Contact a health care provider if you have questions about your health. Metabolic Syndrome Also called: Insulin resistance syndrome, Metabolic syndrome X.

On this page Basics Summary Start Here Symptoms. Learn More Related Issues Specifics. See, Play and Learn No links available. Research Clinical Trials Journal Articles. Resources Find an Expert. For You Children Patient Handouts. What is metabolic syndrome?

These risk factors include: A large waistline, also called abdominal obesity or "having an apple shape. Having a high triglyceride level. Triglycerides are a type of fat found in the blood.

Having a low HDL cholesterol level. HDL is sometimes called the "good" cholesterol because it helps remove cholesterol from your arteries. Having high blood pressure. If your blood pressure stays high over time, it can damage your heart and lead to other health problems.

Having a high fasting blood sugar. Mildly high blood sugar may be an early sign of diabetes. What causes metabolic syndrome? Metabolic syndrome has several causes that act together: Overweight and obesity An inactive lifestyle Insulin resistance, a condition in which the body can't use insulin properly.

Insulin is a hormone that helps move blood sugar into your cells to give them energy. Insulin resistance can lead to high blood sugar levels. Age - your risk goes up as get older Genetics - ethnicity and family history People who have metabolic syndrome often also have excessive blood clotting and inflammation throughout the body.

Who is at risk for metabolic syndrome? Font Size Small Normal Large. Metabolic syndrome insulin resistance syndrome or syndrome X. Formulary drug information for this topic.

No drug references linked in this topic. Find in topic Formulary Print Share. View in. Language Chinese English. Author: James B Meigs, MD, MPH Section Editors: David M Nathan, MD Joseph I Wolfsdorf, MD, BCh Deputy Editor: Sara Swenson, MD Literature review current through: Jan This topic last updated: Aug 23, Insulin resistance, the associated hyperinsulinemia and hyperglycemia, and adipocyte cytokines adipokines may also lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease CVD [ ].

A similar profile can be seen in individuals with abdominal obesity who do not have an excess of total body weight [ ]. To continue reading this article, you must sign in with your personal, hospital, or group practice subscription. Subscribe Sign in. It does NOT include all information about conditions, treatments, medications, side effects, or risks that may apply to a specific patient.

The physical contact site between the mitochondria and endoplasmic reticulum ER is called the mitochondrial-associated membrane MAM. The imbalance of MAMs significantly leads to IR.

ER stress may be the main mechanism by which MAM induces IR in the brain, especially in the hypothalamus , Exosome-like vesicles ELVs are the smallest type of extracellular vesicles released from cells that play a role in cell crosstalk because they regulate insulin signaling and β-cell quality, and released ELVs leading to IR or β-cell apoptosis PTEN is not only a tumor suppressor gene but also a metabolic regulator.

Under physiological and T2D conditions, PTEN also has a negative regulatory function in insulin signaling through its inhibition in the PI3K pathway , PTEN reduces the level of phosphatidylinositol-3, 4, 5-phosphate PIP3.

This leads to impaired insulin signaling and promotion of IR in the pathogenesis of T2D. The function of PTEN in regulating insulin signaling in different organs has been identified.

The role of PTEN in the regulation of insulin action in many cell types has been elucidated through mouse models of lacking PTEN in metabolic organs and in vitro cell culture , Interventions targeting PTEN regulatory signaling may therefore be a promising target aimed at reversing insulin resistance.

In addition to its effects on skeleton, Vit D has significant effects on pancreatic β-cells function and metabolic syndrome including blood pressure, abdominal obesity, glucose metabolism associated with it, as calcitriol functions as a chemical messenger by interacting with calcium flux-regulating receptors on beta cells As the results of a meta-analysis showed, there was an inverse relationship between serum Vit D concentration and metabolic syndrome risk in the general adult population in cross-sectional studies Vitro studies showed that Vit D could regulate lipid and glucose metabolism in adipose tissue, skeletal muscle and liver, and pancreatic insulin secretion Minerals are essential micronutrients for the human body.

Deficiencies in certain micronutrients due to differences in diet composition may lead to imbalances in glucose homeostasis and IR Magnesium is a cofactor required for glucose access to cells and carbohydrate metabolism, and it has the function of regulating the electrical activity of pancreatic beta cells and insulin secretion Mechanistically explained, magnesium is a cofactor in the downstream action of the insulin cascade.

Low magnesium ion levels lead to defective tyrosine kinase activity, blocking intracellular insulin action and altered cellular glucose transport, thus promoting IR On the other hand, magnesium deficiency inhibits cellular defenses against oxidative damage and triggers chronic systemic inflammation that enhances IR.

As demonstrated in a longitudinal study, magnesium intake was also inversely associated with high-sensitivity CRP, IL-6 and fibrinogen levels, as well as HOMA-IR There is evidence suggesting that magnesium supplementation attenuates IR in patients with hypomagnesemia-associated IR Also, animal studies have shown that dietary magnesium supplementation to increase plasma magnesium concentrations reduces blood glucose levels, improves mitochondrial function, and reduces oxidative stress in diabetic mice However, new intervention studies are still needed to clarify the role of nutrients in the prevention of this metabolic disorder, as well as to standardize the type, dose, and timing of magnesium supplementation.

Zinc is an essential micronutrient for metabolism, which plays a particularly critical role in the islets. Diabetes affects zinc homeostasis, and disturbances in zinc homeostasis have been associated with diabetes and IR Because zinc is an essential component of insulin, it regulates islet cell secretion and promotes its binding to hepatocyte membranes while maintaining phosphorylation and dephosphorylation levels of the receptor.

Zinc influx mediated by Slc39a5, a zinc exporter in pancreatic β-cells, plays a role in insulin processing and secretion by inducing Glut2 expression through Sirt1-mediated activation of Pgc-1α In addition, zinc acts as a pro-antioxidant to reduce the formation of ROS, which is particularly beneficial in aging and IR Mineral deficiencies are directly or indirectly associated with oxidative stress, which ultimately leads to IR or diabetes The brain is also an insulin-sensitive organ with a large number of insulin receptors distributed , The action of insulin in the brain produces a variety of behavioral and metabolic effects that influence eating behavior, peripheral metabolism, and cognitive performance Disturbances in the role of insulin in the brain reveal a possible link between metabolism and cognitive health.

The hypothalamus plays a fundamental role in the survival and control of physiological processes necessary for vital physical functions, including various endocrine functions.

Injecting insulin via intranasal administration leads to an increase and subsequent decrease in plasma insulin, affecting peripheral metabolism, and a decrease in BOLD signaling and cerebral blood flow in the hypothalamus is observed , It appears that the effects of central insulin may have a biphasic effect on peripheral insulin sensitivity Insulin signaling has been shown to affect the molecular cascade of hippocampal plasticity, learning, and memory Furthermore, the insulin-responsive glucose transporter GluT4 has a key part in hippocampal memory processes, and reduced activation of this transporter may underlie IR-induced cognitive deficits Autophagy is a self-degrading process that is conserved in all eukaryotic cells and plays a crucial role in balancing energy sources during critical periods of development and in response to nutritional stress.

Autophagy also promotes cellular senescence and cell surface antigen presentation, prevents genomic instability and necrosis, and it is an important mechanism for a variety of physiological processes, such as cellular homeostasis, senescence, immunity, oxidation, differentiation, and cell death and survival Recent studies have shown that autophagy is an important regulator of organelle function and insulin signaling, and that loss of autophagy is a key component of defective insulin action in obesity, which may be specifically related to ER function It has been found that autophagy deficiency and its resulting mitochondrial dysfunction increase fibroblast growth factor 21 Fgf21 expression through the induction of Atf4.

The induction of Fgf21 promotes protection against diet-induced obesity and IR In addition, exercise induces autophagy through the regulator BCL2, which may contribute to beneficial metabolic effects and improve IR in muscle In addition to the aforementioned influences such as metabolites and cytokines, the trillion bacterial colonized gut microbiota can also contribute to IR , Patients with metabolic syndrome showed increased insulin sensitivity after six weeks of infusion of gut microbiota from lean individuals.

Levels of gut microbiota producing butyrate, which has been shown to prevent and treat diet-induced insulin resistance in mice by promoting energy expenditure and inducing mitochondrial function, were also increased , Dietary reasons for obesity may promote IR both through mechanisms independent of the gut microbiota and through mechanisms dependent on the bacterial community Intestinal dysbiosis is associated with the transfer of bacterial lipopolysaccharide LPS into the systemic circulation and its induction of metabolic endotoxemia, leading to a chronic subclinical inflammatory process and the development of IR through activation of toll-like receptor 4 TLR4 — In addition to the LPA mentioned above, branched-chain amino acids BCAAs are another harmful gut microbially regulated metabolite whose levels are increased in the serum metabolome of IR individuals.

Prevotella copri has been shown in mice experiments to induce IR, exacerbate glucose intolerance and increase circulating levels of BCAAs Moreover, gut microbiota-derived short-chain fatty acids SCFA may improve IR and prevent T2DM by reducing the secretion of pro-inflammatory cytokines and chemokines and decreasing local macrophage infiltration, as well as increasing the lipid storage capacity of white adipose tissue , , Taken together, targeting gut microbes may have the potential to reduce IR and decrease the incidence of related metabolic diseases.

This lifestyle triggers several mechanisms such as the development of IR that aggravate metabolic stress. Next, the contribution of non-pharmacological therapies, including exercise and diet, to the alleviation of IR will be elaborated.

Exercise is well known to improve metabolic disease by improving obesity and enhancing insulin sensitivity. A meta-analysis determined the effectiveness of a structured exercise intervention program for IR in T2DM, and the evidence highlights that regular exercise improves glycemic control and therefore can be recommended for reducing IR with a moderate level of evidence As we know, physical exercise increases the oxidative capacity and biogenesis of mitochondrial substrates in skeletal muscle.

It was shown that treadmill training modulates the increase in mitochondrial substrate oxidation in liver and skeletal muscle induced by a high-energy diet in mice, disconnecting it from pyruvate and acetyl CoA-driven lipid synthesis.

This may help prevent the long-term deleterious effects of excessive nutritional intake on liver mitochondrial function and insulin sensitivity, thereby preventing the development of metabolic diseases such as fatty liver and NAFLD As described in the mechanism section, intermittent hypoxia leads to disturbances in the gut microbiota-circulating exosome pathway, disrupting adipocyte homeostasis and leading to metabolic dysfunction manifested as IR, whereas experiments have shown that such changes can be attenuated by physical activity, as regular non-strenuous activity will lead to substantial improvements in the gut microbiota-exosome pathway In addition, available data suggest that aerobic exercise can lead to increased insulin sensitivity and enhanced glucose metabolism through a variety of different molecular mechanisms, including upregulation of insulin transporters on cell membranes of insulin-dependent cells, reduction of adipokines, normalization of redox status, improvement of β-cell function, regulation of IRS-1 phosphorylation, reduction of ceramide plasma levels, and induction of angiogenesis, which may lead to a reduced incidence of diabetic complications, as well as other metabolic effects , Other forms of exercise, such as yoga, have also been shown to improve IR.

Several meta-analyses have shown that yoga is a safe and effective intervention to reduce waist circumference and systolic blood pressure in patients with metabolic syndrome, particularly in improving cardio-metabolic health , Some traditional Chinese health exercises, such as qigong and tai chi, have also been shown to have a measurable effect on weight, waist circumference, leg strength, increase HDL cholesterol, and result in significant improvements in IR , As mentioned above, high-fat diets and the obesity they induce are a major cause of IR.

Conversely, weight loss, when necessary, and dietary interventions such as intermittent fasting programs that reduce carbohydrates in the diet can significantly improve glycemic and insulin responses.

The Mediterranean diet is characterized by a wide range of cardio-protective nutrients, with beneficial effects on several outcomes related to metabolic health, and significant beneficial changes in metabolic risk factors, including HOMA-IR index — There are also RCT studies reporting that a high-protein diet is more effective in controlling IR and glycemic variability compared to a Mediterranean diet, which may be related to the satiety and increased metabolic rate associated with a high-protein, low-sugar diet In terms of dietary composition, a key dietary strategy for treating IR and improving glycemic control is to consume foods and meals that reduce the glucose fluctuations known to induce oxidative stress and beta cell damage The contribution of high-fat diets to obesity and IR is well known.

However, a single-minded approach to weight loss by replacing fat intake with carbohydrates is counterproductive because it could exacerbate IR.

Researchers suggest that calorie restriction for weight loss and rationing of the macronutrient composition of the diet is important. The possible mechanism for this is that calcium and vitamin D in supplemental dairy products may facilitate lipolysis and optimize glucose metabolism Carbohydrates are the main macro-nutrient influencing the glycemic response, especially after a meal.

In recent years, some researchers have proposed that consumption of carbohydrates rich in dietary fiber and low glycemic index, such as whole grains, is beneficial in improving insulin sensitivity and metabolic flexibility, independent of gut hormones , A recent meta-analysis reported that increasing daily fiber intake by 15 or 35 grams compared to a low-fiber diet reduced homeostatic model assessment of insulin resistance HOMA-IR , leading to improvements in glycemic control, lipids, weight, and inflammation, as well as a reduction in premature mortality Not only is the amount of carbohydrate intake important, but the timing of major carbohydrate intake during the day is also a determining factor in the increase in glucose and insulin after meals and the improvement or otherwise of IR The results of some randomized controlled trial RCT studies suggest that it is advisable to consume at least half of the carbohydrates at lunch and to avoid consuming large amounts of carbohydrates at breakfast or dinner in order to control blood glucose spikes, which may be related to diurnal variations in insulin sensitivity — Results of another study showed that 10 hours of restrictive eating improved quality of life by reducing body weight and improving blood glucose, insulin sensitivity and related metabolic disorders Other dietary strategies have been shown to prevent high-fat diet-induced IR, such as the intake of flavonoid-rich natural products, like flavonoids, which upregulate the expression of related genes through cell surface G protein-coupled estrogen receptors Although lifestyle modification and weight loss are highly recommended to improve IR and its associated metabolic disorders, they have limited effectiveness, slow onset of action, and low feasibility.

Pharmacological treatments to increase insulin sensitivity will be described next. Currently, the main drugs that can effectively improve IR are anti-hyperglycemic drugs, including metformin, thiazolidinediones TZD , sodium glucose cotransporter SGLT -2 inhibitors SGLT2i , etc. Metformin, the most commonly used insulin-sensitizing agent, has been a guideline-recommended first-line treatment for T2DM for decades and has recently found new applications in the prevention and treatment of various diseases, including metabolic disorders and cardiovascular diseases Metformin improves IR by modulating metabolic mechanisms and mitochondrial biogenesis through altering microRNAs levels by AMPK-dependent or AMPK-independent mechanisms TZDs, such as pioglitazone, are potent insulin sensitizers targeting PPARγ and PI3K, regulating the transcription of nuclear transcription factors, stimulating mainly white adipose tissue remodeling, and regulating lipid flux for insulin sensitization and beta cell protection , SGLT2i is a relatively new class of glucose-lowering drug that not only lowers blood glucose by inhibiting renal glucose reuptake, leading to increased urinary glucose excretion and lower blood glucose, but also improves insulin sensitivity in patients with T2DM by reducing body weight or glucose toxicity , And in a randomized, double-blind, placebo-controlled clinical trial, it was shown that 8 weeks of treatment with SGLT2i empagliflozin restored insulin sensitivity in the hypothalamus of patients with prediabetes Glucose-lowering drugs have also shown good, stacked effects in patients who do not have good response with one drug alone.

For example, the addition of rosiglitazone to metformin can be clinically important in improving glycemic control, insulin sensitivity and beta-cell function The addition of sitagliptin or metformin to pioglitazone monotherapy also leads to faster and better improvement in IR and inflammatory status parameters Other therapies, as well as some new drugs in clinical trials, such as anti-inflammatory drugs, drugs that target hepatic lipid and energy metabolism, renin-angiotensin-aldosterone system blockers, vitamin D, antioxidants, probiotics and fecal transplants, have also shown improvement in IR Among them, selected clinical trials in the last decade have been listed in Table 2.

As mentioned previously, low-grade chronic inflammation is associated with IR and metabolic disturbances. For example, in in vitro and in vivo mouse models of diet-induced hyperinsulinemia, low-dose naltrexone attenuates hyperinsulinemia-induced proinflammatory cytokine release and restores insulin sensitivity However, it is worth noting that corticosteroids can cause IR and hyperglycemia due to their metabolic effects, and statins also increase the risk of IR, although they can reduce circulating inflammatory markers TCM plays an equally critical role in the treatment of many acute and chronic diseases, especially its adeptness in restoring the dynamic balance of the body in systemic diseases.

Its main therapeutic measures include herbal medicine, acupuncture and Tui Na. Several classical herbal formulations have been widely used in the clinical treatment of T2DM and various other metabolic disorders. For example, GegenQinlian decoction improves IR in fat, liver and muscle tissue through a variety of compounds, targets, pathways and mechanisms Yi Qi Zeng Min Tang has been shown to improve IR in high-fat fed Sprague-Dawley rats without increasing body weight Because it reduced the expression of PI3K p85 mRNA and IRS1 protein, Fu Fang Zhen Zhu Tiao Zhi formula similarly improved IR in vitro and in rats with metabolic syndrome Gui Zhi Fu Ling Wan, Dingkun Pill and Liuwei Dihuang Pills are herbal formulas widely used in the treatment of gynecological disorders and have the effect of harmonizing Qi and blood or dispelling blood stasis in Chinese medical theory.

In addition, the efficacy of acupuncture in improving IR is equally impressive, as a recent meta-analysis showed that acupuncture improved HOMA-IR and ISI as well as fasting blood glucose FBG , 2h postprandial blood glucose 2hPG and fasting insulin FINS levels, with fewer adverse events The increased incidence of IR and its vital role as a major and common cause of numerous metabolic diseases have created an urgent need to gain insight into the etiology and pathogenesis of IR, as well as to explore better early diagnostic methods and therapeutic strategies for it.

The diagnosis of insulin resistance is currently inconclusive, while it is important to detect IR early and predict individual response to treatment. In addition to the few simple indices of IR calculated from biochemical or anthropometric variables currently in use, emerging biomarkers may now be the way forward, but this still needs to be supported by clinical data.

Different ranges and criteria are also needed for the diagnosis and monitoring of different metabolic diseases. As mentioned above, IR is a central mechanism in many metabolic diseases. Since this is the case, IR should be considered as a therapeutic target for patients with a combination of multiple metabolic diseases so that multiple diseases can be treated simultaneously with the same treatment approach, thereby reducing healthcare expenditures.

Although there is no universally accepted theory to explain the mechanisms that cause IR. Nevertheless, there is growing evidence linking ectopic lipid accumulation, ER stress, plasma concentration of inflammatory cytokines, oxidative stress, abnormalities in insulin signaling, and other factors to IR.

In recent years, the exploration of the molecular mechanisms of IR has also led to the emergence of new therapeutic concepts beyond metformin and TZD. Regardless lifestyle modification remains the most basic and least costly intervention.

Normative criteria need to be developed for different metabolic diseases considering IR as a focus. FL and HJ provided the idea of the manuscript. XZ, XA, and CY contributed equally to this manuscript.

XZ, XA, WS, and CY drafted the manuscript and searched the relevant literature. XZ and XA drafted the figures, and all authors approved the final version of the manuscript. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

All authors contributed to the article and approved the submitted version. This work was supported by Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine. No: ZYYCXTD-D The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease.

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