Insulin sensitivity and aging -
As MT1-MMP deficient mice exhibited premature death at around 3—4 weeks after birth, the function of MT1-MMP in insulin resistance was examined in Mmp14 haploinsufficient mice that did not display any gross postnatal phenotypes 9 , 10 , These results suggest that hemizygous depletion of Mmp14 protects mice from glucose intolerance and enhances systemic insulin sensitivity under the condition of overnutrition-induced obesity.
The expression of phosphorylated Akt pAkt in relative to the level of total Akt tAkt in the livers, white adipose tissues WAT and muscles was examined by western blotting and quantified.
Source data are provided as a Source Data file. To investigate the physiological relevance of MT1-MMP-dependent regulation of insulin sensitivity, the change of MT1-MMP expression was examined in both aged and obese mice. The protein and mRNA levels of Mmp14 were significantly upregulated in the liver of a 4-month-old-mice on a high-fat diet Supplementary Fig.
Interestingly, the expression of Mmp14 was elevated significantly in the liver of aged mice on chow diet, similar to the level observed in young mice on high-fat diet Supplementary Fig. The upregulation of Mmp14 was similarly detected in white adipose tissue WAT from aged mice on chow diet Supplementary Fig.
We also measured MMP14 expression in WAT biopsies from lean and obese human adolescents. Consistent with results observed in mice, the expression of MMP14 increased dramatically in obese human subjects Supplementary Fig. Moreover, gel zymography showed a remarkable increase in MMP activity in the liver from both aged and obese mice Supplementary Fig.
We further confirmed this finding by using Mmpspecific activity assay that showed significantly increased Mmp14 activity in the liver of aged and obese mice Supplementary Fig. To further investigate whether the upregulation of MT1-MMP impairs insulin action in vivo, we used an adeno-associated viral vector to ectopically express either wild-type MT1-MMP, catalytic inactive MT1-MMP mutant MT1 EA or GFP control in the liver.
Mice were studied 4 weeks after a single intravenous administration of adenovectors. The expression of MT1-MMP was specifically increased in the liver by approximately fourfolds in mice receiving Mmp14 AAV while no significant change in MT1-MMP expression was observed in other major metabolic tissues Fig.
Despite no significant changes in food intake, weight gain and energy expenditure Supplementary Fig. The GIR and GDR were considerably lower in mice with Mmp14 AAV Fig. Insulin-induced suppression of HGP was similarly decreased in mice with Mmp14 AAV Fig.
However, there was no significant changes in both serum insulin and peripheral glucose uptake in mice with Mmp14 AAV during the clamp Supplementary Fig. These results indicate that ectopic expression of MT1-MMP in the liver is sufficient to impair insulin action and the inhibitory effect of MT1-MMP on insulin sensitivity is dependent of the catalytic activity of MT1-MMP.
In all, week-old male mice were injected intravenously with AAV and fed on a regular diet. c Plasma glucose level during the insulin-tolerance tests. To further address whether MT1-MMP inactivates insulin signaling, HEKT cells were transfected with either empty vector or WT or catalytic inactive MT1-MMP.
Ectopic expression of wild-type MT1-MMP, but not catalytically inactive MT1-MMP, suppressed insulin-induced phosphorylation of Akt Fig. Total Akt serves as a loading control. The total cell lysates were subjected to western blotting analyses using antibodies indicated.
To explore the mechanism by which MT1-MMP regulates insulin signaling, we examined the protein expression of IR. Accordingly, we obtained liver, white adipose tissue WAT and muscle lysates from WT as well as Mmp14 heterozygous and knockout mice and probed their IR levels, since they are the major targets for insulin-induced glucose metabolism.
Western blots against the β-chain of the insulin receptor revealed a dose-dependent elevation in the expression of IR in both liver, WAT, and muscle as Mmp14 copy number was reduced Fig.
As the transcription of IR in these insulin-sensitive tissues was not altered by loss of MT1-MMP Supplementary Fig. To test whether MT1-MMP cleaves IR, WT or activity-dead mutant MT1-MMP were transfected into HEKT cells Fig. Western blotting using the antibody against the β-domain of the insulin receptor revealed that the full-length IR in the total cell lysates was remarkably reduced in WT MT1-MMP transfected cells Fig.
Meanwhile, the ectodomain fragment of IR detected by the antibody against the α-chain of the insulin receptor was increased significantly in WT MT1-MMP transfected cells Fig. In contrast, overexpression of hepatic MT1-MMP did not only reduce the protein level of IR in the liver but also increased the level of sIR in the plasma Supplementary Fig.
Meanwhile, the transcriptional level of hepatic IR was not altered by MT1-MMP overexpression Supplementary Fig.
These results collectively confirmed the significant contribution of MT1-MMP to IR cleavage in vivo. To further confirm the direct cleavage of IR by MT1-MMP, recombinant IR was incubated with the catalytic domain of MT1-MMP cMT1 in vitro. Full-length IR was significantly reduced and truncated fragments of IR were detected in the presence of cMT1, which was inhibited by the potent MT1-MMP inhibitor EDTA Fig.
The cleavage of IR by MT1-MMP was further substantiated by the endogenous interaction between MT1-MMP and IR in mouse primary hepatocytes Fig. MT1-MMP was detected in IR immunoprecipitation Fig. Reciprocally, MT1-MMP immunoprecipitation could pull down IR Fig.
f rIR was incubated with the recombinant catalytic domain of MT1-MMP rMT1. g Co-immunoprecipitation experiments demonstrated the endogenous interaction between MT1-MMP and IR. IR and MT1-MMP immunoprecipitations IP were generated from liver lysates from wild-type mice and examined by western blotting analyses using indicated antibodies.
IgG immunoprecipitation served as controls. To further investigate the therapeutic potential of targeting MT1-MMP in the management of insulin resistance, aged mice on chow diet were administrated with 3A2, a well-characterized anti-MT1-MMP monoclonal antibody with remarkable neutralizing properties 16 , Interestingly, the protein expression of IR was significantly downregulated in the liver of aged mice whereas IR mRNA levels were increased Fig.
In line with reduced IR expression in the liver, the level of sIR was considerably higher in the plasma from aged mice Fig.
Specific inhibition of MT1-MMP via injection of the 3A2 monoclonal antibody restored the protein expression of both IR and sIR to a level comparable to that observed in young mice without altering mRNA expression of IR Fig. Importantly, inhibition of MT1-MMP yielded significant improvements in metabolic parameters including fasting plasma glucose and insulin levels as well as glucose tolerance in aged mice Fig.
Taken together, our results suggest that inhibition of MT1-MMP can improve glucose homeostasis in both aged and diabetic mice. Male mice at 4- and 18 months old on chow diet received treatment twice a week with either 3A2 antibody or control IgG for 4 weeks.
a , b Western blotting a and qPCR analyses c on the expression of IR in the livers. To determine whether our observations from murine models are physiologically relevant to primate ageing, we examined the concentrations of sIR and MMP14 in plasma derived from aged non-human primates and humans.
We found that both sIR and plasma MMP14 are markedly upregulated in plasma of aged non-human primates Fig. Moreover, there was a significant positive correlation between plasma MMP14 and sIR Fig.
c , f There is also a positive correlation between plasma MT1-MMP and soluble insulin receptor in the plasma from aged and young non-human primates c and humans f. The mechanism underlying insulin resistance in physiological aging is not completely elucidated.
We herein identified a previously unappreciated mechanism for the development of age-associated insulin resistance in rodent models involving ectodomain shedding of IR by MT1-MMP. We demonstrated that cleavage of IR is increased in physiological aging and this cleavage event majorly mediated by MT1-MMP contributes to the regulation of insulin sensitivity in late life.
Currently, little is known about the function of MT1-MMP in the setting of insulin resistance and diabetes. We showed that inhibition of MT1-MMP by genetic knockout or pharmacological approach improves insulin sensitivity and glucose tolerance in both aged and diabetic mice.
In contrast to the improved insulin sensitivity caused by MT1-MMP depletion, ectopic MT1-MMP expression in the liver induces insulin resistance, despite no changes in body weight and composition.
In line with our findings, transgenic mice with inducible MT1-MMP overexpression in the established obese adipose tissue have been reported to exhibit reduced glucose tolerance Furthermore, we found that loss of MT1-MMP enhances insulin-induced signaling in peripheral tissues in vitro and in vivo.
These observations suggest that MT1-MMP exerts direct and cell-autonomous inhibitory effects on insulin sensitivity in key metabolic tissues. We demonstrated that IR is a direct substrate of MT1-MMP, and the MT1-MMP-mediated cleavage of IR regulates insulin sensitivity and glucose tolerance.
IR cleavage has been identified for years 5 , 7. However, the major protease responsible for physiological IR cleavage remains to be elucidated. Deficiency in BACE1, a transmembrane aspartyl protease reported to cleave IR, only minorly reduced sIR levels and inhibition of BACE1 using a specific inhibitor does not alter plasma sIR amount 5.
In fact, we showed that inhibition of MT1-MMP leads to a remarkable reduction in sIR generation with a concomitant increase in IR expression in insulin-sensitive tissues, accompanied by robust improvement of insulin sensitivity.
Interestingly, we also found that treatment of metformin, a first-line anti-diabetic medication that has been found to suppress IR cleavage in vitro 7 , significantly reduces the expression of MT1-MMP in the liver of mice with high-fat diet-induced obesity Supplementary Fig.
These findings uncover MT1-MMP as a primary sheddase of IR and the cleavage of IR by MT1-MMP is physiologically relevant. The level of sIR has been shown to correlate with insulin resistance in diabetic human patients 8.
Despite the close association between sIR and diabetes, it remains unknown whether diabetes is the only pathological situation in which IR cleavage is increased. We herein demonstrated that aging and obesity increased the expression of active MT1-MMP which in turn cleaves IR to reduce its cell surface presentation and thereby suppresses insulin signaling.
The released sIR may also function as a decoy receptor to sequester the circulating insulin and decrease receptor signaling 8.
The robust improvement of insulin sensitivity resulted from the prevention of IR cleavage by inhibition of MT1-MMP nicely illustrates that MT1-MMP-mediated cleavage of IR is the major driving force in eliciting insulin resistance in both physiological aging and diabetes.
Moreover, there is a highly significant correlation between sIR and plasma MMP14 in both non-human primates and humans and they are markedly upregulated in the elderly population, suggesting that the regulatory mechanism for ageing-related insulin resistance is likely conserved in both primates and non-primates.
Although age-associated insulin resistance and obesity-associated insulin resistance are distinct forms of diabetes, our findings showed that the underlying cellular mechanisms that drive these diseases are unexpectedly the same. Targeting this common mechanism is therefore a potential strategy for developing efficient therapies for age-related diseases including diabetes and obesity.
Zhou Zhongjun in the University of Hong Kong and genotyped as previously described They were fed with standard laboratory chow, and applied with water ad libitum. Animals of both sexes were used in the experiments unless it was specifically stated in the figure ligand. Young and elderly blood were collected for the isolation of EDTA plasma.
Informed consent was obtained from each individual. The study protocol was approved by the Research Ethics Board of Guanfu Hospital and the Health Commission of Guangdong Province in accordance with China legislation. The study was conducted in accordance with the Declaration of Helsinki.
The standard maintenance diet for non-human primates Jiangsu Synergy Pharmaceutical and Biological Engineering Co. They were female and healthy.
All housing conditions and procedures were approved by and in compliance with the ethical guideline of the Institutional Animal Care and Use Committee IACUC of Guangzhou Huazhen Biosciences Co. The housing facilities were accredited by the Association for Assessment and Accreditation of Laboratory Animal Care AAALAC.
The levels of plasma insulin receptor and plasma MMP14 were measured using ELISA kits from BioVenor and Cloud-clone Corporates respectively. The metabolic measurement of mice was performed as previously described Body weight and food intake were measured daily.
Food intake was recorded by measuring daily changes in the amount of food content in food hoppers. Tail vein blood was drawn to measure plasma insulin with a mouse insulin ELISA kit Novus and plasma glucose using a One Touch Ultra glucometer LifeScan.
For the insulin-tolerance tests, mice were intraperitoneally administrated with 0. Blood was drawn from tail veins for the measurement of blood glucose. Briefly, mice were catheterized with dual catheters MRE, Braintree Scientific for 4—5 days before the experiment.
Glucose uptake was quantified by measuring the radioactivity via scintillation. The level of circulating insulin receptors in mice was measured by ELISA as previously described with slight modification 5.
Briefly, the ELISA plate Perkin Elmer was coated with the monoclonal antibody against the α-subunit of the insulin receptor Invitrogen, AHR The signal amplification and detection were performed as described by the manufacturer of the ELISA plate. AAV-WT MT1-MMP and AAV-MT1 EA virus produced by the pAAV-TBG-sfGFP-WPRE vector plasmid were purchased from Obio Technology Ltd.
This vector plasmid was an AAV vector of serotype 8 under the control of the thyroxine-binding globulin TGB promoter, a well-documented AAV vector for specific transgene expression in hepatocytes. They were delivered by tail vein injection 5. Mice were studied 4 weeks after AAV infection.
The antibodies used in this study include the following: anti-MT1-MMP antibody ab, Abcam; for western blotting ; anti-insulin Rα antibody sc, Santa Cruz, for western blotting ; anti-insulin Rβ antibody sc, Santa Cruz, for western blotting ; anti-insulin Rβ antibody clone CT-3, MAB S65, millipore, for western blotting ; anti-Akt , Cell Signaling, for western blotting : anti-pAkt , Cell Signaling, for western blotting ; anti-β-actin , Cell Signaling, for western blotting ; goat anti-rabbit antibody conjugated with HRP sc, Santa Cruz, ; Rabbit anti-mouse antibody conjugated with HRP sc, Santa Cruz, Takeharu Sakamoto.
HEKT cells obtained from Prof. The cells have recently been tested negative for contamination of mycoplasma. The perfused liver was minced gently in DMEM.
Survived cells were used for the studies. The positive immunoreactions were detected with x-ray film Fuji by chemiluminescence using an ECL kit GE Healthcare. The relative expression of proteins was quantified using Image J software Wayne Rasband, NIH, USA.
Protein bands of western blots were quantified using Image J version 1. cDNA templates were then amplified with specific primers for target genes in the ABI ViiA 7 real-time PCR system Applied Biosystems using 2× SYBR Green PCR Master Mix Applied Biosystems.
Expression of the gene of interest of each sample was normalized to the endogenous control GAPDH, and presented as 2-ΔΔCt using the comparative Ct method.
The results were analyzed by ViiA 7 Real-time PCR system software QuantStudio Software v1. The experiments were performed as previously described The recombinant catalytic domain of MT1-MMP BML-SE and recombinant Insulin Receptor H08H were purchased from Enzo and Sino Biological, respectively.
The rIR consists of human IR protein 1— amino acids. The protein mixture was subjected to western blotting analyses. Each experiment was independently performed for at least three times. Animal experiments involved at least three independent and randomly chosen mice at comparable developmental stages and none of the samples were excluded from analyses.
The sample size was determined from the power of the statistical test performed and was increased in accordance with the statistical variation. All data meet the normal distribution. GraphPad Prism V8 for Window OS was used for statistical analyses.
Further information on research design is available in the Nature Research Reporting Summary linked to this article. All data generated or analyzed during this study are included in this published article and its supplementary information files.
Source data are provided with this paper. Caro, J. et al. Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes. Article CAS Google Scholar. Frojdo, S. Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans.
Biochim Biophys. Acta , 83—92 Article Google Scholar. Olefsky, J. Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. CAS PubMed Google Scholar. Samuel, V. Inhibition of protein kinase C epsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease.
Invest , — Meakin, P. The beta secretase BACE1 regulates the expression of insulin receptor in the liver. Article ADS Google Scholar. Maesako, M. Effect of glycogen synthase kinase 3 beta-mediated presenilin 1 phosphorylation on amyloid beta production is negatively regulated by insulin receptor cleavage.
Neuroscience , — Yuasa, T. Sequential cleavage of insulin receptor by calpain 2 and gamma-secretase impairs insulin signalling. Diabetologia 59 , — Soluble Insulin Receptor Study, G. Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes.
Diabetes 56 , — Holmbeck, K. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. For women with and without diabetes, this can lead to insulin resistance , which keeps your glucose levels high and makes it more difficult to lose weight [10].
Men experience a similar age-related decline in sex hormones called andropause [4]. This gradual decline in testosterone levels affects loss of muscle mass, increased belly fat, mood swings, poor memory and concentration, and loss of libido. Sarcopenia is the age-related loss of skeletal muscle and accumulation of fat mass that typically affects people 60 and older [20].
Sarcopenia commonly occurs in the elderly due to physical inactivity, poor nutrition, a lack of protein in the diet, and decreased protein synthesis, among other factors. Sarcopenia is dangerous — it impairs mobility, increases your risk of falling, and makes it challenging to perform daily tasks and activities.
One form of sarcopenia, called sarcopenic obesity, describes people who have sarcopenia, insulin resistance, and obesity at the same time. Sarcopenic obesity increases your risk of health problems compared to obesity and sarcopenia alone [13].
Currently, the treatment for sarcopenia emphasizes exercise, specifically strength training [14]. Lifting weights or resistance bands can increase muscle strength, improve your fat-mass-to-muscle mass ratio , and promote mobility.
Along with muscular benefits, resistance training is ideal for improving metabolic health as it helps regulate blood glucose [15]. Research shows that two weekly exercise sessions involving a combination of upper and lower body exercises for sets of repetitions are an appropriate treatment for sarcopenia [16].
Getting enough lean protein in your diet is also key for building and maintaining lean muscle as you age. The physical changes of aging are the most well-known - graying and thinning of hair, wrinkles, sun spots, joint pain, loss of muscle and physical strength, hair loss, etc.
Luckily, metabolic health monitoring and improvement can help combat these signs. Insulin plays an important role in skin conditions such as acne and psoriasis [17]. Insulin resistance, however, is associated with mild inflammation throughout the body and can aggravate your skin. It may also increase androgen hormones that can trigger acne development.
Balancing your blood glucose levels and eating anti-inflammatory foods may help mitigate the signs of aging skin. Limited joint mobility , also called diabetic hand syndrome or diabetic cheiroarthropathy, is joint stiffness that impacts the small joints of the hands [18].
The skin on the hands may become waxy and thickened, and finger movement is eventually limited. The cause is unknown, but it's most common in individuals with diabetes. Monitoring blood sugar levels can slow the progression and act as a preventative measure to offset the development of this condition.
One way to monitor your blood glucose levels is by using a continuous glucose monitor CGM. A CGM allows you to view your glucose levels in real-time and your glucose response to food, exercise, and lifestyle factors. Pairing a CGM with the Veri app provides personalized insights into glucose trends and allows you to adapt lifestyle changes according to your results.
You can combat these physical, mental, and clinical changes by incorporating some daily habits and actions slowly and consistently.
Metabolic Health. The 5 Best Exercises for Insulin Resistance and Metabolic Health. The Link Between Insulin Resistance and Aging — and What You Can Do About It. How aging changes our bodies Over the past century, the lifespan for both men and women has increased substantially.
Cardiovascular health The most common change associated with aging involves the cardiovascular system [2]. Bone and muscle health As early as your 40s and 50s, your bones may become weaker, less dense, and more brittle, which increases the risk of fractures [3].
Digestive health Your digestive system also slows down due to changes in your large intestine that can lead to constipation [2]. Menopause and andropause Around age 40, you may begin to experience the physical and emotional symptoms of menopause and andropause i.
Insulin resistance Along with the onset of these symptoms is an increased risk of developing insulin resistance and decreased insulin sensitivity.
Cognitive health, insulin resistance, and blood glucose Your brain health is affected by many age-related changes — including reduced blood sugar regulation and decreased insulin sensitivity [19]. Menopause, andropause, and insulin resistance Menopause is the age-related decline in female hormones that results in losing a menstrual period [8].
Sarcopenia and insulin resistance Sarcopenia is the age-related loss of skeletal muscle and accumulation of fat mass that typically affects people 60 and older [20].
How to treat sarcopenia Currently, the treatment for sarcopenia emphasizes exercise, specifically strength training [14]. Physical changes that come with aging The physical changes of aging are the most well-known - graying and thinning of hair, wrinkles, sun spots, joint pain, loss of muscle and physical strength, hair loss, etc.
Skin health Insulin plays an important role in skin conditions such as acne and psoriasis [17]. Joint elasticity Limited joint mobility , also called diabetic hand syndrome or diabetic cheiroarthropathy, is joint stiffness that impacts the small joints of the hands [18].
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Such conditions may arise as consequence of high anabolic cell activity such as in response to excess concentrations of anabolic hormones like growth hormone, insulin-like growth factor IGF or insulin. The growth hormone — IGF — insulin signaling axis is a major modulator of the aging process 19 In the present review we focus on the role of insulin which differs from that of growth hormone and the IGF system in that it is strongly linked to nutrient sensing.
We suggest here that the age-associated decrease of resistance towards cellular stress may explain the unfavorable effects of insulin during aging.
Figure 1 Functional network of cytoprotective pathways versus aging associated insults. Genetic interference with proper signal transduction by various approaches shares as outcome an extension of lifespan This pituitary hormone promotes IGF-1 production from the liver and other tissues, but the two hormones have partly opposite effects.
For instance, Inxulin hormone induces insulin resistance but promotes insulin production whereas IGF-1 promotes insulin sensitivity and reduces insulin secretion Therefore, outcomes of genetic disturbance of the sensitlvity balance between growth hormone, IGF-1 and insulin are difficult to interpret.
A body-wide knockout of the insulin receptor leads to early postnatal lethality whereas mice heterozygous for mutant and wildtype receptors did not show an altered lifespan despite some functional impairment of insulin signaling In another study, mice heterozygous for a knockout of the insulin receptor showed no differences in lifespan to wildtype littermates in females but an increase in maximum lifespan in males Many studies have observed an extended lifespan in mice if growth hormone expression, or binding to its receptor are impaired.
Longevity is increased in both sexes of Ames or other dwarf mice with deficient production of growth hormone together with prolactin and thyroid stimulating hormone or with isolated growth hormone deficiency 29 Mice with disruption of the growth hormone receptor gene express a similar phenotype The longevity mechanism of mice with deficient growth hormone activity has not been fully elucidated, but it is of interest that there is a strong association with enhanced insulin sensitivity Similar analyses of IGF-1 are hampered by the fact that lack of functional IGF-1 receptors severely impairs development.
Therefore, mice heterozygous for a receptor gene knockout were analyzed. Prolongation of lifespan was modest and seen in female mice only 33 — IGF-1 receptor function can also be affected by deletion of insulin receptor substrate genes.
This approach also impairs insulin signaling. Mice lacking insulin receptor substrate 1 exhibit increased longevity For the insulin receptor substrate 2 gene, deletion in all tissues of mice was not found to increase lifespan while deletion in brain tissue only promoted longevity 38 Table 1.
The opposing effects of growth hormone and IGF-1 on insulin sensitivity and production leads to the question whether insulin action itself is more closely related to longevity than the two other anabolic hormones. In mice, modulation of circulating insulin levels and insulin sensitivity often but not always were reported to affect the lifespan which supports a role of insulin actions in the aging process.
In one study, mice with reduced insulin sensitivity because of impaired insulin receptor function exhibited an increased lifespan in males but not in females. Increased insulin sensitivity because of deficiency of protein tyrosine phosphatase 1B or overexpressed peroxisome proliferator activated receptor gamma coactivator-1α was associated with a shortened lifespan Another strain of mice with impaired insulin receptor function also exhibited insulin resistance and hyperinsulinemia, Insulij without an impact on lifespan The significance of the association was carried by alleles of nine genes, AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2and YWHAG This study did not observe the senwitivity documented association of FOXO3A with longevity, possibly because nonagenarians rather than centenarians were analyzed.
Another additional factor determining the outcome of insulin actions on longevity might be the overall metabolic rate. A high metabolic rate is associated with increased production of reactive oxygen species ROS.
For instance, small-breed domestic dogs exhibit a higher mass-specific metabolic and growth rate than large dogs, and therefore oxidative damage of lipids is seen. Nevertheless, small-breed dogs live significantly longer 46 In mice, heavier body weight is associated with increased epigenetic aging and earlier death 48 Similar findings have been reported for humans.
In Southern Chinese adults, senxitivity basal metabolic rate was inversely correlated with all-cause mortality in males, but not in females Within a local population, people of smaller size have a higher life expectancy, in different regions of the world It may be concluded that within a species a higher growth rate is associated with shorter lifespan, but this is not explained by a higher metabolic rate.
In humans, epidemiological studies suggest a pro-aging effect of insulin. The higher longevity in shorter men is also associated with lower fasting insulin concentrations In adults with normal glucose tolerance, there is a parallel increase of snsitivity insulin levels and insulin resistance with aging, and this is associated with central obesity 56 Hyperinsulinemia and insulin resistance are important risk factors for type 2 diabetes as well as hypertension and cardiovascular disease 58 — Another approach of studying the health impact of hyperinsulinemia is to determine the insulinemic afing of the diet as assessed by food frequency questionnaires ahd by measuring circulating C-peptide concentrations.
Of note, these associations were independent of BMI. Insulin is a potent anabolic hormone. A Mendelian randomization analysis found that genetic variants which code for a higher insulin response to glucose challenge are strongly associated with increased BMI which is considered as proof of a causal relationship between increased insulin secretion and body weight gain This fits with the observation that insulin therapy favors weight gain Conversely, pharmacological lowering of circulating insulin concentrations in obese people by diazoxide caused greater weight loss than diet alone Treatment of obese persons with the somatostatin analogue octreotide led to weight loss in conjunction Insuljn a decrease of insulin levels 68 Lifestyle changes or other interventions known to improve risk factors of age-associated disease and cardiovascular nIsulin cause lower insulin levels, as reported for calorie-restricted diets, intermittent fasting or bariatric surgery 70 — Vegetarian diets are also associated with lower insulin resistance and lower fasting insulin levels, even in comparison with matched lean controls, and appear to improve healthspan and possibly also lifespan 74 Another lifestyle parameter associated with better healthspan is physical exercise, which causes lower fasting and post-challenge insulin levels as well as improved insulin sensitivity 76 — Although insulin is an essential hormone for growth and maintenance of complex organisms 79the above findings suggest that elevated insulin levels promote age-associated diseases.
One cellular response to permanently elevated insulin levels is partial sebsitivity of insulin signaling via the insulin receptor, causing the phenomenon of insulin resistance.
A higher amount of alternatively spliced type A insulin receptor lacking exon 11 also may contribute to insulin resistance by directing insulin signaling towards the mitogen activated kinase pathway which promotes cell proliferation and tumor development Signaling via the PI3K-AKT pathway is not only affected by modulation of insulin receptor function but also enzyme activities downstream.
The diversity of proteins involved in the PI3K-AKT signaling pathway allows for varying outcomes of signaling, and this complexity is only partially resolved.
The resulting decreased arterial smooth muscle relaxation is aggravated by the non-suppressed insulin-dependent influx of calcium ions which enhances vascular contractility, resulting in upregulated vascular tone which increases the risk of vascular events 89 Other hormonal actions that are less or not affected by insulin resistance and may even be upregulated with the concomitant hyperinsulinemia include upregulation of PI3K-AKT dependent lipogenesis in hepatocytes and of the mechanistic target of rapamycin complex 1 mTORC1 activity, the latter resulting in increased protein synthesis and impaired autophagy 91 — Increased systemic insulin levels and concomitant insulin resistance during the progression to type 2 diabetes is associated with chronic overactivation of the mTORC1 signaling pathway and cell stress in the context of a high protein synthesis rate During insulin resistance states and concomitant hyperinsulinemia there is, varying between tissues, phosphorylation of several Forkhead Box O FOXO transcription factors and their retention in the cytoplasm.
resulting in suppression of muscle autophagy and protein degradation, among other effects 8697 — The impact of elevated insulin levels on protein synthesis and autophagy is accompanied by the accumulation of proteins with multiple posttranslational modifications because of insufficient degradation which leads to endoplasmic reticulum stress 95 Insulin signaling via phosphorylation of the Src homology 2 domain-containing transforming proteins SHC and subsequent activation of the mitogen-activated kinase protein kinase kinase MEK - extracellular signal-regulated kinase ERK is not affected by insulin resistance and contributes to these effects of hyperinsulinemia Figure 2 Sejsitivity 2 Elevated insulin levels and insulin resistance favor age-associated diseases in humans.
Modest increases of insulin concentrations suffice to suppress lipolysis and support lipogenesis, promoting obesity.
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I would like to thank Dr Andrew Goldberg for his insightful comments and acknowledge the support of NIH grant KAG, and the Department of Veterans Affairs, Geriatrics Research, Education, and Clinical Center at Baltimore. Division of Gerontology, GRECC 18 , Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, , USA. You can also search for this author in PubMed Google Scholar. Correspondence to Alice S. Reprints and permissions. Ryan, A. Insulin Resistance with Aging. Sports Med 30 , — Download citation. Published : 23 September Issue Date : November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. 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These stimuli include nutrient oversupply especially lipids , endoplasmic reticulum stress, and oxidative stress 6 , 8 — However, in contrast, numerous studies have reported that insulin resistance may cause mitochondrial dysfunction. Holloszy and colleagues 14 have pointed out that reduced mitochondrial content is still sufficient to oxidize fatty acids in the resting state and is unlikely to cause accumulation of fat or insulin resistance. Overview of the major stimuli resulting in insulin resistance. IMCL promotes the production of diacylglycerol, activation of protein kinase CѲ, and increased phosphorylation of IRS Impaired mitochondrial function along with nutrient oversupply can also result in the overproduction of reactive oxygen species and the activation of stress-sensitive signaling pathways. Chronic inflammation, as is observed in obesity, type 2 diabetes, and other conditions, is associated with increased production of tumor necrosis factor-α and other proinflammatory cytokines and iNOS. Each of these can trigger endoplasmic reticulum ER stress and the unfolded protein response. Plasma cell membrane glycoprotein-1 PC-1 binds to the connecting domain of the insulin receptor α-subunit that is located in residues — The connecting domain transmits insulin binding in the α-subunit to activation of tyrosine kinase activation in the β-subunit. When plasma cell membrane glycoprotein-1 is overexpressed, it inhibits insulin-stimulated insulin receptor β-subunit tyrosine kinase activity. Protein tyrosine phosphatase-1B PTP-1B is a negative regulator of insulin and leptin signaling, which causes reduced tyrosine phosphorylation of the insulin receptor and other substrates and the attenuation of insulin action. See text for the references upon which these associations have been based. The insulin receptor substrate IRS proteins mediate the metabolic effects of insulin 7. Increased nitric oxide NO production, especially as a consequence of inducible nitric oxide synthase iNOS , has also been implicated in insulin resistance, especially in the context of obesity iNOS is markedly increased in macrophages and other inflammatory cells stimulated by proinflammatory cytokines. In the presence of O 2 , NO covalently attaches to cysteine residues of target proteins forming S -nitrosothiol adducts in a reversible posttranslational modification termed protein S -nitrosation or S -nitrosylation. Thus, protein S -nitrosation resulting from NO overproduction or impaired denitrosation can be regarded as a causative molecular mechanism for insulin resistance. Insulin resistance increases with aging, and in this issue of Diabetes , Ropelle et al. Elegantly using three independent approaches, including iNOS-null mice, pharmacological inhibition of iNOS, and acute exercise to reduce iNOS expression, they report that each method protected against iNOS-mediated protein S -nitrosation and insulin resistance. These results provide further evidence implicating protein S -nitrosation mechanistically with insulin resistance and extend the mechanism from insulin resistance in the context of obesity to aging. Future work needs to include an assessment of the role of protein S -nitrosation in other conditions and insulin target tissues and on other molecules in the insulin-signaling pathways. The molecular mechanisms of insulin resistance are diverse and likely to be context specific. For example, the decreased whole-body glucose infusion rates during a hyperinsulinemic clamp a measure of whole-body insulin sensitivity that are observed in type 2 diabetic patients are also observed in other conditions including obesity, aging, polycystic ovary syndrome, and hypertension. Are the molecular mechanisms of insulin resistance identical in all these conditions? And are those mechanisms the same for each insulin-regulated pathway? Ropelle et al. have convincingly linked protein S -nitrosation to insulin resistance in aging mice, whereas, previously, it had been linked principally to obesity-related insulin resistance. The emergence of protein S -nitrosation as a causative link to insulin resistance is a welcome advance in the field and suggests additional research and molecular targets for intervention. See accompanying brief report, p. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 62, Issue 2. Previous Article Next Article. Article Navigation. Commentary January 17 Aging and Insulin Resistance: Just Say iNOS Joseph L. Evans ; Joseph L. Corresponding author: Joseph L. Evans, jevansphd earthlink. This Site. Google Scholar. Ira D. Goldfine Ira D. Diabetes ;62 2 — Connected Content. |
| Insulin and aging | This bacterial overgrowth leads Healthy weight supplements Weight control exercises bacterial toxins to be secreted aigng gut Innsulin the blood, contributing to insulin Healthy weight supplements R. Sensktivity this is just an approximation, the fact that the Insulin sensitivity and aging of β-cell response thus determined reflects existing knowledge strengthens our conclusions. Sarcopenia Older people are prone to sarcopenia Mainly aging-associated skeletal muscle alternations are muscle atrophy, often accompanied by sarcopenia [ 36 ]. Download citation. Role of visceral adipose tissue in aging. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor defect of insulin action. Relation of body fat distribution to metabolic complications of obesity. |
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The publisher and the editor s disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. View Metrics. Email alerts Online First Alert. Latest Issue Alert. Citing articles via Web Of Science CrossRef Latest Most Read Most Cited Multi-stakeholder opinion statement on the care of individuals born with differences of sex development: common ground and opportunities for improvement. Department of Medicine, University of Colorado Health Sciences Center, Division of Endocrinology, Denver, Colorado Find articles by Fink, R. in: JCI PubMed Google Scholar. Find articles by Kolterman, O. Find articles by Griffin, J. Find articles by Olefsky, J. Published June 1, - More info. We have studied 17 elderly and 27 non-elderly, nonobese subjects mean age 69±1 and 37±2 yr, respectively to assess the mechanisms responsible for the abnormal carbohydrate tolerance associated with aging. Serum glucose and insulin levels were significantly elevated in the elderly subjects compared with the nonelderly subjects during a g oral glucose tolerance test, suggesting an insulin resistant state. Insulin binding to isolated adipocytes and monocytes was similar in the elderly and nonelderly groups 2. Thus, insulin resistance in the presence of normal insulin binding suggests the presence of a postreceptor defect in insulin action. The results confirm the presence of a postreceptor defect as well as a rightward shift in the dose-response curve. We conclude that carbohydrate intolerance develops as part of the aging process. Studies have shown that after artificially increasing ROS production in myotubes, IRS-1 tyrosine phosphorylation, Akt activation, and GLUT4 translocation to the plasma membrane are impaired [ ]. After treatment with losartan, insulin-stimulated IRS-1 phosphorylation, Akt activation, and GLUT4 translocation could be restored [ ]. In addition, after treating the soleus muscle with nitric oxide, insulin-stimulated glucose uptake and glycogen synthesis were reduced and the phosphorylation of IRS-1 and Akt was also reduced [ 43 ]. These data suggest that increased ROS production in senile skeletal muscle can reduce insulin sensitivity. Studies of the underlying mechanisms have shown that skeletal muscle oxidative stress can impair insulin signaling and induce insulin resistance [ 46 ]. Moreover, oxidative stress can also inhibit the translocation of GLUT4 to the plasma membrane [ 49 ], further reducing the effect of insulin. In addition, oxidative stress can also induce insulin resistance by impairing mitochondrial function. As mentioned earlier, mitochondrial dysfunction can cause a decrease in mitochondrial β-oxidative capacity, leading to IMCL accumulation, inhibiting the activity of PI 3 K, Akt, and GLUT4; and inducing skeletal muscle insulin resistance. However, ROS can damage skeletal muscle mitochondrial function. Protein tyrosine phosphatase 1B PTP1B is an enzyme that regulates insulin-sensitivity. PTP1B phosphorylates IRS-1 tyrosine residues, thereby impairing insulin signaling [ ] and inducing skeletal muscle insulin resistance. Studies have shown that PTP1B knockout animal models exhibit increased skeletal muscle insulin sensitivity and reduced insulin resistance [ 60 ]. However, PTP1B overexpression can promote insulin resistance [ 29 ]. The expression level of PTP1B is increased in senile skeletal muscle. Studies have shown that skeletal muscle PTP1B levels are higher and IRS-1 activity is lower in old males 58 years old than in young males 24 years old [ 37 ]. In addition, PTP1B levels in skeletal muscle were higher, PTP1B interacted with IRS-1 more and insulin resistance was more severe in week-old rats than in week-old rats [ 5 ]. These data indicate increased expression of PTP1B in aging skeletal muscle. Therefore, PTP1B increases the risk of insulin resistance in aging skeletal muscle. The endoplasmic reticulum ER is an important organelle of eukaryotic cells that is involved in synthesizing, folding, packaging and transporting proteins. During skeletal muscle aging, ER stress levels increase. Studies have shown that ER stress-related factors and markers GRP78 and CHOP in the soleus muscles of month-old rats are significantly upregulated compared with the levels in the soleus muscles of 6-month-old rats [ 77 ]. Moreover, the expression of ER stress-related factors and markers GRP78, PDI and CHOP in the gastrocnemius muscles of month-old mice was also significantly higher than that in 6-month-old mice [ 50 ]. These data indicate an increase in ER stress levels in senile skeletal muscle. Studies on the underlying mechanism have shown that ER function declines during skeletal muscle aging, leading to the accumulation of unfolded or misfolded proteins [ 11 ], thereby inducing ER stress. In addition, a high level of mitochondrial ROS can also induce ER stress [ 66 ], and the skeletal muscle aging process can produce a large amount of ROS, thereby further promoting ER stress. ER stress can disrupt protein folding, leading to the accumulation of misfolded protein [ 8 ], which can easily induce inflammation and lipid accumulation, thereby impairing insulin signaling and inducing skeletal muscle insulin resistance [ 69 ]. Studies have shown that ER stress can reduce the phosphorylation of IRS-1 and Akt, decrease the expression of oxygen-regulated protein ORP , which prevents ER stress; and induce insulin resistance [ ]. These data suggest that ER stress reduces skeletal muscle insulin sensitivity and induces skeletal muscle insulin resistance [ 83 ]. ER stress also promotes skeletal muscle insulin resistance through the JNK pathway. Studies have shown that ER stress activates JNK, thereby phosphorylating IRS-1 serine , impairing insulin signaling and inhibiting Akt phosphorylation. As a result, skeletal muscle insulin resistance is promoted [ 87 ]. The use of JNK inhibitors reversed the ER stress-induced inhibition of Akt phosphorylation, thereby improving skeletal muscle insulin sensitivity [ 92 ]. Therefore, ER stress can increase the risk of insulin resistance in aging skeletal muscle by directly impairing insulin signaling or activating the JNK pathway. The autophagic ability of skeletal muscle gradually decreases with age. Studies have shown that the levels of the p62, LC3-II and LC3-I autophagy markers in the skeletal muscle of aged rats are elevated, indicating that the autophagic ability of the skeletal muscle is weakened, resulting in impaired skeletal muscle function, which is more obvious with age [ 7 ]. In addition, the proteolytic capacity of mouse skeletal muscle [ ] and rat skeletal muscle [ 31 ] also decreased with age, which may be related to the decreased lysosomal protease activity. Studies have found skeletal muscle lysosomal lipid accumulation in senile rats, which results in impaired lysosomal function [ 76 ], l decreased lysosomal protease activity [ 7 ], and decreased skeletal muscle autophagic ability. These data indicate that the activation of the autophagy-lysosomal pathway is reduced during skeletal muscle aging, which results in decreased autophagy in senile skeletal muscle. As mentioned earlier, skeletal muscle oxidative damage increases with age. The autophagy-lysosomal pathway degrades large amounts of skeletal muscle protein, thereby reducing the oxidative damage to the skeletal muscle [ 58 ]. Therefore, the decline in skeletal muscle autophagy is not conducive to the prevention of oxidative damage and is closely related to skeletal muscle insulin resistance. Studies have shown that autophagy markers, p62 levels and LC3-II and LC3-I ratios, are significantly increased in insulin-resistant myocytes, and the myocyte autophagic ability is reduced [ 17 ]. In addition, the insulin-stimulated p-Akt Ser levels were decreased and insulin sensitivity was reduced after blocking the autophagy of C2C12 myotubes with the lysosomal inhibitor chloroquine CLQ [ 17 ]. Insulin resistance was improved after increasing the autophagic ability of the C2C12 myotubes [ 17 ] and the L6 myocytes [ 1 ]. Therefore, reduced autophagy can increase the risk of insulin resistance during the process of skeletal muscle aging. Mainly aging-associated skeletal muscle alternations are muscle atrophy, often accompanied by sarcopenia [ 36 ]. Sarcopenia is an age-related progressive decline in skeletal muscle mass and function in the absence of other diseases. Additionally, as age increases, the composition of the skeletal muscle fiber types also changes. The proportion of type II muscle fibers is reduced [ 32 ], resulting in the muscle mass of type II muscle fibers becoming lower than that of type I muscle fibers. In addition, motor neurons also change. Due to the decreased number and vitality of senile skeletal muscle motor units [ 54 ], the neuromuscular dominance is also weakened, which is coupled with the decline in muscle mass in the aging skeletal muscles, resulting in a significant decrease in muscle strength [ 10 ]. In addition, studies on the underlying mechanisms have shown that myostatin is a major regulator of skeletal muscle size and mass and is expressed almost exclusively in skeletal muscle [ 16 ]. The overexpression of myostatin can cause muscle atrophy and plays an important role in sarcopenia [ 91 ]. These data indicate a progressive decline in muscle mass and strength during skeletal muscle aging, which is associated with myostatin. Skeletal muscle mass is an important factor in glucose and energy homeostasis [ ] and is positively correlated with skeletal muscle insulin sensitivity. Studies have shown that increased muscle mass increases skeletal muscle glucose uptake and improves insulin sensitivity [ 20 ]. Sarcopenia can cause skeletal muscle mass and strength to decrease, thereby reducing skeletal muscle insulin sensitivity. Myostatin plays an important role in this process. Studies have shown that elderly mice treated with myostatin inhibitors for 4 weeks exhibited improvements in sarcopenia and increased skeletal muscle insulin sensitivity [ 16 ]. Skeletal muscle glucose utilization and insulin sensitivity are also increased in myostatin knockout mice [ 94 ]. Therefore, the decreased skeletal muscle mass and strength caused by sarcopenia can increase the risk of insulin resistance in aging skeletal muscle. The renin-angiotensin system RAS plays pleiotropic roles in regulating mammalian pathophysiology. Angiotensin II Ang II is a key molecule of RAS and is produced as a result of sequential cleavage of angiotensinogen by renin and angiotensin-converting enzyme ACE [ 56 ]. Ang II can bind to the Ang II type 1 AT 1 receptor, thereby activating the AT 1 receptor [ 2 ], and leading to cell proliferation, hypertrophic responses, apoptosis, generation of ROS, and tissue inflammation [ 56 ]. Ang II is cleaved by ACE2 to form another peptide Ang 1—7. This ACE2-Ang 1—7 axis, acting via another G protein-coupled receptor Mas, is involved in vasodilatory, anti-fibrotic, and anti-inflammatory properties [ 52 ]. These two axes show different changes in aging skeletal muscle. Studies have shown that the skeletal muscle aging process can activate RAS classic axis and activate the AT 1 receptor [ 55 , 56 , 64 ], which induces inflammation and oxidative stress. However, inhibiting the classic axis can prolong the physiological aging process and promotes longevity in rodents [ 12 ]. In addition, RAS non-classical axis weakens in aged skeletal muscles [ 75 ]. However, activating the RAS non-classical axis can reduce the aging phenotype in aged mice [ 75 ]. These data indicate that the RAS classical axis is activated and the RAS non-classical axis is weakened in aging skeletal muscle. Excessive activation of RAS is closely related to skeletal muscle insulin resistance. Studies have shown that after injecting Ang II into rats, skeletal muscle glucose tolerance and insulin signaling pathway are impaired, and skeletal muscle insulin resistance appears [ 90 ]. Studies have shown that after ACE inhibition, skeletal muscle insulin sensitivity is enhanced, and after the Mas receptor is inhibited, the enhancement effect is eliminated [ 28 ]. These data indicate that activation of the RAS classical axis can promote skeletal muscle insulin resistance, while activation of the RAS non-classical axis can inhibit the classical axis, thereby improving skeletal muscle insulin resistance. Therefore, activation of the RAS classical axis and weakening of the RAS non-classical axis in aging skeletal muscle may increase the risk of skeletal muscle insulin resistance. There are also interactions between these mechanisms. Among them, The ER and mitochondria join together at multiple contact sites to form specific domains, termed mitochondria-ER associated membranes MAMs [ 6 , 19 , 68 ]. It is closely related to the autophagy process. There are several important autophagy-related proteins in mitochondria, such as ATG5, which is critical for autophagosome formation, translocates to the MAM compartment during phagophore biogenesis and then dissociates from MAMs upon completion of the autophagosome [ 39 ]. Therefore, MAM plays an important role in autophagy, while mitochondrial dysfunction and ER stress can decrease autophagy capacity. In addition, increased ROS is an important factor inducing inflammation, while mitochondria and ER are important sources of ROS [ 67 ]. Therefore, mitochondrial dysfunction and ER stress can generate a large amount of ROS and induce inflammation and oxidative stress. In summary, mitochondrial dysfunction and ER stress can decrease autophagy capacity, increased ROS production and IMCL accumulation, and then induce inflammation and oxidative stress. Furthermore, the over-activated renin-angiotensin system also increases inflammation levels and induces oxidative stress. In addition, the occurrence of sarcopenia will exacerbate the above processes. Finally, increased inflammation and oxidative stress can impair mitochondrial function and exacerbate ER stress in turn, thereby further exacerbating the above processes and increasing the risk of insulin resistance. The aforementioned mechanisms, such as mitochondrial oxidative ability, inflammation, oxidative stress, insulin sensitivity regulating enzymes, ER stress, autophagy ability, and RAS axis, can be used as targets for the prevention and treatment of aging skeletal muscle insulin resistance. In addition, there are non-pharmacological treatments, such as exercise, that can prevent and treat insulin resistance in aging skeletal muscle. Studies have shown that exercise can increase skeletal muscle mass and improve skeletal muscle insulin sensitivity [ 36 , 65 , 88 ]. Exercise can also enhance mitochondrial oxidative capacity, enhance skeletal muscle autophagy and antioxidant capacity, reduce oxidative stress and inflammation levels [ 36 , 74 ], and improve skeletal muscle insulin resistance. Therefore, both pharmacological treatments targeting these mechanisms and exercise can prevent and treat aging skeletal muscle insulin resistance. An increased risk of senile skeletal muscle insulin resistance is associated with skeletal muscle dysfunction. During the aging of skeletal muscle, mitochondrial dysfunction, intramyocellular lipid accumulation, increased inflammation, oxidative stress, changes in the activities of enzymes that regulate insulin sensitivity, endoplasmic reticulum stress, decreased autophagy, sarcopenia and over-activated RAS all induce skeletal muscle insulin resistance. These processes can impair skeletal muscle insulin sensitivity and increase the risk of insulin resistance and type 2 diabetes during the skeletal muscle aging process Fig. Of course, pharmacological treatments targeting these mechanisms and exercise can prevent and treat aging skeletal muscle insulin resistance. Therefore, in view of the above-mentioned aspects closely related to aging skeletal muscle insulin resistance, further exploration of relevant mechanisms and development of related drugs require further research in the future. Skeletal muscle aging can increase insulin resistance by promoting mitochondrial dysfunction, IMCL accumulation, inflammation, oxidative stress, PTP1B expression, ER stress, decreased autophagy, sarcopenia and over-activated RAS. In addition, skeletal muscle mitochondrial dysfunction promotes IMCL accumulation and induces oxidative stress and ER stress, moreover, IMCL accumulation, oxidative stress, and ER stress can induce inflammation. 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| Publication types | In Food and exercise tracker, week-old sensitivityy mice were injected intravenously with AAV and fed on aand regular Oats and sustainable farming. Mol Cell Sensitiviity. Meneilly GS, Elliott T, Tessier D, Hards L, Tildesley H. Exp Mol Med. Nutritional determinants of the insulin resistance syndrome. Aparecida Emiko H, Fernanda AR, Miriam Sterman D, Mario José AS. Sorry, a shareable link is not currently available for this article. |
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