Потенциал транс-коричной кислоты для профилактики метаболического синдрома

An Evidence-Based Review of Exercise and Metabolic Syndrome

Case Presentation: E.C. is a 53-year-old postmenopausal female, referred for treatment of hypertension, with a family history of type 2 diabetes, hypertension, and coronary heart disease (CHD). Until learning that her blood pressure was “too high” during a routine physical examination, she felt well, and her postmenopausal symptoms had responded to hormone replacement therapy. She was not overweight (her body mass index [BMI] was 23.7 kg/m2), and the only abnormality on physical examination was a blood pressure of 145/95 RAR. Laboratory results revealed a normal blood count and urinalysis, with the following fasting plasma concentrations of relevant metabolic variables (in mg/dL): glucose 102, triglycerides (TG) 238, low-density lipoprotein cholesterol (LDL-C) 147, and high-density lipoprotein cholesterol (HDL-C) 52. E.C. is hypertensive and hypertriglyceridemic and at increased risk for CHD. Less obvious is that these metabolic abnormalities are highly likely to be the manifestations of a more fundamental defect—resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia, changes that greatly increase CHD risk.1,2⇓ The importance of insulin resistance as a CHD risk factor was first explicated in 1998, and the cluster of abnormalities likely to appear as manifestations of the defect in insulin action designated as syndrome X.1 Support for this notion has grown almost as fast as the names used to describe the phenomenon. The Adult Treatment Panel III (ATP III) has recently3 recognized the importance as CHD risk factors of a “constellation of lipid and nonlipid risk factors of metabolic origin,” designated this cluster of abnormalities as “the metabolic syndrome,” and indicated that “this syndrome is closely linked to insulin resistance.” Table 1 lists the criteria the ATP III stipulated be used to diagnose the metabolic syndrome, and a recent report4 has applied these criteria to the database of the Third National Health and Nutrition …

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

This study investigates the therapeutic effects of cinnamic acid (CA) on diabetic nephropathy (DN) and elucidates its mechanisms involving Nrf2 activation and NF-κB suppression. Type 2 diabetes mellitus (T2DM) was induced in Wistar rats through a high-fat diet followed by streptozotocin administration. Rats were assigned to each of the six groups: control, control + CA (40 mg kg-1), T2DM, T2DM + CA (20 mg kg-1), T2DM + CA (40 mg kg-1), and T2DM + CA (40 mg kg-1) with brusatol (an Nrf2 inhibitor; 2 mg per kg per twice per week). Over 8 weeks, we assessed metabolic parameters, serum lipid profiles, renal function, oxidative stress markers, and kidney histology. CA did not significantly affect the body weight or insulin levels in T2DM rats. Nevertheless, it notably reduced the fasting glucose levels and improved the renal function, as evidenced by reductions in serum creatinine and urinary albumin levels. CA treatment significantly decreased the expression of renal inflammatory markers TNF-α, IL-6, and nuclear NF-κB in the kidneys of T2DM rats. Furthermore, CA reduced oxidative stress, as demonstrated by the lower MDA levels and elevated antioxidant marker levels (GSH, SOD, and HO-1) in the kidneys of both control and T2DM rats. CA treatment increased the nuclear Nrf2 levels and decreased the transcription and cytoplasmic Keap1 levels, with the levels of these effects being dose-dependent between 20 and 40 mg kg-1. The addition of brusatol reversed the beneficial effects of CA, underscoring the pivotal role of Nrf2 in mediating CA's protective actions. In conclusion, CA ameliorates renal dysfunction and mitigates oxidative stress and inflammation in T2DM rats via a hypoglycemic effect and activation of the Nrf2 pathway.

See article in J. Gastroenterol. Hepatol. 2003; 18: 588–94. The concept of syndrome X for the clustering of cardiovascular risk factors including hypertension, obesity, high serum triglyceride and low high-density lipoprotein (HDL) was introduced in 1988.1 Since then, several other synonyms including the insulin resistance syndrome, dysmetabolic syndrome, cardiovascular metabolic syndrome, and the deadly quartet, have been coined.2 In 1998, the World Health Organization proposed a unifying definition, using the term ‘metabolic syndrome’.3 This syndrome consists of two of the following conditions: (i) hypertension, (ii) central obesity, (iii) hypertriglyceridemia or low HDL cholesterol, and (iv) microalbuminuria. It occurs in the setting of type 2 diabetes, impaired glucose regulation or insulin resistance. Impaired glucose regulation is a metabolic state intermediate between normal glucose homeostasis and diabetes, and is diagnosed by either impaired fasting glucose (fasting glucose ≥6.1 and <7.0) or impaired glucose tolerance (postprandial hyperglycemia assessed by the oral glucose tolerance test). In those with normal glucose tolerance, subclinical insulin resistance may be identified by the hyperinsulinemic euglycemic clamp study and is defined as the lowest quartile of insulin sensitivity for the background population under investigation. However, there is not yet universal agreement on this definition of the metabolic syndrome and alternative definitions have been proposed.4,5 It is now clear that non-alcoholic fatty liver disease (NAFLD) should be included as one of the associated abnormalities of the metabolic syndrome, as confirmed by Angelico et al. in issue 5 of the Journal.6 The authors used the readily available technique of hepatic ultrasonography to identify subjects attending liver and metabolic outpatient clinics who had increased hepatic echogenicity as a sign of hepatic steatosis. Those drinking more than three standard drinks (>30 g ethanol per day) were excluded. They showed that features of the metabolic syndrome including obesity (body mass index ≥30), hypertension, impaired glucose tolerance or type 2 diabetes and hypertriglyceridemia were com-mon findings in subjects with increased hepatic echogenicity, particularly those with a raised alanine aminotransferase (ALT) level. Of particular interest, the authors were able to demonstrate that an increase in the severity of hepatic echogenicity was associated with the presence of a greater number of features of the metabolic syndrome. It is now generally accepted from multiple studies that insulin resistance is the common link between NAFLD and other features of the metabolic syndrome. In particular, recent studies have demonstrated a high prevalence of insulin resistance and the metabolic syndrome in patients with biopsy-proven non-alcoholic steatohepatitis (NASH).7 Insulin resistance appears to be the result of a complex interplay of genetic and environmental factors, the latter include overnutrition and physical inactivity, with resultant central (visceral) obesity.8 Normally, insulin inhibits the hormone-sensitive lipase, which is an important control point for the release of free fatty acids from adipocytes.9 During states of insulin resistance, increased lipolysis results in enhanced release and transport of free fatty acids from adipose tissue to the liver, where fatty acids provide a substrate for triglyceride synthesis and hepatic steatosis. Hyperinsulinemia, which is the natural corollary of insulin resistance, may directly inhibit mitochondrial β-oxidation of free fatty acids in the liver, leading to further hepatic steatosis.10 A ‘two hit’ hypothesis has been proposed to describe a perpetuating injury mechanism such as oxidative stress/lipid peroxidation, cytokine induction and mitochondrial dysfunction, which converts bland steatosis (‘first hit’) into fibrosing steatohepatitis.11 Diabetes and insulin resistance are risk factors for hepatic fibrosis,12–14 in addition to being pro-steatotic. This suggests that, as well as their undoubted importance to the pathogenesis of hepatic steatosis, they may also be involved in the second hit process. This may be mediated via pro-inflammatory cytokines such as tumor necrosis factor (TNF), which can be released by adipose tissue and is increased in insulin-resistant subjects.15,16 Increased TNF expression also occurs in NASH.17 In the diagnosis of NAFLD, Angelico et al. used ultrasonographic findings in the absence of excessive alcohol intake and viral markers. This has several limitations. First, increased hepatic echogenicity is not specific for steatosis; hepatic fibrosis can give similar sonographic changes, as emphasized by the term ‘fatty-fibrotic pattern’.18 Second, it is now quite clear that degree of steatosis does not correlate with the extent of fibrosis in NAFLD.12 Indeed, steatosis can disappear as NASH progresses to cirrhosis.19 Hence, the finding of mild hepatic steatosis on ultrasonography does not provide any reliable evidence for a pathologically early stage of NAFLD.20 Further, ultrasound and other forms of hepatic imaging (computerized tomography, magnetic resonance imaging) cannot distinguish bland steatosis from steatohepatitis and fibrosis.20 This distinction is clinically important because bland steatosis has a benign prognosis, whereas steatohepatitis can progress to cirrhosis and liver failure.21 Liver biopsy remains the only means to distinguish the different stages of NAFLD. The influence of steatohepatitis on a patient's prognosis was demonstrated in a large population study of diabetic patients that found the standardized mortality rates for liver disease to be even greater than that for cardiovascular disease.22 Another definitional aspect highlighted by the study of Angelico et al. is the inclusion of subjects with an average daily alcohol consumption of up to 30 g per day. There is no consensus regarding the amount of alcohol intake that may contribute to liver injury.23 Alcohol intake as low as 20 g per day can cause hepatic steatosis.24 The risk of alcoholic liver disease and alcohol-induced cirrhosis increases in women with an alcohol intake as low as 10–20 g per day and in men of 20–30 g per day.25 Although clinical practice guidelines or consensus definitions are lacking in the area of NASH/NAFLD, a current USA convention is to include only those who drink <20 g ethanol per day, while others (including ourselves) prefer even more stringent guidelines (<40 g per week) in order to avoid inclusion of possible cases of alcohol/metabolic factor interactions. The study by Angelico et al. used the homeostasis model (HOMA) index, a surrogate marker of insulin resistance that has been validated against the euglycemic hyperinsulinemic clamp study. An increased HOMA index is a common frequent finding in NASH and is associated with an increased risk of cardiovascular events.7,26,27 Because NASH is often the first clinical manifestation of insulin resistance,28 the identification of hepatic steatosis on ultrasonography should prompt clinicians to search for associations with diabetes mellitus, high blood pressure and other features of the metabolic syndrome. This is particularly important as large population studies have shown that up to 50% of those with diabetes are undiagnosed.29 Of those with undiagnosed diabetes, half have fasting plasma glucose concentrations in the non-diabetic range, so it is important that the oral glucose tolerance test be routinely performed in subjects suspected of being insulin resistant. How else should the clinician intervene in patients with hepatic steatosis diagnosed on ultrasound? Short-term studies with lifestyle intervention have shown that exercise (aerobic activity, like walking) and dietary modification reduce hepatic steatosis and correct abnormal biochemical results in NASH.30,31 Importantly, these measures are now proven to reduce the long-term risk of diabetes mellitus levels,32 but any long-term benefit of preventing the progression of NAFLD is yet to be proven. In diabetic patients, weight loss as little as 5% has the benefit of reducing fasting blood glucose, insulin and hemoglobin A1c levels.33 In contrast, rapid and profound weight loss can exacerbate inflammation and fibrosis in NASH and should be avoided.34 Non-alcoholic fatty liver disease affects a large part of the population, in Europe, North America and in the Asia–Pacific region. It is commonly identified on hepatic ultrasound, and should now be considered as a manifestation of the metabolic syndrome. Morbidity and mortality from NASH are increasingly being recognized. An argument can be made for submitting selected patients suspected to have NASH to liver biopsy; the findings can be used to reinforce attempts at correcting the underlying metabolic abnormalities that likely cause progressive liver disease in the metabolic syndrome. Others would argue that, in the absence of evidence that treatment (lifestyle adjustments or pharmacological measures) improves the long-term outcome of the liver condition, it can be debated that performing a liver biopsy in those who appear to be affected by NAFLD is an unwarranted intrusion. The evidence is mounting that steatosis associated with raised ALT, and particularly in persons with risk factors for fibrotic severity such as obesity and diabetes (as reinforced by the Angelico et al. study), are harbingers of a significant form of liver disease (often cirrhosis). These are disorders for which closer monitoring by gastroenterologists may potentially offer improved outcomes.

Association of Metabolic Syndrome With Proximal and Synchronous Colorectal Neoplasm

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease

Obesity and Atherogenic Dyslipidemia

Objective To investigate the relationship between oxidized low density lipoprotein and insulin resistance,the metabolic parameters in patients with metabolic syndrome(MS) or MS complicated with coronary heart disease(MS+CHD).Methods Oxidized low density lipoprotein level and fasting plasma insulin levels were measured by enzyme linked immunosorbent assay method in 17 MS patients , 40 MS+CHD patients and 19 healthy controls. Other information on conventional clinical features of MS, such as waist, BMI, fasting blood glucose and blood fat were collected and the insulin sensitivity index(ISI)were calculated.Results ①There was significant difference in oxidized low density lipoprotein concentrations between controls [(6±5)μg/L] , patients with MS[(25±12)μg/L] and patients with MS+CHD[(41±36)μg/L].② Correlation analysis results suggested that the oxidized low density lipoprotein concentration was related to insulin sensitivity index(r=-0.472,P<0.05),there was no obvious relationship between oxidized low density lipoprotein concentration and the metabolic parameters including body mass index, waist, low density lipoprotein cholesterol and fasting insulin. ③Logistic regression analysis indicated a statistically significant relationship between oxidized low density lipoprotein concentration and ISI ( r 2 = 0. 224, P < 0. 05 ) , the metabolic parameters including body mass index, waist, low density lipoprotein cholesterol, fasting insulin were not correlated with oxidized low density lipoprotein. Conclusions The oxidized low density lipoprotein concentration is highest in patients with MS + CHD, and increased in patients with MS, which were significantly correlated with insulin resistance. This may contribute to the development to coronary heart disease from metabolic syndrome. Key words: Metabolic syndrome; Coronary artery disease; Oxidized low density lipoprotein; Insulin resistance

Recognizing Pregnancy-Associated Cardiovascular Risk Factors

Fat as an Endocrine Organ: Relationship to the Metabolic Syndrome

Aim: Hypothyroidism and metabolic syndrome are well-associated risk factors for atherogenic cardiovascular disease. Insulin resistance, being a common pathogenic mechanism in both, can cause a considerable overlap between hypothyroid and metabolic syndrome population. This cross-sectional study was intended to assess the thyroid function in patients with metabolic syndrome and to investigate the association between hypothyroidism and metabolic syndrome. Materials and Methods: One hundred patients with metabolic syndrome as per National Cholesterol Education Program-Adult Treatment Panel (NCEP ATP) III criteria and 50 controls (0 out of 5 criteria) attending the internal medicine outpatient clinic were included in the study. Patients were subjected to anthropometry, evaluation of vital parameters, and lipid and thyroid profile, along with other routine laboratory parameters. Students' t test, Chi-square test, linear regression, and multiple logistic regression models were used for statistical analysis. P value <0.05 was considered significant. Results: Body mass index, waist circumference, mean systolic pressure, diastolic pressure, fasting blood sugar, total cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, and thyroid stimulating hormone (TSH) were significantly higher, and free triiodothyronine (FT3), free thyroxine (FT4), and high density lipoprotein (HDL) cholesterol were significantly lower in the study group compared to the control group. In the metabolic syndrome group, 22 had subclinical hypothyroidism (22%), 4 were overtly hypothyroid (4%), and 74 were euthyroid (74%). Subclinical hypothyroidism was significantly associated with metabolic syndrome group (P = 0.032). There was significant linear association between TSH levels and total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol across the metabolic syndrome group in the linear regression model. Multiple logistic regression analysis recognized the association between body mass index with subclinical hypothyroidism (P = 0.006) in the metabolic syndrome group. Conclusion: It is concluded from this study that there is significant association between subclinical hypothyroidism and metabolic syndrome, and it highlights the importance of thyroid function tests in patients with metabolic syndrome.

Impact of dietary n‐6/n‐3 polyunsaturated fatty acids (PUFA) ratio on the fructose‐induced visceral obesity and adipose tissue dysfunction was not studied previously. Here we studied the effect of diets containing n‐6 PUFA &amp; α‐linolenic acid (ALA, 18:3 n‐3 PUFA) and n‐6 PUFA &amp; long chain n‐3 PUFA (docosahexanoic acid and eicosapentaenoic acid, DHA and EPA) in the ratio of 2:1 and 5:1 respectively on fructose‐induced metabolic syndrome in the rats.Weanling Wister rats were divided in to four groups and fed with diets containing starch (n‐6/n‐3 PUFA ratio 215:1), fructose (n‐6/n‐3 PUFA ratio 215:1) and fructose‐with n‐6/n‐3 PUFA ratio 2:1 (18:3 n‐3 PUFA) and 5:1 (long chain n‐3 PUFA) diets for twenty‐four weeks. Body composition, adiposity index and adipocyte size were determined along with macrophage infiltration by immunofluorescence. Gene expression of proteins related to pro‐ and anti‐inflammatory cytokines, and pre‐receptor metabolism of glucocorticoids were quantified by quantitative PCR. Plasma fatty acid profile was determined gas chromatography and, circulatory .0lipids and adipokines were measured by kit‐based methods. Insulin resistance was determined by homeostatic measurement of insulin resistance (HOMA‐IR) and oral glucose tolerance test.Both n‐3 PUFA treatments significantly reduced the fructose‐induced visceral obesity and hyperuricemia. ALA and long chain (LC) n‐3 PUFA feeding significantly reduced fructose‐induced macrophage infiltration in adipose tissue, proinflammatory gene expression including monocyte chemoattractant protein 1, E‐selectin, tumor necrosis factor‐α, toll like receptor 2, 4 and corrected circulatory monocyte chemoattractant protein 1 and interleukin‐10 levels. Both n‐3 PUFA treatments significantly reduced fructose‐induced insulin resistance during fasting (HOMA‐IR) and corrected the elevated circulatory adiponectin levels. Interestingly, only LC n‐3 PUFA corrected the insulin resistance after the oral glucose challenge indicated by decreased area under curve for insulin (AUC). Both n‐3 PUFA treatments significantly reduced fructose‐induced gene expression of 11β‐hydroxysteroid dehydrogenase 1, an enzyme involved in pre‐receptor generation of glucocorticoids.We conclude that replacement of dietary n‐6 PUFA with ALA and LC n‐3 PUFA ameliorates fructose‐induced visceral obesity, adipocyte dysfunction and insulin resistance. Though both ALA and LC n‐3 PUFA supplementation significantly reduced fructose‐induced adipose tissue dysfunction, considering beneficial effects LC n‐3 PUFA on insulin resistance and as LC n‐3 PUFA exhibited protective nature at less quantity than ALA, we propose that diets with LC n‐3 PUFA gives better protection against fructose‐induced adipose tissue dysfunction and insulin resistance than the diets with ALA.Support or Funding InformationThe present study was carried out with the financial support of Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, and Indian Council of Medical Research (ICMR), Government of India. AS was supported by Council of Scientific and Industrial Research (CSIR).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hypertriglyceridemia secondary to obesity and diabetes