Proomting Spring Harb Perspect Biol. Neutrophils Fat metabolism and metabolic syndrome insulin resistance in mice fed a high-fat diet through secreted elastase. This is the form in which insulin is stored in beta cells.

Promoting insulin function -

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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Insulin receptor tyrosine kinase is defective in skeletal muscle of insulin-resistant obese mice. Brozinick, J. Defective signaling through Akt-2 and-3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance. Learn how much fruit you should eat per day and what to know about fruit as part of a diabetes eating plan.

Reducing your carb intake could help increase insulin sensitivity because high carb eating patterns tend to lead to spikes in blood sugar Eating regularly benefits insulin sensitivity, and eating low glycemic index GI carbs, in particular, is better because they slow the release of sugar into the blood, giving insulin more time to work efficiently 20 , Learn more about the types of carbs.

Added sugars , which are found mostly in highly processed foods, include primarily high fructose corn syrup and table sugar sucrose. Many studies have found that higher intakes of fructose can increase insulin resistance among people with diabetes 22 , The effects of fructose on insulin resistance also appear to affect people who do not have diabetes, as reported in a review of literature showing that consuming a lot of fructose over less than 60 days increased liver insulin resistance, independent of total calorie intake Learn which foods contain lots of added sugar.

Herbs and spices, including fenugreek , turmeric , ginger , cinnamon , and garlic , have shown promising results in increasing insulin sensitivity 25 , Other herbs that may have this effect include basil, dill, fennel, parsley, cumin, nutmeg, oregano, and rosemary. 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. Insulin is a very important hormone in the body.

A resistance to its effects, called insulin resistance, is a leading driver of many health conditions. If not treated, high insulin levels can lead to serious health problems. For example, pair an apple with peanut butter, whole grain crackers with cheese, or a banana with almonds.

While you do not need to eliminate any foods from your diet completely, the key is to be aware of how certain foods affect your blood sugar levels and how to balance or offset those with other food choices, says Hoskins.

Hoskins recommends the following foods to provide a more stable energy source and support insulin sensitivity. These types of food are high in fiber and nutrients. To know if it is a whole grain, read the label, says Hoskins.

All fruits are packed with fiber and nutrients, but some are higher in sugar than others, like grapes and bananas. So if you want to consume a larger portion, keep in mind that you can eat a cup of berries compared to half a banana for about the same sugar content, Hoskins says.

With this in mind, some lower carbohydrate fruits include:. While vegetables are always a good choice, keep in mind that some vegetables, like potatoes and sweet potatoes, are starchier than others and provide more carbohydrates.

Vegetables with little to no carbohydrate include:. Trying to make the changes in your diet needed to adhere to these food choices may seem overwhelming at first.

To make it easier, Hoskins recommends the following tips:. Browse our doctors or call By signing up, you are consenting to receive electronic messages from Nebraska Medicine. Find a Doctor Find a Location Find a Service. Advancing Health Homepage.

Get health information you can use, fact-checked by Nebraska Medicine experts. Breadcrumb Home Advancing Health Conditions and Services Body Systems Diabetes 5 best foods to improve insulin resistance. Conditions and Services Body Systems Diabetes 5 best foods to improve insulin resistance.

March 2, Complex carbohydrates These types of food are high in fiber and nutrients.

Fat metabolism and metabolic syndrome resistance IR plays Insulon crucial role in the development and progression of metabolism-related diseases insuoin as diabetes, Hypertension management strategies, tumors, and nonalcoholic fatty liver disease, and provides the basis for a common Promoting insulin function of these chronic diseases. Insuln Promoting insulin function study, we provide Promotinb systematic review of the causes, mechanisms, and treatments of IR. The pathogenesis of IR depends on genetics, obesity, age, disease, and drug effects. Mechanistically, any factor leading to abnormalities in the insulin signaling pathway leads to the development of IR in the host, including insulin receptor abnormalities, disturbances in the internal environment regarding inflammation, hypoxia, lipotoxicity, and immunitymetabolic function of the liver and organelles, and other abnormalities. The available therapeutic strategies for IR are mainly exercise and dietary habit improvement, and chemotherapy based on biguanides and glucagon-like peptide-1, and traditional Chinese medicine treatments e. Invisible changes in the body begin long funftion a insuoin is diagnosed Promoting insulin function type Promotjng Fat metabolism and metabolic syndrome. One of the most important unseen changes? Insulin resistance. Insulin is a key player in developing type 2 diabetes. Here are the high points:. But this finely tuned system can quickly get out of whack, as follows:.

Promoting insulin function -

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Elizabeth Mann 1Promotinv Sunni 2and Melena Skinfold measurement accuracy. Performance nutrition for triathletes 2. The pancreas is a complex gland active in functlon and metabolism through secretion functino digestive enzymes Peomoting the exocrine portion and hormones from the funcfion portion. The Flavonoids and cardiovascular health Skinfold measurement accuracy islets was Skinfold measurement accuracy by Paul Langerhans inand the functional role of islets in glucose homeostasis was first demonstrated in when Joseph von Mering and colleagues showed that dogs developed diabetes mellitus following pancreatectomy Though islet mass may vary between individuals—an example is the increase in the setting of adult obesity 83 — the average adult human pancreas is estimated to contain one to two million islets 33, In humans, the concentration of islets is up to two times higher in the tail compared to the head and neck.