Video
Explaining Insulin ResistanceMetabolic syndrome insulin sensitivity -
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. It is not intended to be medical advice or a substitute for the medical advice, diagnosis, or treatment of a health care provider based on the health care provider's examination and assessment of a patient's specific and unique circumstances.
Patients must speak with a health care provider for complete information about their health, medical questions, and treatment options, including any risks or benefits regarding use of medications. This information does not endorse any treatments or medications as safe, effective, or approved for treating a specific patient.
UpToDate, Inc. and its affiliates disclaim any warranty or liability relating to this information or the use thereof. All rights reserved. Topic Feedback.
Definitions of the metabolic syndrome Ethnic specific values for waist circumference Risk-enhancing factors for clinician-patient risk discussion Definitions of metabolic syndrome in children and adolescents.
Definitions of the metabolic syndrome. They occurs when your blood glucose level is higher than normal, but not high enough to be called diabetes.
One third of people who have impaired glucose tolerance or impaired fasting glucose will develop diabetes unless lifestyle changes are made. All of these conditions are interlinked in complicated ways and it is difficult to work out the chain of events.
Which condition — if any — is the main trigger? Some researchers consider that obesity could be the starting point for metabolic syndrome. This may help prevent you from developing type 2 diabetes and cardiovascular disease.
Insulin resistance means that your body does not use the hormone insulin as effectively as it should, especially in the muscles and liver.
Normally, your digestive system breaks down carbohydrates into glucose, which then passes from your intestine into your bloodstream. As your blood glucose level rises, your pancreas secretes insulin into your bloodstream. Insulin allows glucose to move into your muscle cells from your blood.
When a person has insulin resistance, the pancreas needs to produce and release more insulin than usual to maintain normal blood glucose levels. It is thought that more than a quarter of the population has some degree of resistance to insulin.
Insulin resistance increases your risk of developing type 2 diabetes and is found in most people with this form of diabetes. People with type 2 diabetes frequently also have other features of metabolic syndrome and a significantly increased risk of cardiovascular heart and blood vessel disease.
More than half of all Australians have at least one of the metabolic syndrome conditions. Suggestions for reducing your risk include:. This page has been produced in consultation with and approved by:. Content on this website is provided for information purposes only.
Information about a therapy, service, product or treatment does not in any way endorse or support such therapy, service, product or treatment and is not intended to replace advice from your doctor or other registered health professional. The information and materials contained on this website are not intended to constitute a comprehensive guide concerning all aspects of the therapy, product or treatment described on the website.
All users are urged to always seek advice from a registered health care professional for diagnosis and answers to their medical questions and to ascertain whether the particular therapy, service, product or treatment described on the website is suitable in their circumstances.
The State of Victoria and the Department of Health shall not bear any liability for reliance by any user on the materials contained on this website.
Skip to main content. Home Heart. Metabolic syndrome. Actions for this page Listen Print. Summary Read the full fact sheet. On this page. Diagnosis of metabolic syndrome Metabolic syndrome conditions are linked Metabolic syndrome and insulin resistance Insulin resistance and diabetes Reducing your risk of metabolic syndrome Where to get help.
Diagnosis of metabolic syndrome Metabolic syndrome is not a disease in itself, but a collection of risk factors for that often occur together.
IFG occurs when blood glucose levels are higher than normal, but not high enough to be diagnosed as type 2 diabetes. Central obesity Central obesity is when the main deposits of body fat are around the abdomen and the upper body.
Cholesterol and triglycerides Cholesterol is a fatty substance that we make in our liver. Metabolic syndrome conditions are linked All of these conditions are interlinked in complicated ways and it is difficult to work out the chain of events.
Metabolic syndrome and insulin resistance Insulin resistance means that your body does not use the hormone insulin as effectively as it should, especially in the muscles and liver. Insulin resistance and diabetes Insulin resistance increases your risk of developing type 2 diabetes and is found in most people with this form of diabetes.
Reducing your risk of metabolic syndrome More than half of all Australians have at least one of the metabolic syndrome conditions. Suggestions for reducing your risk include: Incorporate as many positive lifestyle changes as you can — eating a healthy diet, exercising regularly and losing weight will dramatically reduce your risk of diseases associated with metabolic syndrome, such as diabetes and heart disease.
Make dietary changes — eat plenty of natural wholegrain foods, vegetables and fruit. To help with weight loss, reduce the amount of food you eat and limit foods high in fat or sugar. Reduce saturated fats, which are present in meat, full-cream dairy and many processed foods.
Stop drinking alcohol or reduce your intake to less than two standard drinks a day. Increase your physical activity level — regular exercise can take many different forms depending on what suits you best. Try and do at least 30 minutes of exercise on at least five days of each week.
Also try to avoid spending prolonged periods of time sitting down, by standing up or going for a one-to-two minute walk. Manage your weight — increasing physical activity and improving eating habits will help you lose excess body fat, and reduce your weight.
Quit smoking — smoking increases your risk of cardiovascular disease, stroke, cancer and lung disease.
Metabolic syndrome is a cluster of conditions that occur together, increasing your risk Mettabolic heart disease, sensiitivity and Meetabolic 2 diabetes. These conditions Metabolic syndrome insulin sensitivity increased Wrestling post-fight nutrition pressure, high blood sugar, excess body fat around the sensitivith, Metabolic syndrome insulin sensitivity abnormal cholesterol or triglyceride levels. People who have metabolic syndrome typically have apple-shaped bodies, meaning they have larger waists and carry a lot of weight around their abdomens. It's thought that having a pear-shaped body that is, carrying more of your weight around your hips and having a narrower waist doesn't increase your risk of diabetes, heart disease and other complications of metabolic syndrome. Having just one of these conditions doesn't mean you have metabolic syndrome. But it does mean you have a greater risk of serious disease.Metabolic syndrome insulin sensitivity -
Biddinger is loath to make dietary declarations without more evidence, but is happy to get behind eating more vegetables. She notes that the two FMO3 inhibitors used in the study are commercially available as nutritional supplements. Learn more about the Division of Endocrinology.
See the paper for a full list of authors. The work was funded by the National Institutes of Health R01HL, R00DK , the American Heart Association, and the German Ministry of Education and Research BMBF and the State of Brandenburg 82DZD Taking an As a newborn, Sam Hoffman never cried or made a sound.
His mother, Carolyn, often had to wake him up Diabetes is challenging to manage at any age, but even more so for young adults who are handling the condition Pancreatic cancers are deadly and hard to treat, in part because they are so often detected at an advanced stage; Chen S; et al.
Reduce cholesterol — High levels of low-density lipoprotein LDL bad cholesterol increase the risk of coronary artery disease. If diet and weight loss do not adequately reduce your LDL levels, a medicine may be recommended.
Treatment of high LDL levels is discussed separately. See "Patient education: High cholesterol and lipids Beyond the Basics ". Reduce blood pressure — Keeping your blood pressure in a healthy range is an important goal, especially in people with metabolic syndrome.
Blood pressure measurements include two numbers: the systolic pressure the higher number , which indicates the pressure when the heart contracts or beats; and the diastolic pressure the lower number , which indicates the pressure when the heart relaxes in between beats.
If diet and weight loss do not reduce your blood pressure enough, one or more blood pressure medicines may be recommended. Treatment of high blood pressure is discussed separately. See "Patient education: High blood pressure treatment in adults Beyond the Basics ".
Quit smoking — Smoking cigarettes significantly increases the risk of coronary artery disease and has many other health risks as well. You and your family are strongly advised to stop cigarette smoking. See "Patient education: Quitting smoking Beyond the Basics ". Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed on our website www. Related topics for patients, as well as selected articles written for healthcare professionals, are also available.
Some of the most relevant are listed below. Patient level information — UpToDate offers two types of patient education materials. The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Patient education: Type 2 diabetes The Basics Patient education: Metabolic syndrome The Basics Patient education: High triglycerides The Basics. Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are best for patients who want in-depth information and are comfortable with some medical jargon. Patient education: Type 2 diabetes: Overview Beyond the Basics Patient education: High cholesterol and lipids Beyond the Basics Patient education: Low-sodium diet Beyond the Basics Patient education: Exercise Beyond the Basics Patient education: High blood pressure treatment in adults Beyond the Basics Patient education: Quitting smoking Beyond the Basics.
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings.
These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
Insulin resistance: Definition and clinical spectrum Metabolic syndrome insulin resistance syndrome or syndrome X. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you. View Topic.
Font Size Small Normal Large. Patient education: Metabolic syndrome Beyond the Basics. Formulary drug information for this topic. This is crucial for understanding and developing new therapies for many chronic diseases, such as tapping into drugs with multi-target therapeutic effects like metformin, which has good clinical guidance.
The aim of this review is to focus on the key role of IR in a variety of metabolic diseases at multiple levels, including etiology, mechanisms and therapeutic approaches. Moreover, we summarize some of the most recent advances on the pathogenesis and mechanisms of IR. In addition, we outline the available methods for the treatment of IR in terms of non-pharmacological treatment and chemotherapy.
As mentioned before, IR is a powerful risk factor for the occurrence and development of a bunch of serious chronic diseases. The relationship between IR and these diseases will be described in turn, based on the clinical researches. Chronic metabolic diseases that may be induced by IR are demonstrated in Figure 1.
According to the 10th edition of the IDF Diabetes Atlas, Since insulin is a pivotal hormone that regulates blood sugar, IR is closely associated with all stages of DM, including prediabetes, diabetes, and its complications.
Impaired β-cell compensation in response to increased IR is a pathophysiological factor associated with poor glucose tolerance, which contributes to the development of DM. Type 1 DM T1DM is caused by the primary loss of β-cells — the cells that release insulin — and the complex autoimmune process of continuous insulin deficiency.
Nevertheless, clinical and experimental evidence have shown that patients with T1DM exhibit IR 14 , which is a prominent feature in adolescents and adults 15 — 17 , mainly involving the liver, peripheral, and adipose tissue Insulin injections are currently the conventional treatment for T1DM, and prolonged overexposure to insulin itself is a trigger for insulin resistance.
patients with T1DM eventually also develop insulin resistance and other features of T2DM, such as cardiovascular disease Type 2 DM T2DM is characterized by defective insulin secretion from pancreatic beta cells. Under normal conditions, increased insulin release by pancreatic β-cells is sufficient of insulin action and maintain normal glucose tolerance However, under the circumstances of IR combined with environmental factors and genetic factors related to T2D, persistent overnutrition sets up a vicious spiral of hyperinsulinemia and insulin resistance, ultimately leading to beta cell failure, possibly due to glucose and lipid toxicity and other factors leading to significant T2D There is a lot of evidence suggesting that both IR and T2D are associated with obesity, especially with high proportion of intra-abdominal and intra-hepatic fat, which is the most crucial factor contributes to the emergence of metabolic disease 22 , IR at the beta-cell level may play a role in the pathogenesis of insulin release defects.
Reduced insulin release may impair adipocyte metabolism, leading to increased lipolysis and elevated levels of non-esterified fatty acid NEFA. Elevation of NEFA and glucose can work together to impair islet health and insulin action.
Therefore, this process may slowly progress forward to develop T2D In addition, IR was independently associated with each of the chronic macrovascular and microvascular complications from diabetes Triglyceride-glucose index TyG index is a convenient measure of IR.
In a large Chinese inpatient cohort study, inpatients with elevated TyG index were shown to be at higher risk for lower extremity macrovascular stenosis, arterial stiffness and renal microvascular injury 25 , In particular, IR or hyperinsulinemia is responsible for the development of diabetic cardiomyopathy by pathophysiological mechanisms including impaired insulin signaling, cardiac mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, impaired myocardial calcium handling, abnormal coronary microcirculation, inappropriate neurohumoral activation and maladaptive immune responses 27 , Regarding chronic kidney disease, although this remains to be proven, IR is considered to be a factor contributing to the development and progression of diabetic nephropathy DN , as well as a consequence of DN.
IR is exacerbated during the development of DN, possibly due to some potentially modifiable changes in circulating hormones, neuroendocrine pathways, and chronic inflammation In recent years, a wealth of experimental, epidemiological and clinical evidence has suggested that IR and its compensatory hyperinsulinemia have a synergistic relationship with the development and progression of certain types of cancer, including breast, colorectal, prostate, pancreatic, adrenocortical and endometrial cancers 30 — To put it in perspective, IR and hyperinsulinemia, even in individuals without diabetes, are independently and positively associated with increased mortality from pancreatic cancer Besides, according to a large observational study, breast cancer incidence in women with high HOMA-IR is associated with all-cause mortality, especially in postmenopausal women Although the underlying mechanisms of the association between IR and tumor remain unclear, it may rely on several mechanisms and is not necessarily the same for different types of cancers.
On the other hand, IR is closely associated with visceral adipose dysfunction and systemic inflammation, both of which favor creating an environment conducive to tumorigenesis 38 , Additionally, epigenetic modifications which are triggered by IR and other environmental factors and chronic disease often involve in oncogenesis, such as DNA methylation, histone modifications, and non-coding RNA 35 , 40 , In addition to the mechanisms described above, recent studies indicate that gut microbiota may be a contributing factor in the relationship between IR and cancer, due to gut dysbiosis Therefore, increasing knowledge about the role of IR in cancer has important implications for cancer prevention and tumor growth inhibition.
IR is thought to be a key risk factor leading to cardiovascular and cerebrovascular diseases in different populations, whether normal or diabetic 43 — Increased plasma levels of fatty acids in patients with IR and dyslipidemia, with or without diabetes, may lead to the development of metabolism-related cardiomyopathy An example is diabetic cardiomyopathy, which is characterized by diastolic dysfunction and left ventricular hypertrophy in the absence of vascular defects.
Diabetic dyslipidemia and lipid accumulation in the myocardium are key pathologic features In animal experiments, mice have shown that when IR develops, insulin receptor substrate-1 IRS1 and insulin receptor substrate-2 IRS2 signaling will be impaired, resulting in impaired expression of cardiac energy metabolism genes and activation of p38α mitogen-activated protein kinase p38 , ultimately leading to abnormal cardiac function The strong association between IR and CVD may be due to the fact that the heart is a target organ for insulin, which requires greater energy consumption, yet when IR occurs, it impedes the normal function of the heart and increases the incidence of CVD 52 , Therefore, improving insulin sensitivity not only reduces plasma glucose concentrations in patients with T2DM, but also reduces the risk of cerebrovascular disease independent of the control of blood glucose levels 43 , The liver is one of the main organs controlling the metabolic balance and there is a close relationship between IR and NAFLD, which could be described as a two-way street 57 , NAFLD is characterized by excessive accumulation of lipids in hepatocytes.
Lipids and metabolites secreted by the liver, including lipoproteins, ketones, acylcarnitine and bile acids, may act as signaling molecules and regulate insulin action 59 , Hyperinsulinemia can drive hepatic lipogenesis and lipid accumulation directly as well as through indirect mechanisms, including excess circulating FFA, that impede the ability of insulin to inhibit hepatic glucose production High IR was found to be the most important predictor of NAFLD in both obese and lean subjects 62 , and studies have shown that serum insulin levels are strongly associated with hepatic lobular inflammation and histological progression such as ballooning Similarly, in patients with NAFLD, glycerol appearance and lipid oxidation were markedly increased, and IR also increased with the degree of steatosis 64 , A meta-analysis showed that compared with those without NAFLD, the risk of T2DM was more than two times higher in patients with NAFLD, with the highest risk particularly in patients with nonalcoholic steatohepatitis NASH In the condition of mildly active hepatic steatosis, IR is associated with hepatocellular injury and atherosclerotic dyslipidemia.
While in steatohepatitis, IR is combined with cytokine pro-inflammatory status and fibrosis indicators PCOS is a complex gynecologic endocrine disease, which is characterized by hyperandrogenism, menoxenia, ovulatory dysfunction and infertility.
A study of obese adolescent girls indicates that the PCOS phenotype with high androgen levels has the greatest degree of insulin resistance and inflammation Although the etiology and pathogenesis behind PCOS remain to be determined, IR and its compensatory hyperinsulinemia is considered to be an important pathological change that led to progression of PCOS and the main pathological basis for its reproductive dysfunction 69 — Excessive insulin secretion triggers insulin receptors in the pituitary gland, promoting androgen secretion from the ovaries and adrenal glands through the pituitary-ovary and adrenal axes, and increases free testosterone levels by inhibiting hepatic sex binding globulin SHBG synthesis 72 , Moreover, insulin, as a reproductive as well as metabolic hormone, has direct effect of stimulating ovarian androgen production by stimulating 17α-hydroxylase activity in the ovarian theca cells and enhance the activity of insulin-like growth factor-1 IGF-1 receptor in the ovary, thus increasing its free IGF level and promoting androgen production 74 , Also, IR has long-term and deleterious effects on the metabolism of women with polycystic ovary syndrome.
In addition to the diseases described above, IR is also associated with many other diseases of various systems throughout the body. This includes liver cirrhosis, which is associated with changes in glucose homeostasis, even in intact liver function.
Essential features of the association between cirrhosis and IR include endocrine dysregulation, liver inflammation, changes in muscle mass and composition, changes in the gut microbiota, and permeability IR may also affect the association between insulinemia and bone mass, and Yi-Hsiu Fu et al.
Additionally, IR is a crucial risk factor for deterioration of renal function in non-diabetic chronic kidney disease CKD and hypertension We also noted the effect of IR in the studies related to postburn trauma 81 , postadolescent acne 82 , gastro-esophageal reflux disease GERD 83 and other diseases.
The pathogenesis of IR is the result of the interaction of environmental and genetic factors. Its mechanism of development mainly includes abnormalities in the internal environment, such as inflammation, hypoxia, lipotoxicity, immune environment abnormalities, and abnormal metabolic functions, including metabolic tissues and metabolites.
IR and metabolic disorders are commonly clustered in families, which is thought to be the result of an interaction of environmental and genetic factors, although the full genetic background of these conditions remains incomplete 84 , Genetic factors associated with IR can be classified as abnormal structure of insulin, genetic defects in the insulin signaling system, genetic defects related to substance metabolism, and other related genetic defects.
There are also rare mutations in insulin receptor genes leading to reduced number of cell surface receptors and defective insulin receptor pathways causing hereditary IR, which are found in patients with genetic syndromes of severe IR, such as type A syndrome of extreme IR, leprechaunism, Rabson-Mendenhall syndrome and Donohue syndrome 88 , More importantly, since many molecular pathways are involved in energy homeostasis and metabolism, IR is the result of a certain number of mutations in multiple genes, such as those related to type 4 glucose transporter GLUT4 , glucokinase, and Peroxisome proliferator-activated receptor PPAR nuclear receptor family, among others 90 , Mutations in lipid metabolic pathways, such as mutations in adipocyte-derived hormones such as leptin, adiponectin, resistin or their receptors, mutations in peroxisome proliferator-activated receptors α, γ, and δ, mutations in the lipoprotein lipase gene, and other mutations in genes related to adipose tissue formation can affect the development of glycolipid metabolism and IR The latest advances in high-throughput genetics have revealed the relationship between protein tyrosine phosphatase N1 PTPN1 and IR, and that the association is mediated by differences in DNA sequences outside the coding region of PTPN1 Healthy carriers of the T allele of TCF7L2 rs, may increase insulin secretion and lead to impaired β-cell function, which is associated with an increased risk of T2DM Obesity-induced IR is characterized by impaired insulin function that inhibits hepatic glucose output and promotes glucose uptake in adipose tissue and muscle It has been found that waist circumference is closely related to IR, and an increase in waist circumference corresponds to a decrease in glucose consumption or an increase in IR.
Hence, obesity, especially central obesity, may induce the development of IR due to the massive accumulation of adipose tissue inducing systemic insulin resistance, including endocrine dysregulation and inflammation In obese individuals, especially in those with abdominal obesity, the increase in adipose tissue tends to be more lipolytic, resulting in higher plasma free fatty acid FFA levels and intracellular lipid accumulation.
Elevated FFA can enhance the phosphorylation of serine residues of insulin receptor substrate IRS by activating a series of protein kinases such as c-Jun N-terminal kinase JNK , whose activity is abnormally increased in obese patients , Another mechanism linking obesity and IR is chronic inflammatory responses, including increased production and release of pro-inflammatory factors such as TNF-α, IL-6, and C-reactive protein, which cause insulin resistance in liver, skeletal muscle, and adipose tissue through insulin-interfering signaling pathways Several physiopathological factors and therapeutic causes, such as chronic hyperglycemia, high free fatty acidemia, certain drugs, such as glucocorticoids, pregnancy, and increased insulin-antagonistic hormones in the body all contribute to the occurrence of IR.
There is a pathophysiological relationship between chronic obstructive pulmonary disease COPD and IR, partly because the two conditions share common risk factors, such as smoking and lack of physical activity.
In addition, systemic effects deterioration of physical inactivity and sedentary behavior, inflammation and corticosteroid therapy in patients with COPD may also play a role Also, IR is a common condition after organ transplantation, which leads to new-onset diabetes and metabolic syndrome after transplantation, and subsequent hyperglycemia may significantly increase the morbidity and mortality of cardiovascular disease after kidney transplantation , This is due to post-transplant treatment with immunosuppressive agents such as sirolimus, cyclosporine, steroids, etc.
In both rodents and humans, exogenous synthetic glucocorticoids such as prednisolone and dexamethasone may induce a number of adverse effects when administered in excess or for prolonged periods, including the development of glucose intolerance, islet-cell dysfunction, IR, hyperglycemia, and dyslipidemia , In contrast, almost all morphophysiological changes induced by dexamethasone in the endocrine pancreas are reversed after cessation of treatment Advanced age is an important factor in increasing susceptibility to IR.
With increasing age, there is insufficient insulin secretion and a progressive decrease in glucose tolerance, as well as increasing IR due to sarcopenia, excess adiposity and osteoporosis , According to epidemiology, the prevalence of IR and T2DM is high in the elderly population , This is associated with an increased prevalence of central obesity and increased visceral fat in the aging population 99 , In addition to this, factors that increase the risk of IR in the elderly are free radicals that contribute to oxidative stress in old age, and mitochondrial dysfunction — The paper by Petersen et al.
published in the journal Science mentions that older subjects clearly showed reduced insulin-stimulated muscle glucose metabolism compared to younger subjects. According to the result of an animal experiment, compared with young mice, aged mice are more susceptible to IR, due to reduced levels of glycolytic proteins and reduced flexible to diet, caused by reduced mitochondrial β-oxidation capacity However, these hypotheses still need to be further tested and further understanding of the metabolic changes associated with aging.
The balance of insulin action involves multiple processes in several glucose-utilizing organs or organs, including the liver, adipose tissue, skeletal muscle and kidneys. These metabolic processes receive complex signal regulation.
The etiology and pathogenesis of IR are complicated, and the main pathological mechanisms include abnormalities in receptor binding, environment inside the host, intracellular factors, autophagy and intestinal microecology. It is noteworthy that the mechanisms of IR occur somewhat differently in different insulin receptor tissues, and IR appears in a different order, where the initial appearance of IR is in adipose tissue.
However, they interact with each other and may eventually develop into systemic IR, a phenomenon verified in observational studies in humans — In-depth study of the pathogenesis of IR and multiple research directions have become the key to solving the challenges of IR and its related metabolic diseases today.
The effects of insulin signaling pathways and the effects of inflammatory cytokines and FFA on them are shown in Figure 2. Figure 2 A The insulin signaling pathway; B Abnormalities in the insulin signaling pathway caused by inflammatory cytokines, FFA, etc.
Insulin receptors INSR which is a tyrosine kinase, bind specifically to insulin and play a key role in insulin-mediated glucose homeostasis and cell growth , Impaired INSR binding mainly refers to a decrease in the affinity and number of target receptors on the cell membrane or structural abnormalities of the target receptors that affect insulin binding to the receptor The insulin receptor substrate protein is generally considered a node in the insulin signaling system, which is closely related to the development of insulin insensitivity.
At the molecular level, the crosstalk between the downstream nucleotide-binding oligomerization domain NOD 1 effector and the insulin receptor pathway may inhibit insulin signaling by reducing the action of insulin receptor substrates Insulin activates insulin receptor tyrosine kinases, which are capable of aggregating and phosphorylating various substrate docking proteins, such as the insulin receptor substrate IRS protein family.
Of the four mammalian IRS proteins IRS-1, IRS-2, IRS-3, IRS-4 , IRS1 and IRS2 play key roles in regulating growth and survival, metabolism and aging. They are key substrates of insulin signaling and play an important role in insulin signaling by binding to PI3K and inducing downstream pathways.
At the molecular level, dysregulation of the signaling pathway by insulin receptor substrates IRS is one of the most common causes of this disease.
For example the double-stranded RNA-dependent protein kinase PKR has also been shown to upregulate the inhibitory phosphorylation of IRS1 and the expression of IRS2 in liver and muscle cells, thereby regulating the insulin signaling pathway.
Mediated by two other protein kinases, JNK and IKK, PKR upregulated the phosphorylation of IRS1 at Ser and inhibited the tyrosine phosphorylation of IRS1 , IRS1 has also been shown to be a target of ceramide-induced Pbx regulating protein 1 Prep1 and p in muscle cells, and the Prep1-p axis also affects IRS-1 stability In addition, protein tyrosine phosphatase 1B PTP-1B , protein kinase C PKC and tyrosine residue receptor phosphorylation levels are involved in the regulation of receptor-insulin binding in target tissues.
It has been shown that inhibition of PTP1B, a main negative regulator of insulin receptor signaling, can improve glucose homeostasis and insulin signaling In the insulin receptor signaling cascade, protein tyrosine kinase amplifies the insulin signaling response, and phosphatase is necessary to regulate the rate and duration of the reaction IR occurs in a variety of tissues, including skeletal muscle, liver, kidney and adipose tissue, and its mechanisms are specific.
Among the target organs of insulin, bone, as an endocrine organ, can regulate energy homeostasis by altering insulin sensitivity, dietary behavior, and adipocytes There seems to be a bilateral relationship between bone and IR that binds them together in a biological partnership Among them, skeletal muscle estrogen receptor α plays a crucial role in maintaining systemic glucose homeostasis and insulin sensitivity It has been repeatedly demonstrated that skeletal muscle tissue plays an important role in the maintenance of systemic glucose homeostasis and overall metabolic health.
In addition, the crosstalk between muscle factors and adipokines leads to negative feedback, which in turn aggravates muscle reduction obesity and IR In the kidney, the effector cells of insulin are podocytes in which nucleotide-binding oligomerization domain 2 NOD2 is highly expressed.
NOD2 is a major member of the NOD receptor family and is involved in the innate immune response. It induces podocyte IR by activating the inflammatory response In terms of hepatic IR, IRA, one of the isoforms of the insulin receptor, whose expression in the liver of mice on a high-fat diet increase hepatic glucose uptake, decrease lipid accumulation, and reduce or at least delay the development of fatty liver and NASH.
This suggests that a gene therapy approach to hepatic IRA expression could act as a facilitator of glucose uptake in IR states — Insulin acts by binding to the INSR and activating downstream signaling pathways which have been extensively studied. Although where the defect occurs in the insulin signaling pathway remains a matter of doubt, many key insulin signaling pathway components have been identified.
IR is caused by defects in one or more of these signaling components Environment, such as diet and exercise, and genetics, as well as the interaction between the two, play a major role in the development of IR and metabolic disease. Exercise and dietary habits may directly or indirectly drive changes in the host internal microenvironment.
Current research suggests that extracellular influences such as inflammation, hypoxic environments, lipotoxicity or immune abnormalities can trigger intracellular stress in key metabolic target tissues, which impairs the normal metabolic function of insulin in these cells thereby causing the progression of whole-body IR Obesity characterized by a chronic, low-grade inflammatory state is closely associated with IR.
The mechanisms of inflammation leading to IR mainly include inflammatory factors acting on the insulin signaling system to interfere with INSR signal transduction. TNF-α and IL-1β are additional macrophage-derived pro-inflammatory mediators that directly affect insulin sensitivity , TNF-α stimulates insulin-resistant adipose tissue through IRS protein interference by abnormal signals on phosphorylated serine residues of IRS1 In addition, TNF-α could affect insulin signaling through serine phosphorylation and kinase pathway defects 99 , CRP is another marker of inflammation associated with IR and metabolic diseases and is a widely used clinical biomarker.
CRP binds to leptin, blocks leptin signaling and modulates its central action and hypothalamic signaling, thereby directly interfering with energy homeostasis, insulin sensitivity and glucose homeostasis , The above pro-inflammatory cytokines exert their effects by stimulating major intracellular inflammatory pathways, and the activation of these pathways also promotes increased expression of the inflammatory factors involved in IR.
Toll-like receptor TLR , especially TLR4, participates in IR-related inflammation by increasing the gene expression of IKKβ, NF-κB transcription factors, and pro-inflammatory mediators in adipose tissue macrophages — IKK is an enzyme complex that activates the NF-κB transcription factor It has also been shown that NF-κB receptor activator RANKL is a potent stimulator of NF-κB and that systemic or hepatic blockade of RANKL signaling leads to significant improvements in hepatic insulin sensitivity and prevents the development of diabetes And JNK signaling in adipocytes leads to an increase in circulating concentrations of hepatic factor fibroblast growth factor 21 FGF21 , which regulates systemic metabolism In the pathogenesis of IR and metabolic diseases, immune cells play a crucial role.
Adipose tissue contains most types of immune cells, which under conditions of obesity contribute to a complex network of inflammation and IR with activation and infiltration of pro-inflammatory immune cells in adipose tissue, including macrophages, neutrophils, eosinophils, mast cells, NK cells, MAIT cells, CD4 T cells, CD8 T cells, regulatory T cells and B cells, as well as high levels of pro-inflammatory molecules Among them, adipose tissue macrophages can be divided into M1 phenotype pro-inflammatory macrophages and M2 phenotype anti-inflammatory macrophages , representing the two extremes of macrophage polarization.
M1 macrophages are highly antimicrobial and antigen-presenting, producing pro-inflammatory cytokines, such as TNF-α, and reactive oxygen species ROS that worsen inflammation, mast cells, neutrophils and dendritic cells directly or indirectly exacerbate IR In contrast, M2 macrophages help maintain insulin sensitivity in lean adipose tissue, as well as eosinophils and innate lymphocytes appear to have a protective effect on glucose homeostasis and insulin sensitivity — Crosstalk between M1-M2 macrophage polarization plays an important role in IR through the shift from M1 to M2 phenotype and activation of transcription factors , Dysregulation of visceral adipose tissue macrophage ATM response to microenvironmental changes underlies the development of abnormal local and systemic inflammation and IR In the obese state, enhanced macrophage infiltration and secretion of various inflammatory cytokines in white adipose tissue activate JNK and NF-κB, causing local and systemic IR , Macrophages can alter their phenotype in response to changes in the microenvironment and macrophage differentiation.
In the past, more attention has been paid to the regulation of insulin sensitivity by innate immune cells, particularly macrophage mediated, which have been mentioned before. Cells of the adaptive immune system, B lymphocytes and T lymphocytes, and their respective subsets, are also thought to be important regulators of glucose homeostasis and play an important role in the immunopathogenesis of autoimmune diabetes , , Impaired through an adaptive immune response, IR can also be driven by inflammation and dysregulation of the gut microbiota, as in pathogen-induced periodontitis In addition, the intestinal immune system is an important regulator of glucose homeostasis and obesity-related IR in turn affects intestinal permeability and thus systemic IR Another essential part of the immune defense system is the complement system.
It plays an important role in activating innate and adaptive immune responses, promoting apoptosis, and eliminating damaged endogenous cells. Patients with obesity exhibit activation of the complement system in their adipose tissue, which is connected to changes in glucose metabolism and subclinical inflammation Adipose tissue hypoxia is causally related to obesity-induced IR, especially in high-fat diet HFD fed and early obese patients, as adipocyte respiration becomes uncoupled, resulting in a state of increased oxygen consumption and relative adipocyte hypoxia Clinically, obstructive sleep apnea OSA , characterized by intermittent hypoxia IH , is a widely prevalent respiratory disorder with a particularly high prevalence in obese patients and is associated with IR and metabolic diseases such as hypertension, cardiovascular risk and NAFLD , Not only in obese individuals, but an animal study found that IH cause acute IR in lean or healthy mice, which is related to reduced glucose utilization in oxidized muscle fibers.
As the glucose infusion rate decreased, hypoxia induced systemic IRA The key regulators of oxygen homeostasis in response to hypoxia are the hypoxia-inducible factors HIFs , a family of transcription factors activated by hypoxia.
Adipocyte hypoxia could trigger HIF-1α induction causing adipose tissue inflammation and IR , HIFmediated activation of NOX4 transcription and the consequent increase in H2O2 led to intermittent hypoxia-induced pancreatic β-cell dysfunction In hypoxic adipocytes, HIF-1α activates the NLRP3 inflammasome pathway and stimulates IR by upregulating the expression of pla2g In obesity-induced intestinal hypoxia, HIF-2α increases the production of ceramide, to promote the expression of the key enzyme sialidase 3 encoding Neu3, which leads to the development of IR in obese mice induced by a high-fat diet While in skeletal muscle, hypoxia is a stimulus stimulating GLUT4 translocation via activation of AMPK, causing defects of glucose transport and this may counteract IR Insulin regulates lipid metabolism through the typical insulin signaling cascade, while metabolites can also directly regulate insulin sensitivity by modulating components of the insulin signaling pathway Lipids have multiple roles as signaling molecules, metabolic substrates and cell membrane components, and can also alter proteins that affect insulin sensitivity Lipotoxicity is when the storage capacity of adipose tissue is overloaded due to obesity, overnutrition, etc.
High concentrations of lipids and lipid derivatives cause deleterious effects on cells through mechanisms including oxidative stress, endoplasmic reticulum ER stress, c-Jun NH2-terminal kinase JNK -induced toxicity, and BH3-pure protein-induced mitochondrial and lysosomal dysfunction , Numerous studies have reported that Adipose tissue dysfunction and lipotoxicity play a role in metabolic disorders and IR , This is associated with a chronic elevation of free fatty acids FFA, also called non-esterified fatty acids in plasma due to adipose tissue dysfunction Adipose malnutrition or adipose tissue dysfunction can lead to pathologically elevated FFAs.
Chronically elevated FFAs appear to cause adipocyte production of inflammatory factors, decreased insulin biosynthesis, glucose-stimulated insulin secretion, and glucose sensitivity in β-cells. The ER stress pathway is a key mediator of inflammation induced by serum excess FFA and IR in various cell types, and PERK and IKKβ are key signaling components The obesity-induced increase in adipocyte volume and tissue mass will lead to inflammation, additional disturbances in adipose tissue function, and ultimately adipose tissue fibrosis Adipose tissue macrophages are an abundant immune component of hypertrophy, which plays a key role in diet-induced T2DM and IR In renal ectopic lipid accumulation, lipotoxicity promotes podocyte injury, tubular injury, thylakoid proliferation, endothelial cell activation and macrophage-derived foam cell formation, which contribute to the development of renal IR and other renal diseases, especially diabetic nephropathy In skeletal muscle, sustained nutrient overload of L6 myotubes leads to lipotoxicity that promotes activation of the IKKβ-NFkB pathway in muscle cells, inducing increased cellular ROS and impaired insulin action in the myotubes Saturated fatty acids are known to increase the production of lipotoxic products such as ceramide and diacylglycerol, which disrupt islet beta-cell function, vascular reactivity and mitochondrial metabolism, and also play a key role in the induction of muscle IR — Similarly, defective fatty acid oxidation FAO and consequent lipotoxicity in cardiac cells induce a range of pathological responses, including oxidative stress, DNA damage, inflammation and insulin resistance.
The obesity-mediated atrial fibrillation and structural remodeling can be attenuated by promoting FAO, activating AMPK signaling and attenuating atrial lipotoxicity through levocarnitine LCA Lysophosphatidic acid LPA is an effective, biologically active lipid. After binding to G protein-coupled receptors, it can profoundly affect cell signal transduction and function.
Metabolic and inflammatory disorders, including obesity and IR, are associated with modifications in LPA signaling as well as the production and function of autocrine motility factors Additionally, it has been discovered that the anti-adipogenic transcription factor GATA-3 is a possible molecular target that affects adipogenesis.
Those with obesity and IR exhibit increased GATA-3 expression when compared to insulin-sensitive individuals with BMI matches While lifestyle interventions such as physical activity have been confirmed to have a positive effect on insulin sensitivity in skeletal muscle, affecting lipid metabolism Ceramides are a family of lipid molecules consisting of sphingosine and a fatty acid.
The synthesis of de novo ceramides depends on the availability of free fatty acids, especially palmitate, whose over-intake may lead to an excessive accumulation of ceramides In addition to their function in lipid bilayers, these molecules are also thought to be biologically active agents involved in a variety of intracellular pathways, such as free radical production, release of inflammatory cytokines, apoptotic processes, and regulation of gene expression.
Ceramides are metabolic products that accumulate in individuals suffering from obesity or dyslipidemia and alter cellular processes in response to fuel overload ceramides accumulation over time modulates signaling and metabolic pathways that drive lipotoxicity and IR, causing tissue dysfunction Numerous studies have been conducted in recent years to confirm the critical role played by ceramides in glucose homeostasis and insulin signaling These evidence are particularly strong in skeletal muscle, while the data in liver and WA are somewhat more equivocal , Ceramides are synthesized by ceramide synthase CerS through N-acylation.
To date, six mammalian CerS have been identified CerS that show different affinities for the fatty acid acyl-CoA chain length used for sphingomyelin N-acylation. CerS6 is specific for C14 and C16 acyl chain lengths, and CerS6 levels are significantly increased in obese adipose tissue , In addition, ceramide may cause IR by accumulating in mitochondria and causing mitochondrial reactive oxygen species ROS or by promoting the secretion of pro-inflammatory factors Another lipid metabolite closely associated with IR is DAG, whose accumulation in skeletal muscle, adipocytes and liver is thought to promote IR by altering cellular signaling at its specific location, due to increased serum FFA levels The DAG hypothesis of IR is that the interference of activated PKC, especially the novel PKC isoforms including δ, ϵ, ν, and θ, with insulin signaling is due to the accumulation of DAG in insulin-sensitive tissues , In particular, 1,2-DAG, which derives from esterification and accumulates mainly in the membranes, is clearly associated with PKC activation, and these isoforms then phosphorylate IRS1 serine with the result that decrease PI3K activation , It is worth noting that the role of intracellular ceramide and DAG in IR is controversial and that defects in these components are unlikely to be the sole cause of IR.
It is true that not all studies have confirmed a role for the DAG-PKC-insulin receptor pathway in IR; for example, some studies have shown that PKCϵ deficiency in the liver has no effect on systemic insulin sensitivity in mice , and there are also experiments in which acute knockout of PKCϵ in the liver protects rats from IR Therefore, more in-depth studies on proximal insulin signaling with DAG and ceramide are still needed.
Organelles, including the endoplasmic reticulum ER , mitochondria and endoplasmata, contribute to a range of cellular functions through their unique local environment and molecular composition. Organelles can actively communicate and cooperate with each other through vesicle trafficking pathways and membrane contact points MCSs to maintain cellular homeostasis, which facilitates the exchange of metabolites and other information required for normal cellular physiology Imbalances in organelle interactions may lead to various pathological processes, such as imbalances in cellular energy metabolism Recent studies have shown that mitochondria could interact with various organelles , which are essential for energy metabolism and cell survival, and increasing evidence shows that mitochondrial dysfunction in skeletal muscle and mitochondrial overactivation may induce IR The production of mitochondrial ROS is thought to adjust skeletal muscle insulin sensitivity.
Mitochondrial quality control mechanisms are regulated by PGC-1α, which may affect age-related mitochondrial dysfunction and insulin sensitivity The continuous processes that occur in the skeletal muscle after excessive intake of a high-fat diet include the accumulation of cytosolic fatty acids, increased production of ROS, mutation, and aging.
The ensuing mitochondrial dysfunction could lead to decreased β-oxidation, respiratory function, and increased glycolipid toxicity. Together, these events induce IR in the skeletal muscle 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.
Up to a third of Obesity and genetics. Subcutaneous fat reduction have metabolic syndrome, a constellation of high blood pressure, snsitivity blood ihsulin, excess body fat around the waist, Metabolic syndrome insulin sensitivity abnormal cholesterol levels. Sensitivityy syndrome Subcutaneous fat reduction closely associated with insulin resistance, in which cells fail to respond appropriately to insulin, a hormone that regulates multiple cell metabolic processes such as taking up sugar from the blood. But thus far, scientists have been unable to understand how insulin resistance might produce the different features of metabolic syndrome. Finally, a new study puts the pieces together. It involves a surprise pairing of two infamous molecules, with diet and gut microbes playing supporting roles.Iinsulin to a third of U. adults have metabolic syndrome, a sensitivitty of high blood Metabolic syndrome insulin sensitivity, high Sensjtivity sugar, excess body fat around the waist, and abnormal Metabolic syndrome insulin sensitivity levels.
Metabolic senaitivity is closely associated with insulin resistance, in which cells Metabooic to respond appropriately to insulin, a hormone that regulates multiple cell metabolic processes such as taking insulni sugar from the blood. But thus far, scientists have been unable Metabollic understand how insulin resistance might Natural digestive aid the different sensitigity Metabolic syndrome insulin sensitivity metabolic syndrome.
Finally, Metabolic syndrome insulin sensitivity new study puts the pieces together. It involves a surprise pairing of two Flaxseeds vs molecules, with diet and Metabolic syndrome insulin sensitivity microbes playing supporting roles.
Over past five years, Subcutaneous fat reduction have found an increase Eating for gut health a compound called TMAO in sydrome with insulin seneitivity, diabetes, kidney disease, cardiovascular disease, and neurodegenerative disease.
Mice fed TMAO have Metabolic syndrome insulin sensitivity found to develop glucose insluin, thrombosis, kidney disease and Cellulite reduction exercises for beginners disease. Subcutaneous fat reduction wanted Metbaolic know how this molecule works.
Synrdome study, published September Metabolic syndrome insulin sensitivity in Metabolic syndrome insulin sensitivity Metabolismidentified, for the Metabklic time, what sensitivihy receptor TMAO uses to insulib its sgndrome a molecule called PERK. PERK is a linchpin of stress signaling within cells — specifically, stress on Meatbolic endoplasmic reticulum ERa part of the cell where proteins are assembled, folded, and dispatched to do their jobs.
Under conditions of ER stress, misfolded proteins accumulate and PERK sends distress signals that can ultimately trigger cell death pathways. The interplay between TMAO and PERK could give a new framework for understanding insulin resistance and metabolic syndrome, and the host of diseases they predispose us to — stroke, heart attack, kidney failure and more, says Biddinger.
An exciting aspect of the study is that TMAO is made from a breakdown product of certain intestinal microbes, courtesy of an enzyme called FMO3. Both approaches reduced PERK activation in the livers of obese, insulin-resistant mice and also reduced hyperglycemia. The inhibitor used to suppress FMO3 and, therefore, TMAO is derived from cruciferous vegetables like cauliflower and brussels sprouts.
In contrast, foods such as red meat and eggs are high in choline, which some gut microbes convert to TMAO. So does this mean we should eat more veggies and less red meat to reduce TMAO levels and improve our metabolic status?
Biddinger is loath to make dietary declarations without more evidence, but is happy to get behind eating more vegetables. She notes that the two FMO3 inhibitors used in the study are commercially available as nutritional supplements.
Learn more about the Division of Endocrinology. See the paper for a full list of authors. The work was funded by the National Institutes of Health R01HL, R00DKthe American Heart Association, and the German Ministry of Education and Research BMBF and the State of Brandenburg 82DZD Taking an As a newborn, Sam Hoffman never cried or made a sound.
His mother, Carolyn, often had to wake him up Diabetes is challenging to manage at any age, but even more so for young adults who are handling the condition Pancreatic cancers are deadly and hard to treat, in part because they are so often detected at an advanced stage; Chen S; et al.
Cell Metabolism Sep 19, DOI Share this:. Conquering a rare metabolic condition: A family, a pediatrician, and two labs join forces As a newborn, Sam Hoffman never cried or made a sound. Going out of the box to tackle pancreatic cancer Pancreatic cancers are deadly and hard to treat, in part because they are so often detected at an advanced stage; Tagged: endocrinologymetabolismmicrobiome.
: Metabolic syndrome insulin sensitivity| What is insulin resistance? What is metabolic syndrome? | Arcidiacono B, Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V, et al. Insulin and the polycystic ovary syndrome. Article CAS PubMed Google Scholar Tomlinson JW, Finney J, Gay C, Hughes BA, Hughes SV, Stewart PM. Therefore, more in-depth studies on proximal insulin signaling with DAG and ceramide are still needed. Annu Rev Physiol. Diabetes 37 — |
| 1 Introduction | A Book: The Essential Diabetes Book. A Book: The Mayo Clinic Diet Bundle. Request an appointment. From Mayo Clinic to your inbox. Sign up for free and stay up to date on research advancements, health tips, current health topics, and expertise on managing health. Click here for an email preview. To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail. Metabolic syndrome is closely linked to overweight or obesity and inactivity. The following factors increase your chances of having metabolic syndrome: Age. Your risk of metabolic syndrome increases with age. In the United States, Hispanics — especially Hispanic women — appear to be at the greatest risk of developing metabolic syndrome. The reasons for this are not entirely clear. Carrying too much weight, especially in your abdomen, increases your risk of metabolic syndrome. You're more likely to have metabolic syndrome if you had diabetes during pregnancy gestational diabetes or if you have a family history of type 2 diabetes. Other diseases. Your risk of metabolic syndrome is higher if you've ever had nonalcoholic fatty liver disease, polycystic ovary syndrome or sleep apnea. Having metabolic syndrome can increase your risk of developing: Type 2 diabetes. If you don't make lifestyle changes to control your excess weight, you may develop insulin resistance, which can cause your blood sugar levels to rise. Eventually, insulin resistance can lead to type 2 diabetes. Heart and blood vessel disease. High cholesterol and high blood pressure can contribute to the buildup of plaques in your arteries. These plaques can narrow and harden your arteries, which can lead to a heart attack or stroke. A healthy lifestyle includes: Getting at least 30 minutes of physical activity most days Eating plenty of vegetables, fruits, lean protein and whole grains Limiting saturated fat and salt in your diet Maintaining a healthy weight Not smoking. By Mayo Clinic Staff. May 06, Show References. Ferri FF. Metabolic syndrome. In: Ferri's Clinical Advisor Elsevier; Accessed March 1, National Heart, Lung, and Blood Institute. Metabolic syndrome syndrome X; insulin resistance syndrome. Merck Manual Professional Version. March 2, About metabolic syndrome. American Heart Association. Meigs JB. Metabolic syndrome insulin resistance syndrome or syndrome X. Prevention and treatment of metabolic syndrome. Lear SA, et al. Ethnicity and metabolic syndrome: Implications for assessment, management and prevention. News from Mayo Clinic. Mayo Clinic Q and A: Metabolic syndrome and lifestyle changes. More Information. Show the heart some love! Give Today. Help us advance cardiovascular medicine. Find a doctor. With the evolution of insulin resistance, endothelial dysfunction, inflammation, and atherosclerosis worsen progressively. The combination of increased triglycerides and reduced high-density lipoprotein HDL cholesterol together with increased apolipoprotein B and small—dense low-density lipoprotein LDL particles best describes the atherogenic lipid profile associated metabolic syndrome. The small—dense LDL is highly atherogenic and therefore has become the main target for lipid lowering therapy. The mechanism of hypertension in metabolic syndrome is multifactorial and may be related, among other factors, to obesity and dietary thermogenesis. Metabolic syndrome predisposes to a prothrombotic state as a result of elevated fibrinogen levels along with decreased fibrinolytic activity due to increased plasminogen activator inhibitor 1. Platelet function is also disturbed, leading to increased aggregation and thrombin generation. Metabolic syndrome is a proinflammatory state. Insulin resistance and the atherogenic dyslipidemia cause up-regulation of inflammatory adipokine tumor necrosis factor α, interleukin 6, and C-reactive protein and a decrease in adiponectin. Patients with metabolic syndrome are at a greater risk of developing coronary artery disease and major adverse vascular events table 2. Patients with metabolic syndrome have fivefold higher risk for developing diabetes. Insulin resistance and altered glucose metabolism, the key component of the syndrome, may be responsible for this increased risk. Metabolic syndrome and its individual components are risk factors for acute stroke in the elderly. Stroke patients with metabolic syndrome exhibited an atherogenic profile with higher concentrations of triglycerides and lower HDL cholesterol. Further, hypertension and fasting hyperglycemia were stronger predictors of cerebrovascular events than other components of metabolic syndrome. The individual components of metabolic syndrome adversely affect the kidney initiating loss of renal function. The constellation of the syndrome acts in synergy, the risk increasing progressively with the number of components involved, to accelerate renal damage from microalbuminuria to eventual end-stage renal disease. Metabolic syndrome has been shown to be associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. A retrospective study of a large cohort of pregnant women showed that features of metabolic syndrome before pregnancy were linked to a higher risk of placental dysfunction, including fetal growth retardation and demise. The study also found that this risk increased progressively with the number of components of metabolic syndrome involved, with the odds ratio increasing from 3. The pathophysiology of metabolic syndrome may have important implications for the surgical patient. Obesity, hypertension, and diabetes mellitus are well-recognized perioperative risk factors that contribute to morbidity and mortality. The incidence and degree of insulin resistance may also be related to the clustering of features of metabolic syndrome. Insulin is secreted mainly in response to plasma glucose. Hyperinsulinemia, glucose intolerance, hyperglycemia, and frank diabetes thus represent a clinical continuum of abnormal glucose homeostasis and insulin resistance. Features of this clinical continuum often coexist, and it may not always be possible to dissect the effects of hyperglycemia per se from the state of insulin resistance. Schematic representation of the temporal progression of insulin resistance. The stress of acute illness and surgery induces transient but reversible acceleration of the progression of insulin resistance. Blood loss may also have a direct and independent correlation with postoperative insulin resistance. Stress response may also be related to the duration of the surgical trauma, because glucose utilization seems to be reduced after prolonged surgery. Nutrition may be another contributing factor. A diet inadequate in calories, besides causing negative nitrogen balance, has been shown to alter the metabolic environment and give rise to insulin resistance. Several alterations in the skeletal muscle, adipose tissue, hormones, and cytokines are proposed to explain the pathogenesis of perioperative insulin resistance. It is now increasingly recognized that perioperative insulin resistance is predominantly an extrahepatic phenomenon, primarily affecting the skeletal muscle. It is characterized by a decrease in peripheral glucose uptake with an increase in endogenous glucose production. A defect at this GLUT4 transporter prevents insulin-stimulated glucose uptake and subsequent glycogen synthesis in skeletal muscle. This is now considered the principal abnormality underlying insulin resistance. Limitation of physical exercise results in down-regulation of these GLUT4 transporters, aggravating insulin resistance. Physiology of glucose uptake and biochemical alterations contributing to perioperative insulin resistance. Lipid and lipoprotein dysregulation are closely linked to the insulin-resistant state. Defects in FFA storage and metabolism result in increased FFA flux in primary insulin sensitive tissues like the liver and skeletal muscle. The FFAs and their metabolites decrease phosphoinositidekinase activity that ultimately leads to failure of GLUT4 translocation and insulin signaling mechanisms. The resulting insulin-resistant state further enhances lipolysis, setting up a vicious cycle fig. Mechanisms of insulin resistance during the perioperative period. Insulin resistance and the inflammatory stress response seem to be interlinked. Plasma insulin levels and interleukin 6 follow a similar pattern during the perioperative period. Insulin-like growth factors IGFs and their binding proteins may also play a role in the pathophysiology of perioperative insulin resistance. IGFs are polypeptides secreted by the liver that mediate the anabolic effects of growth hormone. Most IGF-1 in the plasma is bound to IGF-binding proteins 1—6. Free IGF-1 binds specifically to IGF receptors and weakly to insulin receptors, both of which are tyrosine kinases that enhance glucose uptake. Elevated circulating cortisol, growth hormone, and catecholamines seen during surgical stress exert an antiinsulin effect resulting in enhanced hepatic glucose output. There is mounting evidence attesting to the detrimental effects of hyperglycemia on outcomes in diverse clinical settings table 3. However, a reduction in mortality with intensive insulin therapy was observed in patients who required intensive care for more than 3 days. Table 3. Studies Investigating the Effects of Hyperglycemia on Perioperative Outcome. Hyperglycemia is a frequent metabolic disturbance observed in patients with MI. Stress-induced insulin resistance mediates decreased availability of glycolytic substrate, and increased fatty acid utilization may impair myocardial contractility and increase oxygen requirements, promoting arrhythmias and pump failure. Admission hyperglycemia corresponded with the risk of in-hospital mortality, congestive cardiac failure, and cardiogenic shock after MI in both diabetic and nondiabetic patients, with more pronounced effects in the latter. Fasting glucose was also found to be better at predicting short-term mortality after acute MI than admission glucose levels. Further, these patients had higher rates of intensive care unit admissions and greater risk of infection and acute neurologic events. The insulin resistance and hyperglycemia frequently observed during cardiac surgery occurs as a result of release of inflammatory cytokines during cardiopulmonary bypass, use of heparin, release of stress hormones, and iatrogenic catecholamine use, among others. Hyperglycemia during cardiopulmonary bypass and after cardiac surgery has been associated with increased mortality among both diabetics and nondiabetics. Achieving glycemic control with continuous insulin infusion improved survival in these patients by reducing cardiac mortality. The potential diabetogenicity of uremia and peritransplant therapy may be aggravated further by surgical stress. Glucose uptake into renal tubular cells is insulin independent, making them vulnerable to glucotoxicity related to hyperglycemia. Acute hyperglycemia due to insulin resistance may enhance ischemia—reperfusion injury and antigen presentation, escalating the inflammatory response that mediates graft rejection. Insulin resistance seems to play a central role in the pathophysiology of the glucose intolerance commonly observed in brain-dead donors. Detrimental effects include osmotic diuresis, electrolyte disturbances, and impairment of end-organ function. Insulin therapy to maintain blood glucose levels between 4. Treatment of insulin resistance during the process of graft harvest and transplantation may improve the number and viability of the organs procured. Persistent hyperglycemia 48 h after thromboembolic stroke seems to increase mortality, whereas achieving euglycemia seems to improve outcome. Normoglycemia was reported to be an independent predictor of survival after stroke. This effect seemed to be independent of the method used for blood glucose control. Hyperglycemia has been shown to have detrimental effects on the immune system. Acute hyperglycemia impairs monocyte activation and oxidative burst as well as phagocytic capacity of macrophages. These effects, in conjunction with the enhanced protein breakdown caused by insulin resistance, may predispose to systemic and surgical site infections, impair wound healing, and delay recovery. Hyperinsulinemic euglycemic clamp remains the accepted standard for assessment of insulin resistance. The degree of insulin resistance is inversely related to the amount of glucose required to maintain the target concentration when steady state is achieved. The clamp technique provides a quantitative measure of insulin-mediated glucose disposal and also defines the site of insulin resistance. This is reflected in clinical practice by increasing insulin requirements to achieve blood glucose control. Representation of insulin dose—response curve. A represents normal state of insulin sensitivity. B depicts insulin response curve shifted to right, showing decremented response to insulin. C depicts decreased maximal response to insulin secretion. B and C represent progression of the insulin-resistant state. Several other validated tests are available for the assessment of insulin resistance and are summarized in table 4. These are useful research tools and may provide valuable input for clinical management. Insulin resistance may be quantified by mathematical models, clamp techniques, insulin infusion tests, or by glucose tolerance tests. The complex cellular and molecular mechanisms underlying insulin resistance and metabolic syndrome may be further altered by the dynamics of surgical trauma and the associated stress response, analgesia, nutritional status, and bed rest, among other factors. Active modulation of the altered metabolic status may improve outcome after a surgical injury. Insulin, endogenous and exogenous, has long been recognized as a metabolic hormone. Its primary effect is on glucose homeostasis, i. It promotes protein anabolism while also inhibiting fatty acid breakdown. The nonmetabolic effects of insulin are increasingly being recognized. It is believed to have an antiinflammatory effect while enhancing phagocyte function and opsonic activity. It may maintain fibrinolytic activity, prevent platelet activation, and improve vascular reactivity and endothelial function. These effects may act in synergy with the metabolic effects to promote and maintain organ function. Insulin therapy for the management of insulin resistance and the potential benefits of glycemic control among acutely ill subjects has been well studied table 5. A common method of insulin therapy in acutely ill patients is intravenous insulin infusion. Other methods used include glucose—insulin—potassium infusions, subcutaneous injections, dextrose infusions with insulin boluses, and insulin clamp techniques. Table 5. Studies Investigating the Effects of Glycemic Control Insulin Therapy in the Critically Ill Including MI and CABG. The Leuven study by van den Berghe et al. Furthermore, there was reduced mortality from multiorgan failure irrespective of a history of diabetes, reduced duration of stay in intensive care, and lower requirement for mechanical ventilation and renal replacement therapy. Intensive insulin therapy was also associated with reduced episodes of septicemia and lower levels of inflammatory markers. Furnary et al. Furthermore, the perioperative mortality was significantly lower in the continuous insulin infusion group 2. The decrease in mortality was primarily from a reduction in the incidence of cardiac related deaths. The authors proposed that continuous insulin infusion improves myocardial glycometabolic function by insulin-induced stimulation of pyruvate dehydrogenase activity and enhanced glycolysis that replenishes cytoplasmic adenosine triphosphate stores required for phosphorylation of extracellular glucose, stabilization of membrane function, and maintenance of cellular integrity. Enhanced glycolysis is also believed to inhibit lipolysis and mitochondrial β oxidation, preventing accumulation of toxic FFA metabolites. The IDF currently recommends treatment of individual components of metabolic syndrome in patients where lifestyle modification alone is insufficient or the patient is at high risk of cardiovascular disease table 6. Table 6. Classification of Pharmacologic Agents Used in the Therapy of Metabolic Syndrome. Sulfonylureas close adenosine triphosphate—sensitive potassium K ATP channels on the pancreatic β cells depolarizing the cell and consequently releasing insulin. K ATP channels are tetradimeric molecules that exhibit adenosine triphosphatase activity. K ATP channel isoforms that differ in the composition of the individual subunits are also found on the cell membranes of cardiomyocytes and vascular myocytes, among others, as well as the inner mitochondrial membrane mito K ATP channels. Sulfonylureas differ in their selectivity for the pancreatic and cardiovascular isoforms of K ATP channels, with glibenclamide being one of the least selective table 7. Table 7. The K ATP channels in the cardiac sarcolemma and the mitochondria are now believed to play a central role in the phenomenon of ischemic preconditioning—a phenomenon whereby brief periods of ischemia and reperfusion before prolonged ischemia protects the myocardium from the consequent deleterious effects. The effects of sulfonylurea use on both animal and human myocardium have been extensively researched, and the compound most often studied is glyburide also known as glibenclamide. An increase in vascular tone, decreased tolerance to ischemic injury mediated by an inhibition of ischemic preconditioning, and an antiarrhythmic effect, among others, have been reported. Besides, the proposed subtype selectivity of sulfonylureas has also not been addressed. Sulfonylureas may also adversely affect anesthetic preconditioning. Glibenclamide has been shown to prevent isoflurane-induced anesthetic preconditioning during cardiac surgery in diabetic subjects. Further, preoperative use of insulin instead of glibenclamide seemed to restore the protective effect of anesthetic preconditioning. The University Group Diabetes Program study, a placebo-controlled, multicenter, clinical trial, reported in an increased risk of cardiovascular mortality in patients with type II diabetes treated with tolbutamide. They further reported that intensive glycemic control either with sulfonylureas or insulin reduced microvascular but not macrovascular disease among type II diabetics. Another class of insulin secretagogues introduced recently are the glinides. These molecules resemble the nonsulfonylurea portion of glibenclamide and have a similar mechanism of action. They differ from sulfonylureas in their poor protein binding and shorter duration of action. Their role in clinical management of diabetes is yet to be established. Metformin, the only drug among the biguanide class in clinical use, decreases blood glucose levels by sensitizing target tissues to insulin, especially the liver, inhibiting hepatic glucose production and increasing peripheral glucose uptake. It has good oral bioavailability and negligible protein binding and is almost exclusively excreted unchanged by the kidneys. The United Kingdom Prospective Diabetes Study UKPDS 34 showed that addition of metformin to diet-controlled overweight type II diabetics significantly reduced microvascular and macrovascular disease. Metformin did not induce weight gain and was also associated with fewer episodes of hypoglycemia. The additional benefits observed with metformin monotherapy could not be accounted for by the improvement in glycemic control alone but were suggested to be due to decreases in plasminogen activator inhibitor 1 and enhanced fibrinolysis. A retrospective investigation of diabetic patients undergoing cardiac surgery reported that allowing metformin therapy until the night before surgery and early resumption postoperatively did not increase cardiac morbidity odds ratio [OR], 0. Metformin-treated patients, however, required a shorter course of tracheal intubation and had lower infection-related morbidity OR, 0. Thiazolidinediones are insulin-sensitizing agents that bind to the nuclear γ isoform of peroxisome proliferator—activated receptor PPAR-γ. These receptors are primarily expressed in adipose tissues but also find expression in the skeletal myocytes, hepatocytes, and vascular endothelial and smooth muscle cells. PPAR-γ activation results in the transcription of several genes encoding various insulin-sensitive proteins, including lipoprotein lipase and GLUT4. They have a slow onset, requiring up to 12 weeks to reach maximum effect. They are highly protein bound and undergo extensive hepatic metabolism, in the case of pioglitazone to active metabolites. Thiazolidinediones also increase expression of genes that encode proteins that enhance adipogenesis in the subcutaneous adipose tissue. The net result is believed to be a redistribution of fat stores from the muscle and visceral adipose tissue resulting in a decreased visceral-to-subcutaneous adipose tissue ratio. Whereas pioglitazone alters the profile favorably by decreasing triglycerides, rosiglitazone was associated with an increase in LDL cholesterol and total plasma cholesterol. The mechanism of this differential alteration in lipid profile and its clinical significance are as yet unclear. Thiazolidinediones have favorable effects on markers of atherosclerosis. Further, they decrease the serum high-sensitivity C-reactive protein, tumor necrosis factor-α, and inerleukin-6 levels. While some of the antiatherogenic effects could be associated with improvement of glucose metabolism, thiazolidinediones seem to prevent progression of atherosclerosis independent of their effects on glucose metabolism. PPAR-γ agonists are believed to promote endothelial function by suppression of NADPH oxidase, a major superoxide generating enzyme while inducing the superoxide scavenging cytosolic superoxide dismutase. In animal models, thiazolidinediones seems to limit infarct size and attenuate postinfarct left ventricular remodeling and failure. However, it remains unclear whether this is mediated primarily via improvement in glycemic control, insulin sensitivity, or endothelial dysfunction or is independent via its the blood pressure—decreasing effect. The PROactive study, a large European multicenter study involving 5, patients, showed no significant reduction in the composite primary endpoints with pioglitazone. However, the study found a significant reduction in the secondary endpoints of all-cause mortality, MI, or stroke. This improvement, observed in a group of high-risk patients, was in addition to that with their normal medical care, including antihyperglycemic, antiplatelet, antihypertensive, and lipid-lowering therapies. Glycemic control and lipid profile was better with pioglitazone compared with placebo, despite an increased use of metformin and insulin in the placebo group. They also had a better blood pressure profile at the end of the study than at the beginning. It is suggested that the results need to be confirmed and that they are seen as hypothesis-generating only. A meta-analysis of 22 trials that randomly assigned approximately 6, people to pioglitazone therapy for at least 24 weeks showed no evidence of benefit with respect to patient-oriented outcomes such as mortality, morbidity, adverse effects, cost, and health-related quality of life. Further, metabolic control hemoglobin A 1c was found to be no better when compared with other oral antidiabetic drugs. However, the analysis reported a higher incidence of edema with pioglitazone and concluded that the risk—benefit ratio was unclear until further results were available. It also highlighted the different prescribing indications by the US Food and Drug Administration and the European Medicines Agency. Statins are inhibitors of β-hydroxy-β-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the synthesis of cholesterol. They interrupt cholesterol synthesis in the liver and activate hepatocyte LDL receptors and decrease LDL. Statins have proved beneficial in primary and secondary prevention of adverse cardiovascular events. Evidence suggests that statins, besides their effects on lipids, reduce endothelial dysfunction, inhibit inflammatory responses, stabilize atherosclerotic plaques, and modulate procoagulant activity and platelet function, the so-called pleiotropic effects. Statin therapy was associated with a reduced rate of nonfatal MI or death at the end of 30 days. Requirement for revascularization procedures was reduced, as was hospital stay. However, among patients whose chronic statin therapy was withdrawn after hospital admission, the incidence of death and nonfatal MI increased when compared not only with patients whose statin therapy was continued, but also with patients who did not receive any statin therapy at all. The study also reported that the number needed to treat to prevent a postoperative death was 30 among patients with a higher cardiac risk. The paucity of prospective data and heterogeneity of retrospective data were also highlighted. The authors suggest that with current data preoperative statin therapy be restarted as early as possible postoperatively. Fibrates are lipid-modulating drugs that act as ligands to the α isoform of PPAR nuclear receptors that activates the transcription genes encoding for proteins involved in lipoprotein metabolism. Fibrates induce synthesis of the major HDL apolipoproteins apoA-I and apoA-II. By inducing lipoprotein lipase, fibrates stimulate lipolysis and decrease triglyceride synthesis and very-low-density lipoprotein secretion. However, it did show that fibrates were associated with less albuminuria progression and retinopathy and a significant reduction in incidence of nonfatal MI in low-risk patients. When combined with fibrates, statins further double this risk. Intensive treatment of diastolic hypertension has been shown to reduce the incidence of adverse cardiovascular events, with diabetic patients deriving most benefit. No particular agent has been identified as being preferable for hypertensive patients with metabolic syndrome. Instead, current data suggest that the benefits associated with antihypertensive therapy are largely due to their blood pressure—decreasing effect rather than the drug type. Increased physical activity has been recommended in the primary management of metabolic syndrome because of its beneficial effects on the various components of the syndrome. In diabetic patients, physical rehabilitation and exercise may improve insulin sensitivity and glucose control. Fasting represents an extreme state of nutritional stress, and its adverse effects include depletion of glycogen stores and breakdown of proteins and fat to provide energy. It also impairs mononuclear phagocytic system, increases bacterial translocation, and enhances oxidative stress injury. Preoperative intake of carbohydrate-rich beverage has been shown to maintain insulin sensitivity in surgical patients. Volatile anesthetics protect the myocardium against the effects of ischemia, a phenomenon closely resembling ischemic preconditioning. This phenomenon, called anesthetic preconditioning, is also believed to be mediated by K ATP channels in the myocardial sarcolemma and the mitochondrial membrane. High blood glucose concentrations have been shown to attenuate the protective effects of ischemic and anesthetic preconditioning in both diabetic and nondiabetic animal models. In healthy volunteers, acute pain has been shown to induce insulin resistance and decrease nonoxidative glucose disposal. High-dose opioids have been shown to attenuate the stress response to surgery, but this response lasts only till the high levels are maintained. Decreased hepatic sympathetic efferent tone may reduce glucose output from the liver, whereas a reduced sympathetic stimulation of the adrenals attenuates release of catecholamines and cortisol, promoting peripheral glucose clearance. Metabolic syndrome, a rapidly growing global epidemic, is a cluster of cardiovascular risk factors that is associated with a heightened risk of morbidity and mortality. Lifestyle modification and pharmacotherapy targeting individual components of the syndrome have been recommended as primary and secondary prevention strategies. Insulin resistance and central obesity are increasingly recognized as being central to the pathogenesis of metabolic syndrome. Insulin resistance commonly manifests as hyperglycemia during acute illness and in the perioperative period. Management of insulin resistance to achieve glycemic control improves outcome. It is suggested that preoperative statins be continued uninterrupted or at least reinstated as soon as feasible to harness the benefits derived from its pleiotropic effects. Early postoperative mobilization and exercise have shown some promise, but their role must be defined clearly. Modulation of the other components of the syndrome in the acute phase of illness and in the perioperative period needs further evaluation. Perioperative physicians must identify patients at risk of insulin resistance and metabolic syndrome, and strategies aimed at modulating the altered metabolic milieu should be identified. The authors thank Joel G. Ray, M. Departments of Medicine, Obstetrics and Gynecology and Health Policy Management and Evaluation, St. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Publications Anesthesiology. Advanced Search. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume , Issue 3. Previous Article Next Article. Pathophysiology of Metabolic Syndrome. Systemic Effects of Metabolic Syndrome. Pathophysiology and Molecular Mechanisms of Perioperative Insulin Resistance. Insulin Resistance and Hyperglycemia. Assessment of Insulin Resistance. Strategies for Metabolic Management. Article Navigation. Review Article March Metabolic Syndrome and Insulin Resistance : Perioperative Considerations Hema S. Bagry, M. This Site. Google Scholar. Sreekrishna Raghavendran, M. Franco Carli, M. David S. Warner, M. Mark A. Anesthesiology March , Vol. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Table 1. Definitions of Metabolic Syndrome. View large. View Large. Table 2. Clinical Outcomes of Metabolic Syndrome. View large Download slide. Table 4. Methods of Assessment of Insulin Resistance 9, World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications: Report of a WHO Consultation. Geneva, World Health Organization, World Health Organization. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III. JAMA ; —97 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Alberti KGMM, Zimmet P, Shaw J: Metabolic syndrome: A new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med ; — Utzschneider KM, Carr DB, Hull RL, Kodama K, Shofer JB, Retzlaff BM, Knopp RH, Kahn SE: Impact of intra-abdominal fat and age on insulin sensitivity and beta-cell function. Diabetes ; — Ohlson LO, Larsson B, Svardsudd K, Welin L, Eriksson H, Wilhelmsen L, Bjorntorp P, Tibblin G: The influence of body fat distribution on the incidence of diabetes mellitus: Diabetes ; —8. Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, Willett WC, Manson JE: Abdominal adiposity and coronary heart disease in women. JAMA ; —8. Avramoglu RK, Basciano H, Adeli K: Lipid and lipoprotein dysregulation in insulin resistant states. Clinica Chimica Acta ; — |
| Insulin Resistance and the Metabolic Syndrome | Rights and permissions Reprints and permissions. As we get older, we tend to become less active and may gain excess weight. He FF, Li YM. The deletion of whole-body Irs2 in mice resulted in diabetes owing to pancreatic β-cell failure Withers et al. Metabolism 65 8 — |
| Metabolic syndrome | Other methods Concentration exercises include glucose—insulin—potassium infusions, subcutaneous injections, dextrose Subcutaneous fat reduction with insulin boluses, and lnsulin clamp Wild salmon environmental impact. Stumvoll M, Mitrakou A, Pimenta W, et al. Article Metabolic syndrome insulin sensitivity Jnsulin PubMed Central Google Sydnrome Shen Senstiivity, Reaven Dyndrome, Farquhar JW. Insulin was assayed in duplicate using a specific human insulin ELISA kit from Linco St. From Harold Himsworth to the insulin resistance syndrome. Thus, an abnormality at the level of the pancreas is critical for the development of diabetes, and the correction of the imbalance of hormones between insulin β-cells and glucagon α-cells may provide a potential strategy to prevent diabetes. Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. |
Ich entschuldige mich, aber meiner Meinung nach lassen Sie den Fehler zu. Geben Sie wir werden es besprechen. Schreiben Sie mir in PM, wir werden reden.
Statt besser zu kritisieren schreiben Sie die Varianten.