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Promoting insulin function

Promoting insulin function

Banting and Promoting insulin function presented functiin results ffunction Macleod Promoting insulin function his return to Toronto Aging gracefully lifestyle the fall ofbut Macleod pointed insuoin flaws with the experimental design, and suggested the experiments be repeated with more dogs and better equipment. What is hyperglycemia? By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia. Effects of growth hormone on insulin action in man: mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization. Learn which foods contain lots of added sugar.

Promoting insulin function -

Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase eNOS. Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy.

In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production.

The detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.

Peer Review reports. Most endocrine hormones exhibit a window of optimal physiological concentrations, with compromised function of the organism at levels below or above that range.

For instance, subnormal levels of thyroid hormone define the clinical condition of hypothyroidism, above normal levels represent hyperthyroidism which usually requires therapy.

For insulin, we argue here that not only hypoinsulinemia but also hyperinsulinemia is detrimental to body functions. Hypoinsulinemia causes insulin-deficient diabetes, and the hormonal actions of insulin are necessary for the life of complex organisms [ 1 ].

On the other hand, permanently elevated levels of insulin may cause disturbance of normal cellular physiology and organ function. We describe the molecular basis of these undesired insulin actions and consequences of hyperinsulinemia for health-relevant endpoints, such as obesity or cardiovascular diseases.

Binding of insulin to its cognate cell surface-bound receptor causes a conformational change which initiates a cascade of signaling events. Autophosphorylation by the insulin receptor tyrosine kinase is accompanied by tyrosine phosphorylation of receptor substrates, such as insulin receptor substrate IRS and Src homology 2 domain-containing transforming proteins SHC proteins.

Upon activation, AKT interacts with several substrates which mediate anabolic effects of insulin; these include glucose uptake, glycogen synthesis, de novo lipogenesis, and protein synthesis [ 2 ]. Additional pathways triggered by the activated insulin receptor comprise phosphorylation of SHC, followed by activation of the Rat sarcoma Ras —rapidly accelerated fibrosarcoma Raf —mitogen-activated protein kinase kinase MEK —extracellular signal-regulated kinase ERK pathway.

The terminal kinase ERK is a mitogen-activated kinase promoting cell proliferation and further cellular activities including protein synthesis [ 3 ].

Another pathway triggered by the engaged insulin receptor involves activation of NADPH oxidase 4 and subsequent hydrogen peroxide-mediated inhibition of phosphatase and tensin homolog PTEN , which is an important negative regulator of PI3K signaling [ 4 ] Fig.

Metabolic signaling of insulin is anabolic. Insulin signaling through the insulin receptor engages several pathways and results in an anabolic state of metabolism.

In addition, AKT kinases activate mTORC1 which supports de novo lipogenesis and protein synthesis. The insulin signaling pathway via SHC and the MAP kinases MEK and ERK promotes cell proliferation and protein synthesis.

Another insulin signaling pathway involves NOX4 and the inhibition of PTEN, an inhibitor of the PI3K-AKT pathway. Insulin secretion by pancreatic islet β cells responds to the level of circulating nutrients such as glucose, amino acids, and free fatty acids.

Sweeteners may further increase carbohydrate-induced insulin secretion. A large number of endogenous factors contribute to the regulation of β cell activity, either stimulatory, inhibitory, or both context-dependent. These include hormones, neurotransmitters, and immune mediators [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ].

Insulin is essential for maintaining glucose homeostasis, primarily by facilitating the post-meal uptake of glucose into muscle and fat cells via translocation of the glucose transporter 4 [ 13 ]. In the absence of dietary glucose supply and after depletion of glycogen stores, glucose in circulation primarily comes from gluconeogenesis in the liver.

If circulating insulin levels are below the concentrations required for stimulating glucose uptake from the blood, endogenous stores of fat and protein must be used for energy production. For the maintenance of life in the fasting state, circulating insulin levels range between approx.

In response to meals with varying carbohydrate content, insulin levels may rise to the range of approx. Almost years ago, insulin injections were one of the options of therapy in nondiabetic persons suffering from undernutrition in the context of various diseases.

Insulin doses were in the range of those applied in type 1 diabetes and led to increased appetite and weight gain [ 16 ]. Indeed, one major function of insulin as an anabolic hormone is to favor energy storage over usage. Doubling fasting insulin levels suffices to inhibit lipolysis by approx.

At this insulin level, gluconeogenesis is still ongoing. For half-maximal inhibition of gluconeogenesis, insulin concentrations must rise to approx. In order to stimulate glucose uptake to half maximum, insulin levels must rise to even higher levels, approx.

Thus, a modest rise doubling of fasting insulin levels will already substantially inhibit lipolysis and promote lipogenesis while gluconeogenesis is not yet inhibited.

Since such small increases of systemic insulin concentrations are enough for favoring adipogenesis, fasting and diurnal insulin levels are a determinant of obesity risk.

Indeed, several data support the obesity-promoting role of insulin for a detailed review see [ 18 ] Fig. Insulin promotes obesity. Several independent types of observations support the conclusion that insulin promotes adipogenesis and obesity. For details, see description in the general text.

These include epidemiological studies, which found high fasting insulin levels and concomitant insulin resistance in children and adolescents to be associated with higher weight gain in later years [ 19 ].

Studies in adults are less consistent [ 20 ]. Pharmaceutical interventions that lower insulin secretion, such as treatment with diazoxide or octreotide, led to significant body weight loss [ 21 , 22 , 23 ].

This fits with the observation that insulin therapy promotes weight gain [ 24 ]. One probable reason is that insulin levels in the high normal range are close to EC50 concentrations for inhibition of lipolysis [ 18 ].

In mice, modest lowering of circulating insulin concentrations by genetic manipulation of insulin genes caused resistance to weight gain despite a high-fat diet [ 25 ].

Decreasing insulin gene expression in adult mice via partial gene ablation reversed diet-induced obesity [ 26 ]. A Mendelian randomization analysis showed that persons with genetically determined higher insulin secretion to oral glucose exhibited a higher body mass index BMI [ 28 ], supporting a causal relationship between insulin and obesity risk.

Taken together, moderate to high normal levels of insulin in metabolic healthy persons appear to be a risk factor for the development of obesity. There is ample evidence that transient increases of metabolic or immune mediator levels are benign physiological responses to biochemical challenges, such as the rise of systemic glucose or cytokines following meals.

However, chronic elevations of such mediators, even when modest in amplitude, are usually detrimental to cellular functions [ 29 ]. In the case of glucose, the term glucose toxicity was coined to describe this phenomenon [ 30 ].

Prolonged conditions of elevated glucose concentrations cause dysfunction of numerous cell types in the body, including beta cells, neurons, and the endothelium, via several pathways, including increased oxidative stress and activation of the sorbitol pathway [ 31 , 32 , 33 ].

As described below, there seems to be a similar detrimental outcome of long-term elevated insulin concentrations on cellular functions, a corresponding term would be insulin toxicity.

When cells are exposed to continuously elevated insulin levels, there is a partial downregulation of insulin signaling. In response to prolonged hyperinsulinemia, there is diminished autophosphorylation of the insulin receptor, compared to that observed after short-term exposure to insulin, and subsequent steps of the PI3K—AKT signaling pathway are affected [ 34 , 35 ].

Consequently, in muscle and fat cells, there is less AKT-stimulated translocation of GLUT 4 to the cell surface Fig. Thus, insulin resistance can be seen as a protective mechanism for preventing excess activation of glucose transport from the blood despite chronically elevated insulin levels, for maintaining glucose homeostasis in vivo and for mitigating metabolic and oxidative stress due to excess glucose influx [ 36 , 37 , 38 , 39 ].

Limiting glucose export from the blood does not necessarily require dampening of insulin signaling. During the early weeks of feeding with a high caloric diet, mice show decreased insulin-dependent glucose uptake despite unperturbed insulin-stimulated AKT phosphorylation [ 40 , 41 ] Fig. Signaling of insulin during insulin resistance.

During insulin resistance, signaling through AKT kinases is partially impaired. Not all AKT-dependent pathways are affected, as well as other signaling pathways, indicating that insulin resistance is selective.

Therefore, hyperinsulinemia, in the presence of insulin resistance, promotes anabolic cell activities via the MEK—ERK pathway and via mTORC1. The phenomenon of insulin toxicity partly arises from the fact that there are additional cellular responses to elevated insulin levels which are not toned down during insulin resistance Fig.

These comprise the upregulation of protein synthesis and the accumulation of ubiquitinated or otherwise modified proteins, probably due to insufficient degradation of these polypeptides [ 43 ]. A major role of insulin signaling via the canonical mitogen-activated protein MAP kinase pathway Ras—MEK—ERK, as well as via activation of NADPH oxidase 4, has been observed [ 4 ].

Even some AKT-dependent pathways do not appear to be suppressed by insulin resistance, such as de novo lipogenesis in hepatocytes or the upregulation of mechanistic target of rapamycin complex 1 mTORC1 [ 44 , 45 , 46 , 47 ]. Enhanced activity of mTORC1 leads to increased protein synthesis and to deteriorated cell functions largely because of suppressed autophagy [ 48 ].

The resulting functional state of cells is characterized by an unbalanced anabolic activity of insulin favoring protein synthesis while suppressing autophagy. The latter inhibits autophagic removal and turnover of proteins and lipids, which favors cell senescence [ 49 ].

In short-term experiments of exposure to high insulin levels, a protective cellular stress response is observed, the unfolded protein response, probably due to the accumulation of derivatized proteins in the absence of enough disposal.

In experimentally induced or diabetes-associated chronic insulin resistance and hyperinsulinemia , such a protective stress response of the endoplasmic reticulum to high insulin levels is diminished or absent [ 50 ].

Another activity of insulin is the suppression of transcription of the nuclear factor Nrf2 via induction of heterogeneous ribonucleoproteins F and K [ 51 ]. Nrf2 is the central regulator of the protective response of cells against oxidative and other types of electrophile stress [ 52 ].

Suppression of Nrf2 expression is expected to impair the antioxidant and cytoprotective defense capacity of cells. Insulin signaling required for Nrf2 inhibition occurs via the MAP kinase pathway and thus is not mitigated by insulin resistance [ 53 ] Fig.

It therefore can be assumed that hyperinsulinemia increases the susceptibility of cells against oxidative or other electrophile stress caused by environmental insults. Prolonged exposure of cells to high insulin concentrations can therefore be regarded as toxic. Indeed, exposure to 0.

In the brain of mice, hyperinsulinemia impairs electrophysiological functions of neurons and protein turnover, causing a transition to a senescent cell state and an accompanying cognitive decline [ 56 ].

The direct toxic property of insulin deserves further study. The above list of detrimental cellular responses to high ambient insulin concentrations suggests concomitant functional impairments at the level of the organism. This fits with the observed impact of insulin on longevity.

Studies in nonvertebrate model systems such as the nematode Caenorhabditis elegans or the fruit fly Drosophila melanogaster find that moderate to high insulin activity shortens lifespan [ 57 , 58 ].

A consistent finding from mouse model studies is that decreased signaling of anabolic hormones like insulin, insulin-like growth factor, or growth hormone results in a prolonged lifespan [ 59 ].

Concomitantly, the proteome and transcriptome indicated a profile associated with healthy aging. An important aspect is that this study selectively addressed insulin. Other interventions for promoting longevity or extending healthspan, such as caloric restriction, not only lower circadian insulin levels; but several additional hormones, including IGF-1, are also affected [ 64 ].

The subsequent activation of the protein kinase mTORC1 is a major pathway for supporting somatic growth, protein synthesis, and fertility, while impeding autophagy and lifespan. Suppression of mTOR signaling by treatment with rapamycin prolongs life in model organisms and mice [ 65 ].

In humans, hyperinsulinemia in pre type 2 diabetes is associated with increased mTORC1 activity which may have a negative impact on beta cell survival, healthspan, and longevity [ 66 ].

Since both IGF-1 and insulin employ PI3K and AKT for signal transduction, it is difficult to disentangle the contribution of insulin versus IGF-1 to the modulation of longevity.

In animal models, selective downregulation of circulating insulin levels improved the lifespan of mice, and in elderly persons of the Leiden Longevity Study, only insulin and glucose, but not IGF-1, consistently met all four pre-defined criteria of healthy aging [ 63 , 67 ].

Therefore, it may be concluded that low circulating insulin concentrations are not only a marker of longevity but are causally involved in promoting healthspan or lifespan extension. Insulin resistance is defined as an attenuated effect of insulin on blood glucose homeostasis, primarily by less efficient export of glucose from the blood into skeletal muscle, adipose, and liver tissue.

Permanently elevated insulin concentrations in the blood are often considered as an attempt to overcome insulin resistance. Indeed, induction of insulin resistance by genetic disruption of insulin signaling, as well as by increased growth hormone levels or an inflammatory milieu, causes hyperinsulinemia [ 68 , 69 , 70 ].

The opposite causality is of more relevance. Hyperinsulinemia during insulin infusion in humans leads to systemic insulin resistance [ 71 ], while in vitro, high ambient insulin concentrations cause an increase in insulin resistance in isolated adipocytes [ 72 ]. A summary analysis of nine studies in rodents and seven trials in humans confirmed that the first detectable change in the fasting state, after feeding a high caloric diet for several days, is an increase of basal insulin concentrations, but not of blood glucose concentrations or insulin resistance [ 73 ].

Both increased secretion of insulin by ß cells and decreased insulin clearance in the liver contribute to elevated insulin levels post-meal, the latter being of primary importance in the case of carbohydrate-rich food [ 74 ].

The combination of hyperinsulinemia and insulin resistance appears to promote hypertension and atherogenesis Fig. One important molecule for maintaining vessel function, including relaxation of the arterial smooth muscle layer, is nitric oxide NO which is generated by endothelial NO synthase eNOS.

Decreased local NO production impairs arterial smooth muscle relaxation and concomitant vasodilatation. An important factor in this context is the calcium ion homeostasis of vascular smooth muscle cells. During insulin resistance, NO production is impaired while the supportive effect of insulin on calcium ion influx via PI3K delta and possibly the MEK—ERK pathway and vasoconstriction is still present Fig.

Hyperinsulinemia, insulin resistance, and cardiovascular disease. High insulin concentrations in the blood may occur due to genetic predisposition, overnutrition, or high-dose insulin treatment of type 2 diabetes.

Conversely, insulin resistance may be directly induced such as by growth hormone or pro-inflammatory cytokines. Hyperinsulinemia and insulin resistance enhance the risk of cardiovascular disease, by inducing endothelial dysfunction, suppression of endothelial nitric oxide synthase eNOS , and activation and promotion of calcium ion influx into smooth muscle cells, resulting in increased vascular tone, enhanced reabsorption of sodium ions in renal tubules, adhesion of macrophages to the vessel wall, and development of arterial lesions with increased lipoprotein lipase activity and cardiovascular disease.

At the same time, insulin signals through the mitogen-activated protein MAP kinase pathway to upregulate the expression of endothelin-1 ET-1 , plasminogen activator inhibitor-1 PAI-1 , adhesion molecules, and pro-inflammatory cytokines [ 79 , 80 ]. The renin-angiotensin system is activated in the context of endothelial dysfunction and contributes together with decreased NO production and increased ET-1 secretion to vascular stiffening and upregulation of vascular tone [ 81 , 82 , 83 ].

Elevated insulin levels also increase the risk of hypertension by enhancing renal reabsorption of sodium ions by several transport systems in different segments of the nephron Fig.

Signaling of insulin occurs via insulin receptor substrate 2 IRS2 and is not suppressed during insulin resistance, while signaling via IRS1 for counterregulatory mechanisms, including local NO production, is impaired [ 85 , 86 ].

However, a meta-analysis of 11 prospective epidemiological studies showed that the pooled relative risk of hypertension was 1.

As a consequence of endothelial dysfunction during prolonged treatment with insulin, arterial lesions rich in lipids are formed [ 89 ]. The progression of early fatty streak lesions to plaques is accompanied by the adhesion and pro-inflammatory activity of macrophages, which eventually develop into foam cells.

This process is driven by endothelial and macrophage lipoprotein lipase activity, as demonstrated by the observation of less atherosclerosis in mice with inactivated lipoprotein lipase gene [ 90 , 91 , 92 ].

Lipoprotein lipase activity in macrophages is enhanced with higher insulin levels in vivo, but there is no direct stimulatory effect of insulin on isolated macrophages [ 93 ].

The concern, that hyperinsulinemia might promote arterial disease in diabetic persons, developed in the late s, due to the steady increase of incidences of atherosclerosis in diabetic persons, despite improved glycemia and decreased risk of ketosis due to insulin therapy [ 94 ].

Since then, a wealth of data supports the observation that insulin resistance and hyperinsulinemia is a marker of increased risk of cardiovascular disease in the general population and in patients with diabetes [ 95 ].

However, these trials were not randomized for insulin treatment, and treatment of CVD risk factors was not kept similar between patient subgroups. In the United Kingdom Prospective Diabetes Study UKPDS , hyperinsulinemia and insulin resistance were not mitigated by insulin treatment, and fasting plasma insulin levels even rose [ 97 ].

By contrast, in UKPDS and other trials [ 97 , 99 , , ], oral treatment with the biguanide metformin reduced the risk of cardiovascular events and in parallel decreased insulin resistance and hyperinsulinemia.

In epidemiological studies of type 2 diabetes, it has been consistently observed that the addition of insulin to the treatment regimen or the intensification of insulin treatment result in a higher rate of cardiovascular events [ , , , , , , , , , , , , , , , , , , , ] Fig.

Indeed, it has been shown that the risk increases with increasing insulin dosage [ , ]. These epidemiological studies may suffer from residual confounding, since it is difficult to account for the possibly more advanced disease stage of patients receiving insulin.

A higher rate of hypoglycemic events may be an additional confounder. However, covariates considered in the statistical analyses cover a broad range of potential risk factors from 18 different categories Supplement Table 1. Similar randomized trials of higher-dose insulin therapy, as typical for real-world conditions, have not been conducted.

Recent studies of real-world clinical settings report mean daily basal insulin doses of close to 0. It can be concluded that under real-world conditions, the majority of insulin-experienced patients with type 2 diabetes receive higher insulin doses per day than those tried in UKPDS or ORIGIN.

Hazard ratio of insulin medication versus different reference medications. In the absence of randomized controlled trials, a Mendelian randomization is an appropriate approach of testing for a causal relationship in humans.

Mendelian randomization studies made use of the finding that some genotypes are associated with high or low fasting insulin levels. In two large recent Mendelian randomization studies, a genetic profile predicting high insulin levels in the blood, after adjustment for BMI, was also associated with increased systolic blood pressure and risk of myocardial infarction [ ].

As discussed above, insulin signaling engages at least three different pathways and modifies a large number of cellular responses Table 1. Transient elevations of systemic insulin concentrations are physiological responses to dietary stimuli or other challenges such as environmental toxins [ ].

Consequently, insulin resistance has been considered as a defense response in order to avoid hypoglycemia [ 38 ]. Concomitantly, there is an accumulation of ubiquinated and otherwise modified proteins. Activation of mTORC1 results in the suppression of autophagy, i.

This may be the reason for increased DNA damage in the presence of high insulin concentrations. These mechanistic insights lend support to the view that the association of hyperinsulinemia with several detrimental health outcomes is of causal nature. Outcomes include obesity, endothelial dysfunction, hypertension, myocardial infarction, and decreased lifespan.

We did not discuss the possible contribution of hyperinsulinemia to cancer development or to the deterioration of cognitive functions.

Final proof of a causal relationship between hyperinsulinemia and disease risk cannot be obtained by randomized controlled trials, due to problems with masking the type of intervention, long-term compliance, and because of ethical concerns. Alternatively, Mendelian randomization studies are suitable tools to test for causality in humans, and such studies have found hyperinsulinemia to increase the risk of obesity [ 27 , 28 ] and cardiovascular disease [ , ].

A straightforward approach for lowering circulating insulin levels is restricting the exposure of islet ß cells to insulin secretagogues. One option is limiting calorie uptake, either continuously or during defined periods of the day or week [ , , ]. Another effective way of lowering insulin levels in the blood is the stimulation of insulin clearance via exercise [ ].

A different approach is a bariatric surgery [ , , ]. Gastric bypass leads to rapid regression of hyperinsulinemia and later of insulin resistance; additionally, there are substantial benefits with regard to health outcomes and mortality.

It seems improbable that such marked clinical improvement could have happened in the presence of persistent hyperinsulinemia and insulin resistance.

We conclude that low fasting or circadian insulin levels should be a primary aim of healthy lifestyle guidelines. Insulin treatment of type 2 diabetes seems only warranted if hyperinsulinemia and concomitant selective insulin resistance can be avoided.

This favors insulin treatment only in the late phases of type 2 diabetes as has been suggested in recent guidelines [ ]. Only articles published in English were selected.

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Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots. J Viral Hepat. Del PS, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo RA. Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man.

Kobayashi M, Olefsky JM. Effects of streptozotocin-induced diabetes on insulin binding, glucose transport, and intracellular glucose metabolism in isolated rat adipocytes. 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.

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Insulin sensitivity refers Fuel your performance consistently how responsive your cells are to insulin. You may be able to improve it by getting ijsulin sleep Promtoing exercise Promoting insulin function indulin certain health-promotion foods. Insulin Aging gracefully lifestyle an essential hormone that controls your blood sugar levels. When your pancreas senses high blood sugar, it makes more insulin to overcome the resistance and reduce your blood sugar. Over time, this can deplete the pancreas of insulin-producing cells, which is common in type 2 diabetes. Also, prolonged high blood sugar can damage nerves and organs. If you have insulin resistanceyou have a greater chance of developing prediabetes. Insulin resistance IR plays a Aging gracefully lifestyle role in the development and Lean body mass of Promotinb diseases such Promotingg diabetes, Aging gracefully lifestyle, inulin, and nonalcoholic fatty liver disease, and provides the basis for a common Joint health resilience of Promooting chronic Aging gracefully lifestyle. In this study, we provide a 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.


Regulation of Insulin Release and Insulin Action

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