inositol has been suggested to improve insulin resistance in women with polycystic ovary syndrome. The aim of this study is to examine the impact of myo-inositol supplementation during pregnancy on the incidence of gestational diabetes mellitus. Methods: We will conduct a single-center, open-label, randomized controlled trial. A total of 160 healthy pregnant women with singleton pregnancy at 11-13+6 weeks of gestation will be randomly allocated in two groups: intervention group (N = 80) and control group (N = 80). The intervention group will receive myo-inositol and folic acid (4000 mg myo-inositol and 400 mcg folic acid daily) from 11 to 13+6 weeks of gestation until 26-28 weeks of gestation, while the control group will receive folic acid alone (400 mcg folic acid daily) for the same period of time as intervention group. The primary outcome will be gestational diabetes incidence rate at 26-28 weeks of gestation, according to the results of a 75 g oral glucose tolerance test held at 26-28 weeks of gestation. The secondary outcomes will include fasting blood glucose levels, glycated hemoglobin levels, insulin resistance level (evaluated by homeostasis model assessment of insulin resistance and Matsuda Index), and incidence rate of diet-treated gestational diabetes and diabetes requiring insulin therapy at 26-28 weeks of gestation. Discussion: This trial will provide evidence for the effectiveness of myo-inositol supplementation during pregnancy in reducing the incidence of gestational diabetes mellitus. Trial registration: ISRCTN registry: ISRCTN16142533 . Registered on 9 March 2017.
... The inositol-dependent anticancer effects paved the way for discovering further properties of myo-Ins and its phosphate derivatives. Hence, in recent decades many attempts have been conducted to deepen the understanding of inositol involvement in different physiological and pathological conditions, including fertility [17,18], regenerative processes [19], oogenesis [20] and sperm function [21], glucose [22] and fat metabolism [23], morphogenesis [24,25], neurological disorders [26], and respiratory function in newborn [27]. ...
Article
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Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components—as phytates and inositols—for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability.
... Besides improvement in insulin sensitivity, a marked normalization of several metabolic parameters -including HDL cholesterol, plasma triglycerides and LDL -was recorded after myo-Ins treatment in in PCOS women with insulin resistance [74][75][76]. In the study authored by Santamaria et al. [77], one year of myo-Ins supplementation ameliorated the lipid profile, while inducing a critical reduction in serum insulin. Indeed, inositol mitigates the insulin resistance by doubling the HOMA-IR index in respect to other insulin-sensitizing drugs -like pioglitazone, rosiglitazone or even metformin [78] -currently deemed the gold standard for treatment of patients with impaired glucose tolerance. ...
Article
Insulin resistance indicates a deregulated set of biochemical pathways and physiological functions involved in the pathogenesis of a number of diseases, including type 2 diabetes and cancer. Conversely, a number of synthetic and natural insulin sensitizers, including inositol, have been recognized to exert both anti-diabetic as well as anti-cancer properties. Inositol participates in insulin transduction signaling, and deregulated inositol metabolism has been ascertained in several conditions associated with insulin resistance. Two distinct inositol-phosphoglycans released upon insulin stimulation act as insulin-mimetic by counteracting hyperinsulinemia, hyperglycemia and their metabolic complications. Additionally, inositol may directly interfere with both glucose metabolism and carcinogenesis by modulating a number of critical processes downstream of insulin stimulation, including anti-oxidant defenses, oxidative glucose metabolism and endocrine modulation. A selected cluster of biochemical factors (PI3K/Akt, PDH and AMPK-related pathways), that are presently considered putative targets for anticancer treatments, are also specifically modulated by inositol or its derivatives. What is more, studies on inositol mechanism of action paved the way in understanding that both insulin resistance and cancer share a few perturbed, critical biochemical pathways. Asides from basic investigations, preliminary studies in vivo demonstrated the beneficial effect of inositol in fostering glucose homeostasis as well as in antagonizing cancer growth. Thereby, inositol fulfills the requirement to target both insulin resistance and cancer, and its clinical usefulness deserves to be adequately addressed by specific, randomized trials.
... In particular, available data have shown that in women with MS the treatment for 1 year with MI significantly reduces the parameters related to insulin resistance and dyslipidemia than diet alone. Furthermore, after one year of treatment, 20% of women did not fall more in the diagnostic criteria of MS (23,24). Recent evidences have demonstrated how, in ovarian level, PCOS women are characterized by a deficiency of MI and an excess of D-chiroinositol (DCI). ...
... A restored cyclic ovarian function has been also demonstrated in women affected by polycystic ovary syndrome (PCOS) who were supplemented with the insulin-sensitizer myoinositol (myo-Ins) [4], since hyperinsulinemia impacts on the PCOS related ovarian dysfunction. Similar positive effects by myo-Ins supplementation were demonstrated in post-menopausal women with another hyperinsulinemic disorder, the metabolic syndrome [5,6] . In this study, which was carried out on women during menopausal transition, we used myo-Ins alone or combined with melatonin, with the aim of evaluating the effects of either supplementation on serum insulin or serum thyroid profile. ...
Article
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Introduction: The aim of the study was to evaluate the effects on serum insulin and serum thyroid profile of a dietary supplement, myo-inositol, given alone or in combination with melatonin to women during menopausal transition. Methods: Forty women aged 45–55 years and at least 6 months of amenorrhea were enrolled in this study. They were randomly assigned to two groups of 20 each. One group took myo-inositol (myo-Ins) (2 g twice a day) and the other group took 2 g/d myo-Ins plus 3 g/d melatonin before sleeping. At the beginning of the study and after 6 months, all women were evaluated for the following indices: waist circumference, body mass index, blood pressure, endometrial thickness, as well as serum concentrations of TSH, FT3, FT4 and insulin. Results: Both at baseline and at 6 months, the two groups were statistically similar for each of the considered indices. If percent changes (Δ%, 6 months over baseline) are contrasted in the two groups, serum TSH decreased in the myo-Ins group but increased in the latter, while serum insulin decreased in both groups. Conclusions: The combination of myo-Ins plus melatonin seems to affect positively glucose metabolism, while myo-Ins only seems to improve thyroid function.
... Myo-inositol (MI), a six carbon cyclohexane hexitol, is used as a supplement in treating several pathologies such as PCOS, 685 metabolic syndrome, 686 and gestational diabetes. 687 Myoinositol (MI) biosynthesis from glucose contains three steps in E. coli 688 ( Figure 33): (i) glucose is converted to glucose-6phosphate (G6P) by the native phosphotransferase system (PTS); (ii) G6P is isomerized to myo-inositol-1-phosphate by myo-inositol-1-phosphate synthase (INO1); (iii) myo-inositol-1-phosphate is dephosphorylated to MI by myo-inositol monophosphatase (MIMP). ...
Article
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Chemical synthesis is a well established route for producing many chemicals on a large scale, but some drawbacks still exist in this process, such as unstable intermediates, multistep reactions, complex process control, etc. Biobased production provides an attractive alternative to these challenges, but how to make cells into efficient factories is challenging. As a key enabling technology to develop efficient cell factories, design-construction-evaluation-optimization (DCEO) biotechnology, which incorporates the concepts and techniques of pathway design, pathway construction, pathway evaluation, and pathway optimization at the systems level, offers a conceptual and technological framework to exploit potential pathways, modify existing pathways and create new pathways for the optimal production of desired chemicals. Here, we summarize recent progress of DCEO biotechnology and examples of its application, and provide insights as to when, what and how different strategies should be taken. In addition, we highlight future perspectives of DCEO biotechnology for the successful establishment of biorefineries.
... Given inositol pivotal role in regulating many metabolic pathways and hormonal signalling, its use in clinical settings is steeply growing. Inositol has been mainly used as a supplement in treating several pathologies such as PCOS [8], metabolic syndrome [9,10], and gestational diabetes (GDM) [11]. In the case of GDM, a condition defined as a glucose impairment first detected in pregnancy, a preventive role of inositol for GDM onset was recognized [12][13][14]. ...
Article
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Inositol has been used as a supplement in treating several pathologies such as PCOS, metabolic syndrome, and gestational diabetes. Both myo-inositol and its isomer d-chiro-inositol showed insulin mimetic effects in conditions of insulin resistance. Type 2 diabetes (T2DM) is a condition typically caused by insulin resistance. There is a lack of evidence of inositol use in T2DM. We evaluated the effectiveness and safety of myo-inositol and d-chiro-inositol treatment in T2DM. This was a pilot study involving a consecutive sample of patients with T2DM with suboptimal glycemic control (HbA1c 7.0–10.0%) already treated with glucose-lowering agents. Patients (23.1% males, mean age of 60.8±11.7 years) took for three months a combination of myo-inositol (550 mg) and d-chiro-inositol (13.8 mg) orally twice a day as add-on supplement to their glucose-lowering drugs. Possible occurrence of side effects was investigated. After three months of treatment fasting blood glucose ( 192.6±60.2 versus 160.9±36.4 ; p=0.02 ) and HbA1c levels ( 8.6±0.9 versus 7.7±0.9 ; p=0.02 ) significantly decreased compared to baseline. There was no significant difference in blood pressure, lipid profile, and BMI levels. None of the participants reported side effects. In conclusion, a supplementation with a combination of myo- and d-chiro-inositol is an effective and safe strategy for improving glycemic control in T2DM.
... Inositol(s) may indeed modulate the antioxidant/prooxidant balance, as well as the patient metabolomic fingerprint (downregulation of insulin levels, improved glucose utilization through the oxidative cycle, and inhibition of lipogenesis). Such effects have been extensively recorded in nonneoplastic patients suffering from PCOS or metabolic diseases [3,147] and likely may also be effective in cancer patients. ...
Article
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Inositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, β-catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture.
... To investigate whether SNPs in IMPA2 influence IS susceptibility in a Han Chinese population, we performed a candidate gene association study using a case-control Myo-inositol monophosphatase 2, which is encoded by the IMPA2 gene, converts inositol phosphate into inositol through dephosphorylation. Inositol is an essential intracellular signaling molecule in second messenger pathways that may exert an insulin-like effect and improve blood pressure, cholesterol, high-density lipoprotein, and triglyceride levels which are all involved in the pathogenesis of IS [19]. We found that the IMPA2 rs589247 polymorphism was associated with an increased risk of IS. ...
Article
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Genetic association analysis has suggested that IMPA2 is a susceptibility gene for ischemic stroke (IS). To explore the association between IMPA2 polymorphisms and the risk of IS in a Han Chinese population, candidate gene association was performed using data from a case-control study of 488 IS patients and 503 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association, and associations were evaluated under dominant, recessive, and additive genetic models using PLINK software. There was a statistically significant difference in the "TC" genotype frequency of the IMPA2 polymorphism rs589247, between cases and controls (50.0% vs. 45.3%). Under the dominant model, rs589247 was associated with an increased risk of IS (OR=1.32, 95%CI: 1.01-1.73; P=0.040). There were no other associations between any of the seven additional IMPA2 polymorphisms and IS risk. This study is the first to find a correlation between an IMPA2 polymorphism and IS risk in a northwest Han Chinese population. These results may help to elucidate the molecular pathogenesis of this disease, and could potentially be used to predict IS risk. However, further studies are still needed to validate this association in other populations and with larger sample sizes.
... In particular, cocoa polyphenols have shown a strong beneficial action on the cardiovascular profile of different models [26,27]. Interestingly, there is some evidence showing that the combination of MI and cocoa polyphenols in postmenopausal women with MS was able to restore their metabolic and cardiovascular profile [28,29]. Therefore, it could be speculated that PCOS women could take advantage of MI supplementation from the adolescence up to the menopausal age. ...
Article
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Introduction . Polycystic ovary syndrome (PCOS) is a common disorder in reproductive age. This pilot study investigated the effects of myoinositol (MI) treatment on metabolic and cardiovascular profile in PCOS women over 30 years of age. Methods . Between 2015 and 2016, 50 women with diagnosis of PCOS by the Rotterdam Criteria were included in the study. All women received MI 2 g plus 200 μ g of folic acid (Inofolic, Health Parsian, Iran; twice daily) for 3 months. Baseline and 3-month serum samples were taken after an overnight fast to evaluate the insulin resistance index (HOMA-IR), fasting glucose, and the levels of triglyceride, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine, systolic blood pressure, and diastolic blood pressure. Participants’ weight was measured before and after treatment and body mass index (BMI) was calculated. Results . The data showed a significant improvement in the serum level of insulin sensitivity and a reduction of cholesterol, LDL, and homocysteine after three months of treatment. Furthermore, blood pressure was significantly reduced in the treated patients. Three participants became pregnant during treatment. Conclusion . Results showed that supplementation with MI and folic acid in PCOS patients over 30 years of age could decrease the risk of cardiovascular problems by normalizing the metabolic profile.
... Patients were randomized to receive MYO-INS 2 g BID or placebo for 12 months. At the end of the study there was an improvement of all the metabolic parameters such as glucose, insulin, HOMA-IR (Homeostasis Model Assessment-Insulin Resistance), triglycerides, total and high density lipoprotein cholesterol, body mass index (BMI), waist circumference, and blood pressure [24]. Pregnant women with gestational diabetes were randomized to receive MYO-INS supplementation (4 g daily) plus folic acid (400 g daily) or folic acid only (400 g daily) as supplement to controlled diet for 8 weeks. ...
Article
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A growing body of research is currently focused on the role of inositol isomers and in particular myo-inositol (MYO-INS) and D-chiroinositol (DCI) in the treatment of insulin resistance states. Both isomers have been shown to exert insulin-mimetic action and to lower postprandial glucose. Further, insulin resistance-related diseases were associated to derangements in inositol metabolism. Thus, the aim of this review is to provide current evidence on the potential benefits of inositol isomers (MYO-INS and DCI) in the treatment of disease associated to insulin resistance such as polycystic ovary syndrome (PCOS), gestational diabetes, and metabolic syndrome. Finally, molecular insights into inositol insulin-sensitizing effects will be covered focusing on the possible role of inositol glycans as insulin second messengers.
... It is therefore not surprising that genetic mutations of enzymes involved in Ins signaling cause numerous pathologies [87]. Additionally, deregulation of myo-Ins metabolism has been shown to occur in several chronic human diseases, including cancer, metabolic syndrome [88], diabetes [89], thyroid dysfunctions [90], respiratory distress syndrome and infertility (Tab. I). ...
Article
Introduction: Inositol and its derivatives comprise a huge field of biology. Myo-inositol is not only a prominent component of membrane-incorporated phosphatidylinositol, but participates in its free form, with its isomers or its phosphate derivatives, to a multitude of cellular processes, including ion channel permeability, metabolic homeostasis, mRNA export and translation, cytoskeleton remodeling, stress response. Areas covered: Bioavailability, safety, uptake and metabolism of inositol is discussed emphasizing the complexity of interconnected pathways leading to phosphoinositides, inositol phosphates and more complex molecules, like glycosyl-phosphatidylinositols. Expert opinion: Besides being a structural element, myo-inositol exerts unexpected functions, mostly unknown. However, several reports indicate that inositol plays a key role during phenotypic transitions and developmental phases. Furthermore, dysfunctions in the regulation of inositol metabolism have been implicated in several chronic diseases. Clinical trials using inositol in pharmacological doses provide amazing results in the management of gynecological diseases, respiratory stress syndrome, Alzheimer's disease, metabolic syndrome, and cancer, for which conventional treatments are disappointing. However, despite the widespread studies carried out to identify inositol-based effects, no comprehensive understanding of inositol-based mechanisms has been achieved. An integrated metabolomics-genomic study to identify the cellular fate of therapeutically administered myo-inositol and its genomic/enzymatic targets is urgently warranted.
... 7 56 In 80 postmenopausal women with metabolic syndrome, 2 g/day of myo-inositol improved blood glucose, insulin, HOMA-IR value, triglycerides, total and HDL cholesterol and blood pressure compared with placebo. 57 Additionally, there was a significant improvement in BMI and waist circumference in the myo-inositol group versus baseline after 12 months. After taking myo-inositol, eight women (20%) no longer had metabolic syndrome compared with only one in the control group. ...
... Finally, insulin resistance leads to complications, including high blood pressure, dyslipidemia, and the risk of type 2 diabetes (Lobo & Carmina, 2000). Many studies have shown that MI treatment in people with metabolic syndrome reduced dyslipidemia and insulin resistance within one year (Giordano et al., 2011;Santamaria et al., 2012). ...
Article
Assisted reproductive techniques can help many infertile couples conceive. Therefore, there is a need for an effective method to overcome the widespread problems of infertile men and women. Oocyte and sperm quality can increase the chances of successful in vitro fertilisation. The maturation environment in which gametes are present can affect their competency for fer-tilisation. It is well established that myo-inositol (MI) plays a pivotal role in reproductive physiology. It participates in cell membrane formation, lipid synthesis, cell proliferation, cardiac regulation, metabolic alterations, and fertility. This molecule also acts as a direct messenger of insulin and improves glucose uptake in various reproductive tissues. Evidence suggests that MI regulates events such as gamete maturation, fertilisation, and embryo growth through intracel-lular Ca 2 þ release and various signalling pathways. In addition to the in-vivo production of MI from glucose in the reproductive organs, its synthesis by in vitro-cultured sperm and follicles has also been reported. Therefore, MI is suggested as a therapeutic approach to maintain sperm and oocyte health in men and women with reproductive disorders and individuals of reproductive age.
... Inositol(s) may indeed modulate the antioxidant/prooxidant balance, as well as the patient metabolomic fingerprint (downregulation of insulin levels, improved glucose utilization through the oxidative cycle, and inhibition of lipogenesis). Such effects have been extensively recorded in nonneoplastic patients suffering from PCOS or metabolic diseases [3,147] and likely may also be effective in cancer patients. ...
... Such an improvement was noted in only 1 out of the 40 control participants. [14] In another study of 60 postmenopausal women with metabolic syndrome, 2 g MI + 30 mg cocoa polyphenols + 80 mg isoflavones, was compared with placebo over 6 months. The combination of MI and nutraceutical improved glucose (−12 mg %), triglycerides (−20 mg %), visfatin (−0.9 ng/ml), resistin (−5 μg/l), and bone-specific alkaline phosphatase (+4ug/ ml) as compared to placebo. ...
Article
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This review describes the mechanistic, animal, and clinical data related to the use of inositols in midlife. It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol and randomized controlled trials conducted in postmenopausal women with metabolic syndrome and supports these data with the results of in vitro and animal studies on inositol in nephropathy and other related conditions. Recent advances related to biochemistry, pharmaceutical science, and genetics are discussed. It concludes that inositols have a potential role to play in maintaining metabolic health in postmenopausal women.
... D-Chiro-Ins is implicated in the storage of sugars as glycogen, in the regulation of the respiratory chain for the production of ATP, and in the control of insulin secretion by pancreatic b-cells (25). Due to these increasing set of evidence, inositols have been studied in women in the context of a variety of conditions where defective insulin function and excessive body mass index are present, such as PCOS, gestational diabetes and menopausalrelated weight gain (26)(27)(28). ...
Article
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D-Chiro-Inositol (D-Chiro-Ins) is a secondary messenger in the insulin signaling pathway. D-Chiro-Ins modulates insulin secretion, the mitochondrial respiratory chain, and glycogen storage. Due to these actions D-Chiro-Ins has been proposed to correct defective insulin function in a variety of conditions characterized by metabolic dysfunction, such as polycystic ovary syndrome (PCOS), obesity, gestational diabetes and fat accumulation at menopause. Since it is unclear whether D-Chiro-Ins directly acts on adipocytes, we aimed to study D-Chiro-Ins’s actions on adipocyte viability, proliferation, differentiation, and insulin-related protein expression using a human adipocyte cell line derived from Simpson–Golabi–Behmel Syndrome (SGBS) which fully differentiates to mature adipocytes. Throughout differentiation, cells were treated with D-Chiro-Ins, 17β-estradiol (E2) or Insulin. Cell viability and proliferation were not affected by D-Chiro-Ins, then D-Chiro-Ins promoted cell differentiation only during the final days of the process, while E2 enhanced it from the first phases. D-Chiro-Ins stimulated lipid storage and the production of big lipid droplets, thus reducing the content of free fatty acids. We also found that D-Chiro-Ins, either alone or in combination with insulin and E2 increased the expression and activation of insulin receptor substrate-1 (IRS1) and glucose transporter type 4 (GLUT4). In conclusion, this work shows that D-Chiro-Ins plays a direct role in the differentiation and in the function of human adipocytes, where it synergizes with insulin and estrogen through the recruitment of signal transduction pathways involved in lipid and glucose storage. These findings give clear insights to better understand the actions of D-Chiro-Ins on fat metabolism in women in physiology and in a variety of diseases.
... Myoinositol is one of the inositol isomers that could improve insulin sensitivity [51] and has been shown to be related to insulin resistance and microvascular complications in diabetic patients [59]. Meanwhile, myo-inositol could relieve insulin resistance in diseases such as polycystic ovary syndrome and metabolic syndrome [60,61]. ...
Article
Background and aim Essential hypertension (EH) is one of the most important public health problems worldwide. However, the pathogenesis of EH is unclear and early diagnostic methods are lacking. Metabolomics demonstrates great potential for biomarker discovery and mechanistic exploration of metabolic diseases. Methods and results This review included human and animal metabolomics studies related to EH in the PubMed and Web of Science databases between February 1996 and May 2020. The study designs, EH standards and reported metabolic biomarkers were systematically examined and compared. Pathway analysis was conducted through the online software MetaboAnalyst 4.0. Twenty-two human studies and fifteen animal studies were included in this systematic review. There were many frequently reported biomarkers with consistent trends (e.g., pyruvate, lactic acid, valine, and tryptophan) in human and animal studies, and thus had potential as biomarkers of EH. In addition, several shared metabolic pathways, including alanine, aspartate and glutamate metabolism, aminoacyl-tRNA biosynthesis, arginine biosynthesis, were identified in human and animal metabolomics studies. These biomarkers and pathways, closely related to insulin resistance, the inflammatory state and impaired nitric oxide production, were demonstrated to contribute to EH development. Conclusions This study summarized valuable metabolic biomarkers and pathways that could offer opportunities for the early diagnosis or prediction of EH and the discovery of the metabolic mechanisms of EH.
... MYO is considered as a precursor of second messengers in the cellular signal transduction system and consequently involves in the regulation of intracellular calcium concentration (26,27). Therefore, it plays an important role in the cardiac regulation, insulin sensitization, metabolic alterations and particular-ly reproduction (28)(29)(30)(31). On the other hand, it has been demonstrated that MYO has an antioxidant effect and reduces the oxidative stress (32,33). ...
Article
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Background: It is demonstrated that optimal preincubation time improves oocyte quality, fertilization potential and developmental rate. This study aimed to evaluate the effect of preincubation time in the simple and myo-inositol supplemented medium on the oocyte quality regarding oxidative stress and mitochondrial alteration. Methods: Cumulus oocyte complexes (COCs) retrieved from superovulated NMRI mice were divided in groups of 0, 4 and 8 hr preincubation time in the simple and 20 mmol/L myo-inositol supplemented media. Intracellular reactive oxygen species (H2O2), glutathione (GSH), mitochondrial membrane potential (MMP), ATP content, and mitochondrial amount were measured and analyzed in experimental groups. One-way ANOVA and Kruskal-Wallis were respectively used for parametric and nonparametric variables. Statistical significance was defined as p<0.05. Results: In comparison to control group, variables including ROS, GSH, mitochondrial amount, fertilization and developmental rates were significantly changed after 4 hr of preincubation in the simple medium, while MMP decreased following 8 hr of preincubation in the simple medium (p˂0.001). Preincubation of oocytes up to 8 hr in the simple medium could not decrease ATP content. For both 4 and 8 hr preincubation times, myo-inositole could decrease H2O2 and increase GSH and MMP levels and consequently could improve fertilization rate compared to oocytes preincubated in the simple culture. Conclusion: It seems that 4 hr or more preincubation time can decrease the oocyte quality and lead to reduced oocyte fertilization and developmental potential. Howevere, myo-inositol may prevent oocyte quality reduction and improve fertilization potential in comparision to the equivalent simple groups.
... It is not clear if it depends on a reduction in the membrane availability of IPGs or an impairment in the epimerase activation. However, many studies have demonstrated the beneficial role of INS in conditions with underlying insulin resistance [19][20][21][22][23][24]. ...
Article
Full-text available
Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.
... Among its nine possible stereo-isomers, MI is the most abundant 18 . MI is a common ingredient in food 19 , and it is also used as a food supplement to alleviate a variety of diseases 20 , including diabetes 21 and polycystic ovary syndrome (PCOS) 22 . An isomer of MI, D-chiro-Inositol, which does not exist endogenously in either C. elegans or Drosophila melanogaster, has been reported to extend fly lifespan through unknown mechanisms and was speculated to act through dFOXO 13,23 . ...
Article
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Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.
... In addition to PCOs, MI has been observed to be effective in the treatment of certain other insulin resistant metabolic disorders, such as the metabolic syndrome ( (Giordano et al. 2011;Santamaria et al. 2012) and gestational diabetes mellitus (Celentano et al, 2016;D'Anna et l. 2015;D'Anna et al. 2013;Santamaria etal. ...
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Inositol is one of nine biologically significant isomers of hexa hydroxy-cyclohexane which plays important role for bone formation and bone mineral density. The study was conducted to quantify and characterize the myo inositol crystals isolated from the pine nuts and peanuts. High-performance liquid chromatography, UV, FTIR and XRD was utilized for the rapid, on-line detection of inositol phosphate (InsP). The absorption peaks at 382.63nm for 0.10mg peanuts and 382.68 for 0.07mg pine nuts by UV-Visible spectroscopy confirmed the presence of myoinositol. Total concentration of myoinositol obtained was 0.23 and 5.31mmol/kg. The X-ray crystallography analysis showed that the unit-cell parameters a = 6.7226 (3) Å, b = 12.1462 (5) Å, c = 18.9942 (8) Å, α= 89.00, β= 94.98, δ= 989.00. The crystal density was reported at 1.6 cm −3 while the crystal volume was recorded at 1504.7(11) Å 3. The stretching frequencies of myo-inositol crystals were observed in the region of 3800-3778 cm −1 related to alcohol O-H groups of myo-inositol. It is therefore concluded and recommended that dry fruits being the rich source of myo-inositol can be used as functional food for the treatment of polycystic ovarian syndrome.
... 17 Regarding inositol, it has been shown that some isomers, myo-inositol and D-chiro-inositol, perform the function of second messengers of insulin: 18 clinical studies have shown that taking these compounds improves insulin resistance and reduces cardiovascular risk factors in women with polycystic ovary syndrome, 19,20 gestational diabetes mellitus 21,22 and metabolic syndrome postmenopause. 23,24 The aim of this study was to evaluate the effects of a nutraceutical containing Berberine, Curcumin, Inositol, Banaba, and Chromium Picolinate (Reglicem ® ) on the regression of the impaired fasting glucose (IFG) or IGT condition in patients with dysglycemia and on the glycolipid metabolism in patients with IFG or IGT status. ...
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Aim: To evaluate if a nutraceutical containing Berberine, Curcumin, Inositol, Banaba, and Chromium Picolinate (Reglicem®), can ameliorate glycemic status in patients with dysglycemia. Methods: We enrolled 148 patients with impaired fasting plasma glucose or impaired glucose tolerance, not taking any hypoglycemic compounds. Patients were randomized to take nutraceutical or placebo for 3 months, in a randomized, double-blind, placebo-controlled design. Both nutraceutical and placebo were self-administered once a day, 1 tablet during the breakfast. Results: A reduction of fasting and post-prandial plasma glucose was observed with the nutraceutical combination (p < 0.05 vs baseline and p < 0.05 vs placebo, respectively). Furthermore, a decrease of glycated hemoglobin, and fasting plasma insulin was observed with the nutraceutical combination (p < 0.05 vs baseline and p < 0.05 vs placebo, respectively). Then, there was a reduction of homeostasis model assessment index with the nutraceutical combination (p < 0.05 vs baseline and p < 0.05 vs placebo). M value was higher (p < 0.05 vs baseline and p < 0.05 vs placebo) in the nutraceutical combination group at the end of the treatment. We observed a reduction of total cholesterol (TC) (p < 0.05 vs baseline) and triglycerides (Tg) (p < 0.05 vs baseline and p < 0.05 vs placebo) with the nutraceutical combination, respectively. Finally, high sensitivity C-reactive protein was reduced after 3 months with nutraceutical combination therapy (p < 0.05 vs baseline and p < 0.05 vs placebo, respectively). Conclusion: A nutraceutical containing Berberine, Curcumin, Inositol, Banaba, and Chromium Picolinate can be helpful in improving glyco-metabolic compensation, TC and Tg value, and in reducing inflammatory status in patients with dysglycemia.
... Eighty patients were prescribed diet, then randomized to receive additional MI 4 g/day or nothing, for 12 months. Those ones supplemented with MI reported a significant reduction of Homeostasis Model Assessment (HOMA) index, fasting insulin and blood glucose level, respect to controls (diet only) [20,21]. ...
... The absence of cytoplasmic defense systems and the presence of polyunsaturated fatty acids-rich membrane renders sperm more prone to oxidative damage [15]. However, ROS should not be completely eliminated because a certain level of ROS is required for normal reproductive functions including sperm capacitation, acrosome reaction, and fertilization [16]. Therefore, to achieve the optimal outcome following semen cryopreservation, efforts should focus on creating a balance between ROS production and elimination. ...
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Oxidative stress during freeze–thaw procedures results in reduced semen fertility. A decrease in free radical levels can improve the post-thaw sperm quality. We examined the effects of myoinositol supplementation in freezing medium on the structure and function of cryopreserved dog sperm. Pooled ejaculates were diluted with buffer without or with myoinositol (1 or 2 mg/mL). Analysis of fresh semen revealed that the optimal concentration of myoinositol was 1 mg/mL, and this concentration was used in further experiments. Post-thaw semen quality in the myoinositol-supplemented group was superior (p < 0.05) compared with that in the control group in terms of motility (57.9 ± 0.4% vs. 47.8 ± 0.2%), sperm viability (57.5 ± 0.5% vs. 44.6 ± 0.6%), intact plasma membrane (56.6 ± 0.4% vs. 46.2 ± 0.6%), and acrosome membrane (59.3 ± 0.5% vs. 51.8 ± 0.5%). In addition, sperm in the myoinositol-supplemented group showed a significantly lower expression of pro-apoptotic (BAX) and mitochondrial reactive oxygen species (ROS) modulator (ROMO1) genes but higher expression of anti-apoptotic (BCL2), and protamine-related (PRM2 and PRM3) genes compared with that in the control group. Therefore, myoinositol supplementation before freezing can protect against oxidative stress and improve post-thaw dog sperm quality.
... MYO is a precursor of second messengers in the cellular signal transduction system and consequently participates in the regulation of calcium intracellular concentration (Marat and Haucke 2016). Therefore, it plays crucial role in insulin sensitization, metabolic alterations and particularly reproduction (Santamaria et al. 2012(Santamaria et al. , 2016. MYO concentration is significantly higher in the seminiferous tubules than in the serum (Chauvin and Griswold 2004). ...
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The aim of this study is to evaluate the beneficial effect of Myoinositol (MYO) supplement in freezing media on the post thaw sperm quality. Semen samples from 40 normozoospermic men were divided into two aliquots and frozen with simple or 2 mg/mL MYO supplemented freezing medium. Post thaw process including, computer-assissted sperm analysis was used to analyze sperm motility and morphology. Reactive oxygen species was evaluated by the fluorometry of DCFH-DA, as well as total antioxidant capacity and lipid peroxidation were measured based on colorimetric assay by ELISA reader. Eventually, DNA fragmentation was assessed using TUNEL staining. MYO significantly improved progressive motility and normal morphology in treated samples (p < 0.05). Lipid peroxidation (malondialdehyde level) can be diminished in samples were frozen by MYO supplemented freezing media (p < 0.05). While MYO did not affect the amount of ROS (p > 0.05), it was associated with high values of total antioxidant capacity (p < 0.05). DNA integrity was significantly affected by MYO, as in MYO treated samples, DNA fragmentation was decreased compared to control ones (p < 0.001). The findings support the use of 2 mg/mL myoinositol supplemented freezing media in sperm cryopreservation to increase sperm quality after freezing–thawing procedures.
... bei menopausalen Frauen mit metabolischem Syndrom haben. Wie in präliminaren Studien [12,22,40] gezeigt wurde, kommt es durch eine tägliche orale Verabreichung auch hier zu einer signifikanten Verbesserung bezüglich Glukose-und Insulinspiegeln, HOMA- IR (Homeostatic Model Assessment for Insulin Resistance), Triglyzeriden, HDL- Cholesterol und Gesamtcholesterol so- wie des Blutdrucks. Auch wenn natürlich noch keine Studien mit harten Endpunk- ten wie Herzinfarkt oder Schlaganfall vorliegen, dürfte hiermit vermutlich auch das kardiovaskuläre Risiko ver- mindert werden. ...
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Myo-Inositol ist das wichtigste Isomer der Inositol-Familie und ein intrazellulärer „second messenger“. Eine orale Verabreichung führt zu positiven Effekten auf die Insulinresistenz und den Fett- und Glukosemetabolismus sowie zu einer Senkung der Androgenspiegel. Zusätzlich zu diesen Effekten konnten auch günstige Auswirkungen im Rahmen von In-vitro-Fertilisations(IVF)-Zyklen auf Eizell- und Spermienqualität in kleineren Studien gezeigt werden.
... Increase HDL cholesterol Reduce serum triglycerides [11,[16][17][18][19] HDL high-density lipoprotein, HOMA-IR homeostatic model assessment and insulin resistance, LDL low-density lipoprotein, MI myo-inositol syndrome and in pregnant women at risk for developing or with GDM [22]. ...
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Gestational diabetes mellitus (GDM) is a common complication characterized by increased insulin resistance, and by increased risk for adverse pregnancy outcomes affecting both the mother and the fetus. International guidelines describe optimal ways to recognize it, and the recommended treatment of patients affected to reduce adverse outcomes. Improving insulin resistance could reduce incidence of GDM and its complications. Recently, a few trials have been published on the possible prevention of GDM. Inositol has been proposed as a food supplement that might reduce gestational diabetes incidence in high-risk pregnant women.
... The consequence of these adverse renal events is that any person or animal that is diabetic and/or insulin-resistant, and so is likely to be hyperglycaemic and/or to have elevated circulating insulin, will lose Ins by one or both of these routes and Men with poor sperm quality Improved sperm quality and fertility; increased sperm motilityin vitro and with vaginal pessaries N/A (158)(159)(160)(161)(162)(163)(164)(165) Women undergoing assisted reproduction to relieve fertility problems Improved quality of cultured IVF embryos; more pregnancies with fewer complications (except reference (168)) Yes (66,(166)(167)(168)(169)(170)(171) Women with PCOS and insulin resistance, including some non-obese adolescents Improved hormonal profile; more frequent ovulation and menstruation; improved fertility; improved insulin sensitivity N/A (6,64,65,(172)(173)(174)(175)(176)(177)(178)(179) Pregnant women with or at risk of GDM Decreased GDM incidence (except reference (188) Women (and a few men) with high BMI and/or at risk of MetS and/or T2D Improvement of symptoms in a significant proportion of patients Yes (189)(190)(191)(192)(193)(194)(195) Women at risk of adverse pregnancy outcomes (e.g. from diabetes) ...
Article
This review attempts to explain why consuming extra myo inositol (Ins), an essential component of membrane phospholipids, is often beneficial for patients with conditions characterised by insulin resistance, non-alcoholic fatty liver disease and endoplasmic reticulum (ER) stress. For decades we assumed that most human diets provide an adequate Ins supply, but newer evidence suggests that increasing Ins intake ameliorates several disorders, including polycystic ovary syndrome, gestational diabetes, metabolic syndrome, poor sperm development and retinopathy of prematurity. Proposed explanations often suggest functional enhancement of minor facets of Ins Biology such as insulin signalling through putative inositol-containing ‘mediators’, but offer no explanation for this selectivity. It is more likely that eating extra Ins corrects a deficiency of an abundant Ins-containing cell constituent, probably phosphatidylinositol (PtdIns). Much of a cell’s PtdIns is in ER membranes, and an increase in ER membrane synthesis, enhancing the ER’s functional capacity, is often an important part of cell responses to ER stress. This review: (a) reinterprets historical information on Ins deficiency as describing a set of events involving a failure of cells adequately to adapt to ER stress; (b) proposes that in the conditions that respond to dietary Ins there is an overstretching of Ins reserves that limits the stressed ER’s ability to make the ‘extra’ PtdIns needed for ER membrane expansion; and (c) suggests that eating Ins supplements increases the Ins supply to Ins-deficient and ER-stressed cells, allowing them to make more PtdIns and to expand the ER membrane system and sustain ER functions.
... Ins is a saturated, circular, polyhydric alcohol that serves as the backbone and precursor of inositol phosphates. It is primarily used to treat diabetes, hepatitis, polycystic ovary syndrome [11][12][13], cardiovascular disease and other diseases. It exhibits moderate anticancer activity, and it synergistically enhances the inhibitory effects of IP6 on the growth of colon and mammary cancers [14,15]. ...
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Inositol hexaphosphate (IP6) and inositol (Ins), naturally occurring carbohydrates present in most mammals and plants, inhibit the growth of numerous cancers both in vitro and in vivo. In this study, we first examined the anti-metastatic effects of IP6 and Ins using a liver metastasis model of colorectal cancer (CRC) in BALB/c mice. CT-26 cells were injected into the splenic capsule of 48 BALB/c mice. The mice were then randomly divided into four groups: IP6, Ins, IP6 + Ins and normal saline control (n = 12 per group). IP6 and/or Ins (80 mg/kg each, 0.2 mL/day) were injected into the gastrointestinal tracts of the mice on the second day after surgery. All mice were sacrificed after 20 days, and the tumor inhibition rates were determined. The results demonstrated that the tumor weights of liver metastases and the tumor inhibition rates were reduced in the experimental groups compared to the control group and that treatment with the combination of IP6 and Ins resulted in greater inhibition of tumor growth than treatment with either compound alone. These findings suggest that IP6 and Ins prevent the development and metastatic progression of colorectal cancer to the liver in mice by altering expression of the extracellular matrix proteins collagen IV, fibronectin and laminin; the adhesion factor receptor integrin-β1; the proteolytic enzyme matrix metalloproteinase 9; and the angiogenic factors vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor beta in the tumor metastasis microenvironment. In conclusion, IP6 and Ins inhibited the development and metastatic progression of colorectal cancer to the liver in BALB/c mice, and the effect of their combined application was significantly greater than the effect of either compound alone. This evidence supports further testing of the combined application of IP6 and Ins for the prevention of colorectal cancer metastasis to the liver in clinical studies.
... In women with PCOS, myo-inositol supplementation can restore ovarian activity, and improve hormonal parameters, insulin sensitivity and markers of cardiovascular risk (5) . A number of recent studies have shown that inositol consistently improves glucose metabolism, insulin resistance and dyslipidemia in post postmenopausal women with metabolic syndrome (6,7) , and in pregnant women with gestational diabetes, or at risk of developing the disease (8) . In addition, myo-inositol supplement has been shown to prevent or delay the development of certain microvascular complications of diabetes in animal models (5) and to improve glycemic control in human patients with type 2 diabetes (9) . ...
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Background: Supplementation of myo-inositol has proved effective in different pathological conditions associated with insulin-resistance, including polycystic ovary syndrome, diabetes, gestational diabetes, and metabolic syndrome. At the same time, dietary habits in developed countries tend to reduce inositol intake , due to reduced consumption of whole grain foods, legumes, and nuts, rich in phytic acid, the main source of inositol. Aim: The review aims at providing a collection of foods with high phytic acid content to be used for diets that can make available as much inositol as is obtained from nutritional supplements commonly present in the market. Methods: An extensive review concerning the phytic acid content of foods was obtained from literature; furthermore, we designed an exemplifying phytic acid rich diet in by means of a specific nutritional software. Results: Foods with high phytic acid content are: cereals (0.04-3.3% on the dry matter), legumes (0.2-2.4%), oil seeds (0.4-5.7%), and nuts (0.2-9.4%). A moderate amount of phytic acid has been found in root vegetables, tubers and fruits, while low levels are found in the leafy green vegetables. Using these data, we developed an example of weekly diet which provides a mean phytic acid content of 5 g/1660Kcal. Conclusions: This study shows that it is possible to increase phytic acid intake, and consequently inositol availability, by means of an appropriate diet as a complementary treatment to dietary supplements. In people who regularly consume fruits and vegetables, the gut microbiota efficiently degrades phytic acid to myo-inositol phosphate products, therefore this diet could be proposed to patients with increased inositol needs, such as those suffering from polycystic ovary syndrome and in insulin resistance.
Chapter
The menopause transition or perimenopause begins several years before the menopause, when the ovaries gradually begin to produce less estrogen, and it ends on the first year after menopause, when a woman has gone 12 months without having her period. Decreasing endogenous estrogens after menopause may be the critical factor in removing the relative protection against cardiovascular diseases (CVDs) that women have in their premenopausal years. CVD risk in women until menopause is considerably less than in men, after menopause the risk is overlapped. So that CVD represents the leading causes of morbidity and mortality for both men and women in developed countries. Deep metabolic changes involving women in the menopause transition are responsible for the onset of metabolic syndrome. It is characterized by hyperinsulinemia with underlying insulin resistance, and a cluster of other CVD risk factors including impaired glucose regulation, elevated levels of triglycerides, decreased levels of HDL-cholesterol, raised blood pressure, and centrally distributed obesity. First-line intervention in the management of metabolic syndrome is to reduce the modifiable, underlying risk factors (obesity, physical inactivity, and atherogenic diet) through lifestyle changes, including low-caloric diet and physical activity. A new chance in pharmacological treatment may be myoinositol, which is a natural supplement, capable of reducing insulin resistance and all other features of metabolic syndrome. Key Points The menopause transition or perimenopause begins several years before the menopause, when the ovaries gradually begin to produce less estrogen, and it ends on the first year after menopause, when a woman has gone 12 months without having her period. Decreasing endogenous estrogens after menopause may be the critical factor in removing the relative protection against cardiovascular diseases (CVDs) that women have in their premenopausal years. CVD risk in women until menopause is considerably less than in men, after menopause the risk is overlapped. So that CVD represents the leading causes of morbidity and mortality for both men and women in developed countries. Deep metabolic changes involving women in the menopause transition are responsible for the onset of metabolic syndrome. It is characterized by hyperinsulinemia with underlying insulin resistance, and a cluster of other CVD risk factors including impaired glucose regulation, elevated levels of triglycerides, decreased levels of HDL-cholesterol, raised blood pressure, and centrally distributed obesity. First-line intervention in the management of metabolic syndrome is to reduce the modifiable, underlying risk factors (obesity, physical inactivity, and atherogenic diet) through lifestyle changes, including low-caloric diet and physical activity. A new chance in pharmacological treatment may be myoinositol, which is a natural supplement, capable of reducing insulin resistance and all other features of metabolic syndrome.
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Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-cut consensus about the best strategy for their treatment. We hypothesized that a combination, including boswellic acid, betaine, and myoinositol, would be beneficial in breast disorders by exerting a pleiotropic effect on multiple pathways. Indeed, myoinositol has already been proven to modulate some factors involved in the genesis of breast diseases, such as fibrosis and metabolic and endocrine cues. In our study, 76 women were randomly assigned to either the experimental or the placebo arm. After six months of treatment, statistically significant differences between the two groups were recorded for pain relief (56% vs 17%) and breast density reduction (60% vs 9%). Furthermore, benign breast mass dimension showed a reduction in the experimental group (40% vs 16%). The combination of boswellic acid, betaine, and myoinositol has been demonstrated to be effective in the treatment of breast pain and radiologically and histologically confirmed benign breast mass and in the reduction of breast density, one of the pivotal risk factors for the development of breast cancer, without any side effects.
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Background: Myoinositol and D-chiroinositol improve insulin resistance in women with obesity and gestational diabetes and in postmenopausal women with metabolic syndrome. We previously reported that offspring born to hypertensive dams lacking endothelial nitric oxide synthase and fed a high-fat diet develop metabolic-like syndrome phenotype. Objective: The objective of the study was to investigate the effect of a mixture of myoinositol/D-chiroinositol supplementation during pregnancy on the maternal metabolic profile in pregnancies complicated by the metabolic-like syndrome and obesity using a pregnant mouse model. Study design: Female heterozygous endothelial nitric oxide synthase(-/+) mice with moderate hypertension were placed on a high-fat diet for 4 weeks to induce a metabolic-like syndrome phenotype. Similarly, wild-type C57BL/6 mice were placed on a high-fat diet for 4 weeks to induce a murine obesity model. Mice were then bred with wild-type males. On gestational day 1, dams were randomly allocated to receive either a mixture of myoinositol/D-chiroinositol in water (7.2/0.18 mg/mL, respectively) or water as control (placebo). At term (gestational day 18), maternal weights, systolic blood pressure, and a glucose tolerance test were obtained. Dams were then killed; pups and placentas were weighed and maternal blood collected. Serum levels of metabolic biomarkers relevant to diabetes and obesity (ghrelin, gastric inhibitory peptide, glucagon-like peptide 1, glucagon, insulin, leptin, resistin) were measured by a multiplex enzyme-linked immunosorbent assay. Analysis was done comparing metabolic-like syndrome-myoinositol/D-chiroinositol-treated vs metabolic-like syndrome-nontreated mice and obese-myoinositol/D-chiroinositol-treated vs obese nontreated mice. Results: Mean systolic blood pressure was lower in metabolic-like syndrome pregnant mice treated with myoinositol/D-chiroinositol compared with placebo (P = .04), whereas there was no difference in systolic blood pressure between treated and placebo-treated obese pregnant mice. Pregnant metabolic-like syndrome mice treated with myoinositol/D-chiroinositol showed lower glucose values during the glucose tolerance test and in the area under the curve (myoinositol/D-chiroinositol: 17512.5 ± 3984.4 vs placebo: 29687.14 ± 8258.7; P = .003), but no differences were seen in the obese pregnant mice. Leptin serum levels were lower in the metabolic-like syndrome-myoinositol/D-chiroinositol-treated mice compared with the placebo group (myoinositol/D-chiroinositol: 16985 ± 976.4 pg/dL vs placebo: 24181.9 ± 3128.2 pg/dL, P = .045). No other differences were seen in any of the remaining serum metabolic biomarkers studied in metabolic-like syndrome and in obese pregnant mice. Maternal weight gain was not different in the pregnant metabolic-like syndrome dams, whereas it was lower in the obese myoinositol/D-chiroinositol-treated dams compared with the placebo group (myoinositol/D-chiroinositol: 10.9 ± 0.5 g vs 12.6 ± 0.6 g, P = .04). Fetal and placental weights did not differ between myoinositol/D-chiroinositol-treated and nontreated pregnant dams with metabolic-like syndrome and obesity. Conclusion: Combined inositol treatment during pregnancy improves blood pressure, glucose levels at the glucose tolerance test, and leptin levels in pregnant dams with metabolic-like syndrome phenotype but not in obese pregnant dams. In addition, inositol treatment was associated with lower gestational weight gain in the obese but not in the metabolic-like syndrome pregnant dams.
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Objetivo: analizar los suplementos nutricionales con ácidos grasos de cadena larga, micronutrientes y antioxidantes en la población adulta, como posibles modificadores del riesgo cardiovascular en pacientes con diagnóstico de síndrome metabólico, o alguno de sus componentes. Métodos: Se realizó una revisión de la literatura en las bases de datos Medline y Embase, utilizando los términos “Metabolic Syndrome” AND “Dietary supplements” y ‘Metabolic Syndrome’/exp AND ‘Dietary supplement’/exp, respectivamente, sobre el papel de los suplementos nutricionales en la modificación del riesgo cardiovascular en adultos con síndrome metabólico o alguno de sus componentes. Resultados: De 475 artículos depurados, se seleccionaron 37 que estudiaran el posible beneficio de los suplementos nutricionales en el síndrome metabólico. Algunos estudios muestran un potencial de ácidos grasos de cadena larga y antioxidantes (vitamina D, vitamina E) para reducir el riesgo cardiovascular de pacientes con síndrome metabólico, evidenciado en la reducción de parámetros como colesterol total, glucemia, índice de masa corporal y perímetro abdominal. Conclusión: El uso de suplementos nutricionales con ácidos grasos de cadena larga y antioxidante podría tener efectos benéficos en la disminución de riesgo cardiovascular en pacientes con diagnóstico de síndrome metabólico o alguno de sus componentes. El uso de suplementos con otros componentes debe estudiarse a mayor profundidad para efectuar recomendaciones.
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Colorectal cancer (CRC) is one of the most common human malignancies and encompasses cancers of the colon and rectum. Although the gold-standard colonoscopy screening method is effective in detecting CRC, this method is invasive and can result in severe complications for patients. The purpose of this study was to determine differences in metabolites between CRC and matched adjacent non-tumor tissues from CRC patients, to identify potential biomarkers that may be informative and developed screening methods. Metabolomic analysis was performed on clinically localized CRC tissue and matched adjacent non-tumor tissue from twenty CRC patients. Unsupervised analysis, supervised analysis, univariate analysis, and pathway analysis were used to identify potential metabolic biomarkers of CRC. The level of twenty-five metabolites in CRC tissues were significantly altered compared to the matched adjacent non-tumor tissues. Four metabolites (lactic acid, alanine, phosphate, and aspartic acid) demonstrated good area under the curve (AUC) of Receiver- Operator Characteristic (ROC) with acceptable sensitivities and specificities, indicating their potential as important biomarkers for CRC. Alterations of amino acid metabolism and enhanced glycolysis may be major factors in the development and progression of colorectal cancer. Lactic acid, alanine, phosphate, and aspartic acid could be effective diagnostic indicators for CRC.
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Background & aims: The effect of inositol on glucose homeostasis is not well characterized. The aim of the present meta-analysis is to synthesize the effects of inositol on glucose homeostasis in different clinical conditions. Methods: We performed a systematic review (CRD42017057927) following PRISMA guidelines. Web of Science and Medline were searched for randomized controlled trials (RCTs) that addressed supplementation with compounds of the inositol family in humans and assessed their effects on glucose homeostasis. Results: We screened 476 abstracts and included 20 RCTs with a total of 1239 subjects. Meta-analysis showed in the treatment arm a reduction in fasting plasma glucose (Mean difference (MD) -0.44 mmol/l, 95% CI -0.65, -0.23), 2 h PG after 75 g OGTT (MD -0.69 mmol/l, 95% CI -1.14, -0.23), abnormal glucose tolerance (Relative risk (RR) 0.28, 95% CI 0.12, 0.66), fasting insulin (MD -38.49 pmol/l, 95% CI -52.63, -24.36), and HOMA-IR (MD -1.96 mmol × mUI/l, 95% CI -2.62, -1.30). No differences were observed in BMI, HbA1c and % of patients requiring insulin treatment. Sensitivity analysis did not change treatment estimates. Mention to adverse events was only present in 13 articles with no sign of seriousness. Conclusions: Inositol supplementation decreases blood glucose through an improvement in insulin sensitivity that is independent of weight. Assessment of adverse effects is scarce among published trials and should be fully addressed before considering inositol as a therapeutic agent for glucose-related outcomes. The characterization of the subjects achieving benefit from the intervention and the formulations to be used should also be known.
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Background: Inositol is a sugar-alcohol and recognized as a key component of cell membrane phospholipids. It has crucial role in the cell signaling pathways and contribute to improving glycemic responses. Although some earlier studies have revealed the effect of inositol mediating glucose uptake by improving insulin sensitivity, the benefit of inositol supplementation in patients with overweight and obesity is not completely understood. This study aimed to assess the impact of inositol supplementation on body mass index (BMI) through a systematic review and meta-analysis of controlled clinical trials. Methods: A systematic search was performed to August 2021 in the following databases: PubMed-Medline, Embase, Web of Science and Scopus. Fifteen controlled clinical trials investigating the effect of inositol on adult's BMI were finally included in the study. A random-effects model was employed to estimate the effect size. Subgroup analysis was performed by dose, duration, age, type of inositol. Meta-regression was used to investigate presence of any linear relationship. Begg's and Egger's tests were carried out to detect small study effect. Results: The results of pooled analysis showed that inositol supplementation significantly decreased BMI scores (WMD = -0.41 kg/m2; 95% CI: -0.78, -0.04; p = 0.028). Subgroup analysis was performed to identify the source of heterogeneity among studies (I 2 = 73.9%, p < 0.001), demonstrating supplementation duration, baseline BMI, mean age of participants, type of inositol and dosage were potential sources of heterogeneity. The effect of intervention was more clinically significant in participants with polycystic ovary syndrome (PCOS) and overweight/obesity. Inositol in the form of myo-inositol (MI) had stronger effect on BMI reduction. Conclusion: The meta-analysis suggests that oral inositol supplementation has positive effect on BMI reduction. Inositol supplementation could be considered as an adjunct treatment to improve body mass index.
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To determine whether myo-inositol supplement will increase the action of endogenous insulin, which is mainly measured by markers of insulin resistance such as homeostasis model assessment of insulin resistance. PubMed, Cochrane Library, Embase, and web of science were comprehensively searched using “gestational diabetes mellitus” and “myo-inositol” to identify relevant studies. Both subject headings and free texts were adopted. The methodological quality of the included studies were assessed and pooled analyzed by the methods recommended by the Cochrane collaboration. A total of 5 trials containing 513 participants were included. There was a significant reduction in aspects of gestational diabetes incidence (risk ratio [RR], 0.29; 95% confidence interval (95% CI), 0.19–0.44), birth weight (mean difference [MD], −116.98; 95% CI, −208.87 to −25.09), fasting glucose oral glucose tolerance test (OGTT) (MD, −0.36; 95% CI, −0.51 to −0.21), 1-h glucose OGTT (MD, −0.63; 95% CI, −1.01 to −0.26), 2-h glucose OGTT (MD, −0.45; 95% CI, −0.75 to −0.16), and related complications (odds ratio [OR], 0.28; 95% CI 0.14–0.58). On the basis of current evidence, myo-inositol supplementation reduces the development of gestational diabetes mellitus (GDM), although this conclusion requires further evaluation in large-scale, multicenter, blinded randomized controlled trials.
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Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a D-chiro-inositol-containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of D-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of D-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation. In the 22 women given D-chiro-inositol, the mean (+/-SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417+/-11,572 to 5158+/-6714 microU per milliliter per minute (81+/-69 to 31+/-40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1+/-0.8 to 0.5+/-0.5 ng per deciliter (38+/-7 to 17+/-3 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women's diastolic and systolic blood pressure decreased by 4 mm Hg (P<0.001 and P=0.05, respectively, for the comparisons with the changes in the placebo group), and their plasma triglyceride concentrations decreased from 184+/-88 to 110+/-61 mg per deciliter (2.1+/-0.2 to 1.2+/-0.1 mmol per liter) (P=0.002 for the comparison with the change in the placebo group). None of these variables changed appreciably in the placebo group. Nineteen of the 22 women who received D-chiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P<0.001). D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.
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Few studies have evaluated the associations between the metabolic syndrome (by any definition) and mortality. This study examined the age- and sex-specific prevalence of the metabolic syndrome and its association with all-cause and cardiovascular mortality in nondiabetic European men and women. The study was based on 11 prospective European cohort studies comprising 6156 men and 5356 women without diabetes and aged from 30 to 89 years, and had a median follow-up of 8.8 years. A modification of the World Health Organization definition of the metabolic syndrome was used. The subjects were considered to have the metabolic syndrome if they had hyperinsulinemia and 2 or more of the following: obesity, hypertension, dyslipidemia, or impaired glucose regulation; however, other definitions were also studied. Hazard ratios for all-cause and cardiovascular mortality were estimated with Cox models in each cohort. Meta-analyses were performed to assess the overall association of the metabolic syndrome with mortality risk. The age-standardized prevalence of the metabolic syndrome was slightly higher in men (15.7%) than in women (14.2%). Of the 1119 deaths recorded during follow-up, 432 were caused by cardiovascular disease. The overall hazard ratios for all-cause and cardiovascular mortality in persons with the metabolic syndrome compared with persons without it were 1.44 (95% confidence interval [CI], 1.17-1.84) and 2.26 (95% CI, 1.61-3.17) in men and 1.38 (95% CI, 1.02-1.87) and 2.78 (95% CI, 1.57-4.94) in women after adjustment for age, blood cholesterol levels, and smoking. The overall prevalence of the metabolic syndrome in nondiabetic adult Europeans is 15%. Nondiabetic persons with the metabolic syndrome have an increased risk of death from all causes as well as cardiovascular disease.
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The aim of this study was to assess the effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome. This was a randomized, double-blind, controlled clinical trial. One hundred subjects (54 men and 46 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III, were followed for 12 months after random assignment to rosiglitazone (4 mg/day) or placebo. Primary end points were flow-mediated dilation and high-sensitivity C-reactive protein (hs-CRP) levels; secondary end points were lipid and glucose parameters, homeostasis model assessment (HOMA) of insulin sensitivity, endothelial function score, and circulating levels of interleukin (IL)-6, IL-18, and adiponectin. Compared with 60 control subjects matched for age and sex, patients with the metabolic syndrome had decreased endothelial function, raised concentrations of inflammatory markers, and reduced insulin sensitivity. After 12 months, subjects with the metabolic syndrome receiving rosiglitazone showed improved flow-mediated vasodilation (4.2%, P < 0.001) and reduced hs-CRP levels (-0.7 mg/dl, P = 0.04), compared with the placebo group. Moreover, HOMA (-0.8, P = 0.01) and serum concentrations of IL-6 (-0.5 pg/ml, P = 0.045) and IL-18 (-31 pg/ml, P = 0.036) were significantly reduced in subjects receiving rosiglitazone, whereas adiponectin levels showed a significant increment (2.3 microg/ml, P = 0.02). High-density lipoprotein-cholesterol levels increased more and triglyceride levels decreased more in the rosiglitazone group compared with the placebo group. At 1 year of follow-up, 30 subjects receiving rosiglitazone still had features of the metabolic syndrome, compared with 45 subjects receiving placebo (P < 0.001). Rosiglitazone might be effective in reducing the prevalence of the metabolic syndrome.
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To evaluate the effects the administration of myo-inositol (MYO) on hormonal parameters in a group of PCOS patients. Controlled clinical study. PCOS patients in a clinical research environment. 20 overweight PCOS patients were enrolled after informed consent. All patients underwent hormonal evaluations and an oral glucose tollerance test (OGTT) before and after 12 weeks of therapy (Group A (n = 10): myo-inositol 2 gr. plus folic acid 200 mug every day; Group B (n = 10): folic acid 200 mug every day). Ultrasound examinations and Ferriman-Gallwey score were also performed. Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide concentrations, BMI, HOMA index and glucose-to-insulin ratio. After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the patients treated with folic acid. Myo-inositol administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.
Conference Paper
Despite significant advances in past years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of the actions of insulin. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second-messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosylphosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.
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LR: 20061115; JID: 7501160; 0 (Antilipemic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 57-88-5 (Cholesterol); CIN: JAMA. 2001 Nov 21;286(19):2401; author reply 2401-2. PMID: 11712930; CIN: JAMA. 2001 Nov 21;286(19):2400-1; author reply 2401-2. PMID: 11712929; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712928; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712927; CIN: JAMA. 2001 May 16;285(19):2508-9. PMID: 11368705; CIN: JAMA. 2003 Apr 16;289(15):1928; author reply 1929. PMID: 12697793; CIN: JAMA. 2001 Aug 1;286(5):533-5. PMID: 11476650; CIN: JAMA. 2001 Nov 21;286(19):2401-2. PMID: 11712931; ppublish
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The aim of this study was to evaluate whether myo-inositol, an insulin-sensitizing substance, may improve some features of metabolic syndrome in postmenopausal women. Eighty postmenopausal women affected by the metabolic syndrome were enrolled prospectively in the study and treated with diet plus supplementation of myo-inositol (2 g BID plus diet: intervention group) or with diet plus placebo (control group) for 6 months. They were evaluated at baseline and after 6 months for insulin resistance (homeostasis model assessment ratio [HOMA] insulin resistance), lipid profile, and blood pressure. Myo-inositol plus diet improved systolic and diastolic blood pressure, HOMA index, cholesterol, and triglyceride serum levels with highly significant differences, compared with the groups treated only with diet and placebo. In the group treated with myo-inositol, a decrease in diastolic blood pressure (-11%), HOMA index (-75%), and serum triglycerides (-20%) and an improvement in high-density lipoprotein cholesterol (22%) were shown. Supplementation with myo-inositol may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women.
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Obese women with polycystic ovary syndrome (PCOS) manifest impaired insulin-stimulated release of a d-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) insulin mediator during oral glucose tolerance testing (OGTT), which appears to be restored by the administration of metformin. This suggests that either obesity or PCOS is associated with a defect in the coupling of the stimulation of the insulin receptor by insulin to the release of the DCI-IPG mediator. The objective of this study was to compare the release of bioactive DCI-IPG between normal nonobese women and obese PCOS women during stimulation with two different concentrations of insulin when glucose levels are clamped. We performed a cross-sectional case-control study at the clinical research center of an academic medical center. A two-step euglycemic-hyperinsulinemic clamp was carried out in 8 nonobese normal and 8 obese PCOS women, during which DCI-IPG bioactivity was monitored. At baseline, PCOS women were significantly more obese, hyperinsulinemic, and insulin resistant than the controls. During the clamp studies, DCI-IPG bioactivity increased significantly over the first 45 min of the low-insulin step of the clamp in normal nonobese women (P = 0.046) and then decreased to baseline levels; DCI-IPG increased again after initiation of the high-insulin step (P = 0.029). Despite higher insulin levels during the clamp in PCOS women, DCI-IPG bioactivity remained flat throughout both insulin steps and was thus significantly lower than in controls during the initial periods of both steps. The coupling between insulin action and the release of the DCI-IPG mediator is selectively impaired in obese PCOS women, which may contribute to the insulin resistance in these women.
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Metformin has recently been considered as a possible pharmacological complement to lifestyle measures for preventing type 2 diabetes in high-risk subjects. However, little is known of its effects on metabolic and cardiovascular risk factors in non-diabetic subjects. The BIGPRO1 trial was a 1-year multicentre, randomized, double-blind, controlled clinical trial of metformin versus placebo, carried out in the early 1990s, in 457 upper-body obese non-diabetic subjects with no cardiovascular diseases or contraindications to metformin. We compared the changes (1-year minus baseline) in cardiometabolic risk factors between treatment groups in two subsets of trial subjects: those with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (n=101); and those who fulfilled the inclusion criteria of the Diabetes Prevention Program (DPP) (n=51). Comparisons were adjusted for age and gender. In the IFG/IGT subset, significant differences in 1-year changes were observed for systolic blood pressure, which decreased markedly more in the metformin group than in the placebo group (P<0.003), and for fasting plasma glucose, and total and LDL cholesterol, which decreased slightly in the metformin group, but increased in the placebo group (P<0.04). Similar results were observed in the subset with DPP criteria. Also, there were no significant differences in 1-year changes for weight, waist-to-hip ratio, 2-h post-load blood glucose, fasting and 2-h post-load insulin, HDL cholesterol, triglycerides and fibrinolytic markers between the two treatment groups. In subjects at high risk of developing diabetes, the use of metformin showed beneficial and no untoward effects on cardiometabolic risk factors.
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Treatment with thiazolidinediones (TZDs) produces weight gain. To test whether a portion control diet could prevent weight gain during treatment with pioglitazone in patients with type 2 diabetes mellitus (T2DM). This 16-week randomized, open-label, parallel arm study compared three groups: (i) pioglitazone plus the American Diabetes Association diet (Pio + ADA); (ii) pioglitazone plus a portion control weight loss diet (Pio + PC); (iii) metformin plus the American Diabetes Association diet (Met + ADA). All participants received the same advice about calorie reduction, lifestyle change and exercise. Fifty-one men and women with T2DM, naive to TZDs, were randomized to a 16-week study. Pioglitazone (Pio) was titrated to a dose of 45 mg/day and metformin (Met) to a dose of 2 g/day. Fasting blood was collected for lipids, insulin and glycosylated haemoglobin A1c (HbA1c) at baseline and 16 weeks. Forty-eight of fifty-one randomized subjects completed the study. Patients treated with Pio + ADA gained 2.15 +/- 1.09 kg (mean +/- SD) compared with a weight loss of 2.59 +/- 1.25 kg (p < 0.05) in the Pio + PC group, and a weight loss of 3.21 +/- 0.7 kg (p < 0.05) in the Met + ADA group. Waist circumference and visceral adipose tissue decreased significantly more in the Pio + PC group than in the Pio + ADA group. High-density lipoprotein cholesterol levels were significantly increased in the Pio + PC group compared with the Met + ADA group. Pioglitazone reduced insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) more than metformin. No significant differences between groups were seen for glucose, insulin, HbA1c or low-density lipoprotein cholesterol levels. Pio + PC, prevented weight gain, reduced waist circumference and visceral fat compared with Pio + ADA diet.
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The relation of fasting and 2-hour serum insulin to the risk for fatal cardiovascular disease was examined in men and women without diabetes. Between 1984 and 1987, 80% of all surviving local members of the Rancho Bernardo Study cohort had measures of insulin and glucose levels obtained before and after a 75-g oral glucose tolerance test. Over the next 5 years, there were 24 cardiovascular disease deaths among 538 men and 21 cardiovascular disease deaths among 705 women. Fasting insulin was unrelated to cardiovascular disease death in men or women; 2-hour insulin was significantly lower in men (but not in women) who died from cardiovascular disease. In men, a 1-standard deviation increase in 2-hour insulin was associated with a 36% reduction in cardiovascular disease mortality (p = 0.01). The significant inverse association of 2-hour insulin with cardiovascular disease death persisted in multiply adjusted models (relative hazard = 0.68; 95% confidence interval 0.47-0.96). Patterns were similar when the analysis was repeated, including men with non-insulin-dependent diabetes mellitus or heart disease at baseline. These findings were not explained by antihypertensive drug use or cigarette smoking. Hyperinsulinemia was not a risk factor for cardiovascular disease in these older men or women. The role of insulin as a cardiovascular disease risk factor requires further investigation.
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Both insulin resistance and decreased insulin secretion have been shown to predict the development of NIDDM. However, methods to assess insulin sensitivity and secretion are complicated and expensive to apply in epidemiological studies. The homeostasis model assessment (HOMA) has been suggested as a method to assess insulin resistance and secretion from the fasting glucose and insulin concentrations. However, this method has not been extensively evaluated, particularly in different ethnic groups. We applied the HOMA model to cross-sectional analyses of the San Antonio Heart Study (n = 2,465). HOMA insulin resistance (IR) was very strongly correlated with fasting insulin (r = 0.98) and HOMA beta-cell function (beta-cell) was moderately correlated with the 30-min increment in insulin concentration over the 30-min increment in glucose concentration (delta I30/delta G30) in an oral glucose tolerance test (OGTT) (r = 0.44). NIDDM was characterized by both high HOMA IR and low HOMA beta-cell function. In Mexican-Americans, HOMA IR in NIDDM subjects was 9.5 compared with 2.7 in normal glucose tolerance (NGT) subjects. In contrast, HOMA beta-cell function showed only small differences in Mexican-Americans (176 NIDDM; 257 NGT). However, the delta I30/delta G30 (pmol/mmol) showed much larger differences (75 NIDDM; 268 NGT). When modeled separately, impaired glucose tolerance (IGT) was characterized by high HOMA IR and high HOMA beta-cell function. However, when analyzed in the same regression model, high HOMA IR and low HOMA beta-cell function characterized subjects with IGT. These results were similar in both ethnic groups. Mexican-Americans had increased insulin resistance (as judged by both HOMA IR and fasting insulin) and insulin secretion (by HOMA beta-cell and delta I30/delta G30) relative to non-Hispanic whites. We conclude that HOMA provides a useful model to assess insulin resistance and beta-cell function in epidemiological studies in which only fasting samples are available and that, further, it is critical to take into account the degree of insulin resistance in assessing insulin secretion by the HOMA model.
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The objective of this study was to examine the association of Joint National Committee (JNC-V) blood pressure and National Cholesterol Education Program (NCEP) cholesterol categories with coronary heart disease (CHD) risk, to incorporate them into coronary prediction algorithms, and to compare the discrimination properties of this approach with other noncategorical prediction functions. This work was designed as a prospective, single-center study in the setting of a community-based cohort. The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up. During the 12 years of follow-up, a total of 383 men and 227 women developed CHD, which was significantly associated with categories of blood pressure, total cholesterol, LDL cholesterol, and HDL cholesterol (all P<.001). Sex-specific prediction equations were formulated to predict CHD risk according to age, diabetes, smoking, JNC-V blood pressure categories, and NCEP total cholesterol and LDL cholesterol categories. The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used. After adjustment for other factors, approximately 28% of CHD events in men and 29% in women were attributable to blood pressure levels that exceeded high normal (> or =130/85). The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol (> or =200 mg/dL) was 27% in men and 34% in women. Recommended guidelines of blood pressure, total cholesterol, and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample. A simple coronary disease prediction algorithm was developed using categorical variables, which allows physicians to predict multivariate CHD risk in patients without overt CHD.
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Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and "diabetic cardiomyopathy." The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.
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It has been recognized over the past years that women form a distinct subpopulation within patients with coronary heart disease. This phenomenon should be acknowledged in the management and in the assessment of coronary heart disease. Over the past years remarkable progress has been made concerning our knowledge of cardiovascular risk factors related to gender. For instance, diabetes, high density lipoproteins and triglycerides levels have been found to have a greater impact on coronary heart disease risk in women compared to men. On the other hand, evidence showing that lipoprotein (a) is a cardiovascular risk factor seems to be stronger in men than in women. For optimal treatment and prevention of coronary heart disease it is necessary to acknowledge that it is not self-evident that women and men show similar responses to risk factors or to treatment. This review article addresses the role of cardiovascular risk factors focusing on the differential impact they might have on men and women.
Article
Epidemiological studies have found no relationship between total cholesterol and stroke risk, but little attention has been paid to high-density lipoprotein-cholesterol (HDL-C). We performed a systematic PubMed literature search for epidemiological studies that examined the association between HDL-C level and stroke or carotid intima-media thickness (IMT). We identified 18 studies on the relationship between HDL-C and stroke risk and 37 on HDL-C and carotid IMT. Eight of ten prospective cohort studies (n=238,739) and three of eight case-control studies (n=3604 cases, 8220 controls) supported an association between elevated HDL-C level and decreased risk of stroke. Prospective cohort studies reporting on relative risk per unit increase in HDL-C showed an 11-15% decreased stroke risk per 10-mg/dl increase in HDL-C. Of 37 studies on carotid IMT, 31 reported cross-sectional, one longitudinal, and five both cross-sectional and longitudinal associations between HDL-C level and carotid IMT. Of 36 cross-sectional studies (n=51,288), 20 showed an inverse association between HDL-C level and carotid IMT. Of six longitudinal studies (n=20,065), three showed no association, one showed a weak association in a subgroup of white women and two showed a significant inverse relationship between HDL-C level and carotid IMT. Pooled estimates could not be calculated because of the variation in study designs and analysis. The weight of evidence in the literature supports an inverse association between HDL-C level and stroke or carotid atherosclerosis, but more data are needed to firmly establish this protective effect.
Article
The molecular events involved in coupling the insulin receptor to the regulation of cellular metabolism remain unknown. Recent studies indicate that some of insulin's actions may be mediated by a novel oligosaccharide. This molecule is generated in cells by the insulin-dependent hydrolysis of a novel membrane glycolipid, termed a glycosyl-phosphatidylinositol. This glycolipid is structurally similar to a newly described protein anchor. The evaluation of the hormonal regulation of this new glycolipid may yield information on a new mechanism of signal transduction.
The homeostasis model in the San Antonio Heart study
  • Sm Haffner
  • H Miettinem
  • Mp Stern
Prevalance of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women
  • G Hu
  • Q Qiao
  • J Tuomilehto
Effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome
  • K Esposito
  • M Ciotola
  • D Carleo