Research has identified at least compounds contained in a variety of herbs and spices that may contribute to reducing insulin resistance Several studies have found that drinking green tea can help increase insulin sensitivity and reduce blood sugar 27 , These beneficial effects of green tea could be due to its powerful antioxidant epigallocatechin gallate EGCG , which helps increase insulin sensitivity Vinegar could help increase insulin sensitivity by reducing blood sugar and improving the effectiveness of insulin It also appears to delay the stomach from releasing food into the intestines, giving the body more time to absorb sugar into the bloodstream Unlike other fats, trans fats provide no health benefits and increase the risk of many diseases Evidence on the effects of high trans-fat intake on insulin resistance appears to be mixed.

Some human studies have found it harmful, while others have not 33 , Many different supplements can help increase insulin sensitivity, including vitamin C , probiotics , and magnesium. That said, many other supplements, such as zinc, folate, and vitamin D, do not appear to have this effect, according to research As with all supplements, there is a risk they may interact with any current medication you may be taking.

Insulin is an important hormone that has many roles in the body. When your insulin sensitivity is low, it puts pressure on your pancreas to increase insulin production to clear sugar from your blood. Low insulin sensitivity is also called insulin resistance.

Insulin sensitivity describes how your cells respond to insulin. Symptoms develop when your cells are resistant to insulin.

Insulin resistance can result in chronically high blood sugar levels, which are thought to increase your risk of many diseases, including diabetes and heart disease. Insulin resistance is bad for your health, but having increased insulin sensitivity is good.

It means your cells are responding to insulin in a healthier way, which reduces your chance of developing diabetes. Consider trying some of the suggestions in this article to help increase your insulin sensitivity and lower your risk of disease but be sure to talk with a healthcare professional first before making changes, especially adding supplements to your treatment regimen.

Read this article in Spanish. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. VIEW ALL HISTORY. This article is based on scientific evidence, written by experts and fact checked by experts.

Our team of licensed nutritionists and dietitians strive to be objective, unbiased, honest and to present both sides of the argument. This article contains scientific references.

The numbers in the parentheses 1, 2, 3 are clickable links to peer-reviewed scientific papers. Has taking insulin led to weight gain for you? Learn why this happens, plus how you can manage your weight once you've started insulin treatment.

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Oct 30, Written By Ryan Raman. Sep 18, Medically Reviewed By Kelly Wood, MD. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Nestel, P. Effects of increasing dietary palmitoleic acid compared with palmitic and oleic acids on plasma lipids of hypercholesterolemic men.

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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.

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

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

XZ and XA drafted the figures, and all authors approved the final version of the manuscript. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy. All authors contributed to the article and approved the submitted version.

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

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

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

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This condition alters cellular metabolism and intracellular signaling that negatively impact cells. In the cardiomyocyte, this damage can be summarized into three actions: 1 alteration in insulin signaling. All these effects induce cellular events including: 1 gene expression modifications, 2 hyperglycemia and dyslipidemia, 3 activation of oxidative stress and inflammatory response, 4 endothelial dysfunction, and 5 ectopic lipid accumulation, which, favored by obesity, perpetuates the metabolic deregulation.

Overall, insulin resistance contributes to generate CVD via two independent pathways: 1 atheroma plaque formation and 2 ventricular hypertrophy and diastolic abnormality.

Both effects lead to heart failure. Future research is needed to understand the precise mechanism between insulin resistance and its progression to heart failure with a focus on new therapy development.

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Mol Metab. Mandavia CH, Aroor AR, Demarco VG, Sowers JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. Download references. VO, SN, OE, CA and FZ conducted a review of the literature and contributed to conception and design and wrote the first draft the review; CS contributed to conception and design of the article and critically reviewed the drafts of the manuscript.

All authors read and approved the final manuscript. This study was supported by Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT , Lions Medical Research Foundation Australia , and Diabetes Australia. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile. Faculty of Pharmacy, Department of Clinical Biochemistry and Immunology, University of Concepcion, Concepción, Chile.

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A relatively safe and well accepted approach in the prevention and treatment of IR is via lifestyle interventions. Nutritional intervention is an important first step that emphasizes a low-calorie and low-fat diet that stimulates excessive insulin demands. In addition, increased physical activity is recommended to help increase energy expenditures and improve muscle insulin sensitivity, this two approach represent the fundamental treatment for IR.

In this review, the mechanism of insulin action and IR are first described to promote the development of new therapeutic strategies.

Further, the direct and indirect effects of insulin on target tissues are discussed to better understand the pivotal role of tissue crosstalk in systemic insulin action. Lastly, diseases associated with IR are discussed and summarized. Many methods and multiple surrogate markers have been developed to calculate the IR.

We then summarize the current measurements and potential biomarkers of IR to facilitate the clinical diagnosis. Finally, we provide the general approaches including lifestyle intervention, specific pharmacologic interventions and clinical trials to reduce IR.

Insulin is an endocrine peptide hormone with 51 amino acids and composed of an α and a β chain linked together as a dimer by two disulfide bridges 18 along with a third intrachain disulfide bridge in the α chain.

Accumulation of reports have demonstrated that IR is a complex metabolic disorder with integrated pathophysiology. The exact causes of IR has not been fully determined, 36 , 37 , 38 but ongoing research seeks to better understand how IR develops. Here, we focus on the underlying mechanism of IR including direct defective of insulin signaling, epidemiological factors, interorgan metabolic crosstalk, metabolic mediators, genetic mutation, epigenetic dysregulation, non-coding RNAs, and gut microbiota dysbiosis.

As has been mentioned, the proper modulators acting on different steps of the signaling pathway ensure appropriate biological responses to insulin in different tissues. Thus, the diverse defect in signal transduction contributes to IR.

Insulin exerts its biological effects by binding to its cell-surface receptors, therby activating specific adapter proteins, such us the insulin receptor substrate IRS proteins principally IRS1 and IRS2 , Src-homology 2 SH2 and protein-tyrosine phosphatase 1B PTP1B , eventually promoting downstream insulin signaling involving glucose homeostasis.

Most individuals that are obese or diabetic exhibit decreased surface INSR content and INSR kinase IRK activity. Second, decreased expression or serine phosphorylation of IRS proteins 44 , 45 can reduce their binding to PI3K, thereby down-regulating PI3K activation and inducing apparent IR.

It is generally accepted that diverse downstream targets of Akt activation lead to different distal signaling in target tissues response to insulin. Different investigations have indicated that premenopausal women exhibit many less metabolic disorders than men, including lower incidence of IR, although this effect diminishes severely when women reach the postmenopausal situation.

Concomitantly, clinical and experimental observations 70 , 71 have revealed that endogenous estrogens can protect against IR primarily through ER-α activation in multiple tissues, including in the brain, liver, skeletal muscle, and adipose tissue, in addition to pancreatic β cells.

Further, female hormone estrogens are determinants that mediate body adiposity levels and body fat distribution in addition to glucose metabolism and insulin sensitivity.

Specifically, insulin sensitivity and capacities for insulin responses in women is significantly higher than men. Male homozygous for the polymorphism of PPP1R3A gene that involved in glycogen synthase activity are significantly younger at diagnosis than female.

Thus, additional studies are required to understand mechanisms underlying sex differences and IR development. South Asian children exhibit greater IR compared with white European children, while girls are more insulin resistant than boys, with sex and ethnicity differences related to insulin sensitivity and body composition.

Despite the above objective factors, some modifiable lifestyle factors including diet, exercise, smoking, sleep and stress are also considered to contribute to IR.

Further, circadian clocks disruption might also be an important factor to IR development via various factors including clock gene mutations, disturbed sleep cycles, shift work and jet lag. Different investigations suggest that vitamin D supplementation might reduce IR in some people due to increasing insulin receptor genes transcription and anti-inflammatory properties, 95 while some researchers found that Vitamin D has no effect on IR.

Both experimental animals and clinical studies have shown that many hormones can induce IR including glucocorticoids GCs , 97 cortisol, 98 growth hormone, 99 and human placental lactogen, which may decrease the insulin-suppressive effects on glucose production and reduce the insulin-stimulated glucose uptake.

Several other clinical medications including anti-adrenergic such as salbutamol, salmeterol, and formoterol , HIV protease inhibitors, , atypical antipsychotics and some exogenous insulin that may improve IR because of the disordered insulin signaling. All together, there may have synergistic effects of different risk factors on insulin resistance, scientific researchers should cooperate with medical experts to reduce the chances of becoming insulin resistant.

As discribed above, insulin signaling calibrates glucose homeostasis by limiting hepatic glucose output via decreased gluconeogenesis and glycogenolysis activities.

These processes consequently increase the glucose uptake rates in muscle and adipose tissues. In addition, insulin profoundly affects lipid metabolism by increasing lipid synthesis in liver and fat cells Fig. Despite stimulated glucose uptake, insulin rapidly reduces hepatic glucose output and hepatic glucose production HGP by activating glycogen synthesis, and suppressing glycogenolysis and gluconeogenesis in liver.

Insulin induces SREBP-1c maturation via a proteolytic mechanism started in the endoplasmic reticulum ER , wherein hepatic IR is highly associated with hepatic steatosis.

Accordingly, restoration of nuclear SREBP-1c expression in liver-specific Chrebp defective mice normalized expression of some lipogenic genes, while not affecting glycolytic genes expressing. In contrast, ChREBP overexpression alone failed to promote the expression of lipogenic genes in the livers of mice lacking active SREBPs.

Together, these data demonstrate that SREBP-1c mediates the induction of insulin lipogenic genes, but that SREBP-1c and ChREBP are both necessary for harmonious induction of glycolytic and lipogenic genes. Altogether, these above pathways and components can be used to clarify the popular pathophysiology of hepatic IR.

The lipid metabolisms including increased de novo lipogenesis and attenuation of lipolysis in the adipose tissue largely coordinate with glucose homeostasis response to insulin stimulation. De novo lipogenesis regulation in adipose is similar to that in livers, wherein adipose-ChREBP is a major determinant of adipose tissue fatty acid production and systemic insulin sensitivity, that is induced by GLUT4-mediated glucose uptake, and genetically ablating ChREBP impairs insulin sensitivity in adipose tissue In addition, lipogenic gene FASN and DGAT mRNA expression in adipose tissue have been shown to correlate strongly and positively with insulin sensitivity, which were may reduced by larger adipocytes in adipose tissue of obese individuals.

The lipogenesis stimulation of insulin is also reduced in larger, more insulin-resistant cells. Insulin suppression of lipolysis includes the hydrolytic cleavage of triglycerides, resulting in the generation of fatty acids and glycerol. The best understood effectors for this process are PDE3B and ABHD15 that operated by the suppression of cAMP to attenuate pro-lipolytic PKA signaling toward adipose triglyceride lipase ATGL , hormone-sensitive lipase HSL , and perilipin PLIN.

Further, inhibition of PDE3B inhibits insulin-induced glucose uptake and antilipolysis. Insulin stimulated protein synthesis is mediated by activation of the protein kinases Akt and mTOR specifically mTORC1 and mTORC2 in numerous insulin-responsive cell types, such as hepatocytes, adipocytes, and myocytes.

Inhibition of mTOR by rapamycin obviously impairs insulin-activated protein synthesis. Amino acids metabolic substrates enhance insulin sensitivity and responsiveness of the protein synthesis system by increasing mTOR activity and inhibiting protein degradation in liver, muscle, and heart tissues.

These processes, in turn, promote protein synthesis and antagonize protein degradation. Adiponectin is the most abundant protein secreted by adipose tissue and exhibits potent anti-inflammatory properties. Moreover, targeted disruption of AdipoR1 results in halted adiponectin-induced AMPK activation, increased endogenous glucose production and increased IR.

Similarly, AdipoR2 deletion results in decreased PPAR-α signaling pathway activity and IR. In addition, chemerin is a chemokine highly expressed in liver and white adipose tissue that regulates the expression of adipocyte genes involved in glucose and lipid homeostasis like IRS-1 tyrosine phosphorylation activity, GLUT4, fatty acid synthase and adiponectin.

Thus, chemerin may increase insulin sensitivity in adipose tissue. Leptin is a cytokine encoded by ob gene and produced by the adipocytes. In summary, adipose tissue is a central node for distinct adipokines and bioactive mediators in IR pathophysiology. Consequently, identifying the effects of new adipokines will help in the development of new therapeutic strategies for obesity-induced diseases.

The specific insulin actions in adipose tissue include activation of glucose uptake and triglyceride synthesis, suppression of triglyceride hydrolysis and free fatty acids FFA and glycerol release into the blood circulation. Once the adipose tissue expandability exceeded limit under overnutrition, excess lipids and toxic lipid metabolites FFA, diacylglycerol, ceramide accumulated in non-adipose tissues, thus leading to lipid-induced toxicity lipotoxicity and developed IR in liver and muscle.

This process would in turn induce increased intracellular citrate levels, thereby inhibiting glucosephosphate G6P accumulation. Increased G6P levels then result in decreased hexokinase activity, increased glucose accumulation, and reduced glucose uptake. Other studies have demonstrated the relevance of the glucose-fatty acid cycle to lipid-induced IR.

For example, lipid infusions combined with heparin can be used to activate lipoprotein lipase, thereby increasing plasma concentrations of fatty acids. Further, these infusions promote muscle lipid accumulation and effectively induce IR.

Consistent with the above studies, elevated plasma fatty acid concentrations can result in increased intracellular diacylglycerol DAG levels, leading to the activation of protein kinase C isoform PKC-θ and PKC-ε isoforms in skeletal muscles and liver respectively.

Since diacylglycerol acyltransferase 1 DGAT1 can increase the conversion of DAG into triacylglycerol TAG , DGAT1 overexpression could decrease DAG levels and improve insulin sensitivity partially attenuating the fat-induced activation of DAG-responsive PKCs.

Taken together, these studies strongly support that DAG as a key intermediate of TAG synthesis from fatty acids has central modulation and potential therapeutic values in IR. Ceramide is another specific lipid metabolite that increases in concentration, along with DAG, in association with IR in obese mice.

Thus, ectopic lipid metabolite concentrations e. Consequently, concerted efforts to decrease lipid components in these organs are the most efficacious therapeutic targets for treating IR and metabolic diseases.

Some human genetic studies indicated that different genomic loci were associated with fasting insulin levels, higher triglyceride and lower HDL cholesterol levels, , which are different hallmarks of IR. The peroxisome proliferator-activated receptor gamma PPARγ variant Pro12Ala was one of the first genetic variants identified that is involved in fatty acid and energy metabolism and that is associated with a low risk of developing T2DM.

Nevertheless, additional studies are needed to assess the functional relationships between the genetic variants and IR, that are also influenced by various lifestyle and environmental factors. Recent studies have suggested that epigenetic modifications such as DNA methylation DNAm and histone post-translational modifications PTM are implicated in the development of systemic IR.

Global and site-specific DNA methylation is generally mediated by DNA methyltransferases DNMTs. These processes mainly occur in the context of CG dinucleotides CpGs and promoter region, while also involving covalent addition or removal of methyl groups as a means to repress or stimulate transcription, respectively.

For example, increased INS promoter methylation levels and INS mRNA suppression were observed under over-nutrition conditions and obese T2DM patients.

Another study demonstrated that increased IGFBP2 DNA methylation levels were are associated with lower mRNA expression levels in Visceral Adipose tissue VAT of abdominal obesity.

Moreover, the first global genome-wide epigenetic analysis in VAT from IR and insulin-sensitive IS morbidly obese patients identified a novel IR-related gene, the zinc finger protein ZNF exhibited the highest DNA methylation difference, and its methylation levels is lower in IR patient than in IS patient, consistent with increased transcription levels, such studies provide potential epigenetic biomarkers related to IR in addition to novel treatment targets for the prevention and treatment of metabolic disorders.

For example, peroxisome proliferator-activated receptor-α and -γ PPAR-α and PPAR-γ, respectively are encoded by PPARA and PPARG , respectively, and they are the two primary nuclear peroxisome proliferator-activated receptors involved in lipid metabolism. Higher PPARA and PPARG methylation levels were observed in association with obesity, consistent with decreased PPAR-α and PPAR-γ protein expression levels, that lead to dyslipidemia and IR.

SLC19A1, a gene encoding a membrane folate carrier, was reduced in obese WAT and induced global DNA hypermethylation of chemokine C-C motif chemokine ligand 2 CCL2 that is a key factor in WAT inflammation, resulting in increased CCL2 protein secretion and the development of IR in obese. In addition, several genes methylation involved in hypoxia stress and endoplasmic reticulum stress were regulated in obesity related metabolic diseases.

Recent epigenetic genome-wide analysis identified low HIF3A methylation levels upregulates HIF3A expression in adipose tissue, thereby leading to adipose tissue dysfunction and adiposity.

Ramos-Lopez et al. Specifically, increased insulin concentrations and HOMA-IR index were accompanied by lower ERO1LB and NFE2L2 methylation levels. The histone modification effect on gene expression mainly includes histones methylation and acetylation. Histone methylation could either activate gene transcription H3K4, H3K36, and H3K79 or silence gene expression H3K9 and H3K27 , which depends on the modification site.

Histone acetylation increases the accessibility and gene expression of various transcription factors by reducing the positive charge and histone affinity for DNA.

Increasing evidence indicates , that IGFR, InsR, IRS1, Akt, GLUT4, and PPAR are more deacetylated in association with IR than in normal physiological conditions. In contrast, IRS2, FoxO, JNK, and AMPK are usually acetylated in association with IR.

Castellano-Castillo, D. Further, global proteomic analyses have revealed 15 histone modifications that are differentially abundant in hepatic IR.

MicroRNAs miRNAs are small ncRNAs nucleotides incorporated into Argonaute Ago protein to form miRISCs, which can inhibit the expression of partially or completely complementary target mRMAs. Several miRNAs are involved in β cell differentiation and mature β cell functioning.

For example, islet-specific miR overexpression represses glucose-stimulated insulin secretion GSIS and insulin gene transcription, that is then reversed upon miR inhibition. Thus, these markers may improve disease prediction and prevention in individuals at high risk for T2DM.

Furthermore, pdx1, neurogenin-3 ngn3 , and a transcriptional factor essential for insulin transcription MafA are essential transcription factors for β-cell differentiation.

Thus, miRa2 can directly modulate insulin expression through foxA2 and then pdx1. miR expression is induced by the cellular redox regulator thioredoxin-interacting protein TXNIP that then represses MafA, thereby inhibiting insulin production. Numerous studies suggest that miRNAs have pivotal roles in glucose and lipid metabolism.

miR was first reported to directly regulate GLUT4 expression in adipocytes. In addition, the anti-diabetic drug metformin can up-regulate miRp expression to suppress G6Pase and inhibit hepatic gluconeogenesis.

The balance of low-density lipoprotein LDL and high-density lipoprotein HDL molecules that are synthesized in hepatocytes is critical for lipid homeostasis.

Many miRNAs have been identified as critical regulators of HDL and LDL biogenesis. For example, miR, miR, miR, and miRa repress expression of the ATP-binding cassette transporter ABCA1 that mediates hepatic HDL generation.

In addition, miRc targets the gene encoding microsomal triglyceride transfer protein MTP that is required for the lipidation of newly synthesized APOB in the liver for LD lipoprotein production.

miRc overexpression reduces the assembly and secretion of these APOB-containing lipoproteins, resulting in decreased plasma LDL levels. miRa and miR repress LDLR expression and inhibition of these miRNAs results in enhanced LDLR expression and clearance of circulating LDL.

Further, miR and miRd target the LDLR chaperonin PCSK9 and IDOL in addition to the rate-limiting enzyme in cholesterol biosynthesis, HMGCR. Chronic inflammation in insulin-reactive tissues is one of the most important causes of IR and increasing evidence suggests that miRNAs has a pivotal role in the inflammatory process.

Obesity inhibited miR expression in adipose tissue macrophages ATMs , and miR was shown to target Delta-like-4 DLL4 , a Notch1 ligand is associated with ATM inflammation. Conversely, Wang et al.

discovered that miRp is significantly upregulated in Natural killer NK cells-derived exosomes from lean mice, which directly targets SKI family transcriptional corepressor 1 SKOR1 , subsequently downregulated the expression levels of pro-inflammatory cytokine factors including IL-1β, IL-6, and TNF-α levels and attenuated IR.

Therefore, it might be that metabolism-regulating miRNAs play a vital role in the dynamics of metabolic homeostasis. Long non-coding RNAs lncRNAs are non-coding transcripts more than nucleotides, and the subcellular localization of lncRNAs determines their function.

LncRNAs located in the nucleus could affect chromosomal biology or interact with transcription factors to regulate gene transcription; lncRNAs located in cytosol could modulate mRNA stability and translational efficiency by acting as sponges for miRNAs or direct pairing with mRNA.

Recent advances have shown that lncRNAs play crucial roles in the pathologys of IR and diabetes. Glucose and lipid metabolism disorders are the primary causes for the pathophysiological development of IR. The lncRNA SRA promotes insulin-stimulated glucose uptake by co-activating PPARγ, leading to increased phosphorylation of the downstream targets Akt and FOXO1 in adipocytes.

These processes are closely related to the genes PGC1a and CPT1b that reverse FFA-induced lipid accumulation and improve IR. In addition the insulin target tissues, transcriptome profiling and different studies have identified several β-cell specific lncRNAs that contribute to obesity-mediated β-cell dysfunction and apoptosis.

LncRNA MALAT1 downregulation may lead to pancreatic β-cell dysfunction and T2DM development by direct interaction and regulation of polypyrimidine bundle binding protein 1 PTBP1. Further, lncRNA-p overexpression can decrease the β cell apoptosis ratio and partially reverse the glucotoxicity effects on GSIS function.

Contrary to conventional linear RNA, circRNAs are noncoding RNAs that generated from precursor mRNAs by back-splicing circularization, which is derived from exonic circRNAs, intronic circRNAs, exonic-intronic circRNAs and ntergenic circRNAs.

Recent studies have suggested that newly identified circRNAs are novel factors in the initiation and development of IR. CircHIPK3 is one of the most abundant circRNAs in β-cells and regulates hyperglycemia and IR by sequestering miRp and miRp, thereby increasing mRNA expression of key β-cell genes e.

Similar to the miRNAs and lncRNAs, several circRNAs also contribute to the the regulation of glucose and lipid homeostasis. Deep sequencing analysis of adipose circRNA revealed that circArhgap is highly upregulated during differentiation of human white adipocytes.

Thus, circRNAs likely serve as important regulators of adipocyte differentiation and lipid metabolism. Another circRNA deep sequencing analysis of sera from patients with metabolic syndrome MetS identified the presence of a novel circRNA, circRNF, involved in MetS progression.

AMPK is a critical factor in energy homeostasis including glycolysis, lipolysis, and fatty acid oxidation FAO. CircACC1 is a circRNA derived from the human acetyl-CoA carboxylase 1 ACC1 gene and directly binds to the β and γ subunits of AMPK, facilitating its activity, and promoting glycolysis and fatty acid β-oxidation during metabolic stress.

circMAP3K4 is another potentially important circRNA involved in glucose metabolism that is highly expressed in the placentas of patients with gestational diabetes mellitus GDM and the IR model.

Nevertheless, the exact roles and regulatory mechanisms of circRNAs in IR require additional clarity. The microbes living in the human gut are key contributors to host metabolism and immune function through mediating the interaction between the host and environment, or releasing metabolites and cytokines.

Different factors influencing these alterations of gut microbiome composition have been explored including diet, exercise, circadian disruption, antibiotics treatments, and genetics. The gut microbial communities of the groups significantly diverged over time, with participants on animal diets experiencing proliferation of bile-tolerant microorganisms e.

For example, microbiome genome-wide association studies mGWAS have identified that variants of different genes for example, VDR , LCT , NOD2 , FUT2 , and APOA5 that are associated with distinct gut microbiome compositions. Growing evidence in the last two decades has suggested that gut microbial dysbiosis contributes to increased risks of metabolic defects like obesity, IR, and diabetes.

LPS circulation then contributes to the chronic inflammation of liver and adipose tissue that is associated with the development of IR, in addition to other conditions associated with metabolic syndromes. As we all know, IR is a state in which higher than normal concentrations of insulin are needed for a normal response, leading directly to hyperinsulinaemia and impaired glucose tolerance.

Non-alcoholic fatty liver disease NAFLD is one of the most common liver diseases worldwide. Adipose tissue is a physiologic reservoir of fatty acids, when the storage capacity is exceeded, the accumulation of heterotopic lipids leads to lipotoxicity, thereby promoting low-grade inflammation and IR in the liver.

Lipotoxic injury appears to occur in response to excessive levels of serum free fatty acids FFAs in hepatocytes. At present, the molecular mechanism of insulin in PCOS has been well described. Such modifications then activate NF-κB that is involved in the expression of proinflammatory mediators such as TNF and IL-6, , and that induces key steroidogenic molecules, like CYP11A1, CYP17A1 and StAR, leading to further aggravation of hyperandrogenemia.

Cardiovascular diseases CVDs are the leading causes of death globally. The World Health Organization estimates that Moreover, over 23 million people are estimated to die from CVDs each year by However, the most common types of CVDs include high blood pressure, coronary artery disease CAD , stroke, cerebrovascular disease and rheumatic heart disease RHD.

Identifying new therapies to reduce IR may contribute to the reduced prevalence of CVDs. Insulin primarily enters the brain via selective, saturable transport across the blood-brain barrier BBB , , Peripherally produced insulin can also be actively transported into the brain via an endocytic-exocytic mechanism.

Current researches have demonstrated that the mechanisms of systemic IR and brain-specific IR have close links with AD pathogenesis. Pioglitazone acts similarly as Rosiglitazone by reducing tau and Aβ deposits in the hippocampus, and improving neuronal plasticity and learning in AD.

Moreover, overlapping pathological features exist for diabetes, IR, and AD. Chronic kidney disease CKD involves a gradual loss of kidney function and inability to filter blood , and is a major risk factor for end-stage kidney failure ESKF and CVDs.

Numerous recent epidemiological studies have suggested that IR increases the risks for different cancers including colon, liver, pancreas, breast, endometrium, thyroid and gastric cancer. Further, a growing body of evidence suggests that increased insulin, in addition to IGF1 and IGF2 levels critically influence tumor initiation and progression in IR patients.

As we all know, IR is related to several metabolic abnormalities including obesity, glucose tolerance, dyslipidemia, type 2 diabetes and other metabolic syndrome.

Actually, IR precedes the occurrence of T2DM, so how to increase the accurate assessment of insulin sensitivity is very important to predict the risk and evaluate the management of impaired insulin sensitivity and metabolic syndrome in research and clinical practice. HOMA2 updated HOMA model which took account of variations in hepatic and peripheral glucose resistance , homeostatic Model Assessment for IR HOMA-IR , the oral glucose insulin sensitivity index OGSI , fasting Insulin FINS , and fasting plasma glucose FPG based on fasting glucose and insulin levels , , , , are widely utilized IR measurements in clinical research.

Other indices based on fasting insulin include the glucose to insulin ratio GIR , the quantitative insulin sensitivity check index QUICKI , , , triglycerides McAuley Index alone or in accordance with HDL cholesterol HDL-C , whole-body insulin sensitivity index WBISI , Matsuda Index to evaluate whole body physiological insulin sensitivity by the above methods.

Indeed, the early symptoms of IR in different individuals are not obvious, and the related symptoms are very complex, combining with screening indicators may provide more precise diagnosis for IR in the general population.

No medications exist currently that are specifically approved to treat IR, but IR management 91 , , is possible through lifestyle changes like dietary, increased exercise, and disease prevention in addition to alternative medications Fig. Among these treatments, lifestyle changes should be the main focus for IR treatment, with nutritional intervention to decrease calories, avoidance of carbohydrates, and focusing on aliments with low glycemic index including vegetables, fruits, whole-grain products, nuts, lean meats or beans to provide higher fiber, vitamins, healthy fats and protein are particularly helpful for people trying to improve insulin sensitivity.

Table 1. Metformin is a first-line medication and the most widely-prescribed insulin-sensitizing agent in T2DM and PCOS patients. For example, 1 Glucagon-like peptide 1 GLP1 is an intestinal hormone that can enhance insulin secretion in a glucose-dependent manner by activating the GLP-1 receptor GLP-1R that is highly expressed on islet β cells.

are now world-wide therapy of T2DM since and could improve insulin sensitivity. In clinical research, scientists and physicians have explored different strategies to prevent and treat diabetes mellitus and IR.

gov to reduce IR and summarized them mainly include: 1 Diet intervention, such as Low-fat vegetarian Food, high-protein food, calorie restriction, vitamin D supplementation to reduce the IR in human obesity.

We present some clinical trials of IR intervention in Table 2. Over the past years, our knowledge of the pathogenesis of IR and T2DM has improved, the development of new treatments of IR and metabolic syndrome have gained certain success, while the complexity of IR and the presence of multiple feedback loops make a challenge to the specific intervention.

In recent years, accumulating preclinical studies on the intervention of IR have been reported, which have important reference significance for the development of new drugs.

We present the related studies on IR reported in recent years in Table 3 , including animal models, treatment methods and results.

Pre-clinical IR intervention mainly includes drug intervention, probiotic therapy and exercise supplement. Drug therapy to improve IR is the main research direction at present.

Researchers found that Valdecoxib VAL can inhibit inflammation and endoplasmic reticulum ER stress through AMPK-regulated HSPB1 pathway, thus improving skeletal muscle IR under hyperlipidemia.

The researchers found that the mixed nasal administration of GLP-1 receptor agonist and L-form of peneracin can effectively alleviate the cognitive dysfunction of SAMP8 mice. Natividad et al. Regular exercise is an alternative intervention measure to maintain the blood sugar level in the normal range and reduce the risk factors.

Hsu and colleagues found that exercise combined with probiotics intervention can have a positive effect on blood sugar and increase insulin sensitivity in mice. The above results show that drug intervention, probiotic supplementation and intensive exercise can improve IR but more clinical data are still needed.

Overall, the increased incidence of IR and the key roles of IR plays in many diseases, urgently require a better understanding of IR pathogenesis in addition to how IR interacts with genetics and different environments.

A deeper understanding of IR can be achieved with a more systematic approach involving large-scale omics to study the molecular landscape is of major importance in addition to exploring new intervention strategies to prevent abnormal IR syndrome.

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More from Oxford Academic. Clinical Medicine. Endocrinology and Diabetes. Medicine and Health. 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.

In recent years, the exploration of the molecular mechanisms of IR has also led to the emergence of new therapeutic concepts beyond metformin and TZD.

Regardless lifestyle modification remains the most basic and least costly intervention. Normative criteria need to be developed for different metabolic diseases considering IR as a focus. FL and HJ provided the idea of the manuscript. XZ, XA, and CY contributed equally to this manuscript.

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

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

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

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

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