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Insulin resistance and aging

Insulin resistance and aging

Published in Volume Rseistance, Issue 6 on June resisyance, J Clin Invest. Insulin rapidly stimulates tyrosine phosphorylation of a Mrprotein in intact cells. Pharmacological agents that directly modulate insulin secretion.

Insulin resistance and aging -

cinnamon rolls, biscuits, … , snack foods e. microwave popcorn , fast-food e. frozen pizza , ready-to-eat meals, various vegetable shortenings made from partially hydrogenated vegetable oil , French fries, and omega-6 rich oils and fasts, like sunflower oil, corn oil, safflower oil, margarine, sesame oil, mayonnaise and many salad dressings.

Try to eat more healthy fats like in olives, olive oil, walnuts, seeds flaxseed, chia seed , fatty fish, avocado and so on.

The toxic substances inhaled from smoke increase insulin resistance, inflammation and DNA damage. Milk is made by nature to make calves grow fast. It contains lots of growth stimulating substances that stimulate insulin, insulin like growth factor and other pro-aging pathways.

Research shows that drinking milk can increase insulin resistance R , R , R , R. In one study, children drank 1. Just ml 7 ounces of milk combined with a low-glycemic index meal causes a percent increase in insulin R.

Exercise improves insulin sensitivity in many ways. For example, exercise leads to increased uptake of glucose in the muscles, and increases mitochondrial biogenesis mitochondria are the tiny power plants in our cells that burn up glucose.

Both aerobic exercise e. running, swimming, dancing and anaerobic exercise e. weight lifting improve insulin sensitivity R , R , R. Combining the two has an extra synergistic effect R , R.

HIIT high intensity interval training is renowned to improve insulin resistance very rapidly. Avoid sitting too much. Some people call sitting the new smoking. Many people sit the whole day behind their desk, which is very bad for our metabolism.

Try to go for a little walk after every hour of desk sitting, and try to sneak in some exercise during the day, like taking the stairs or doing some push ups or squats.

Sleep deprivation leads to increased insulin resistance. Even one night of too little sleep increases insulin resistance in healthy people R. Also, people with irregular sleep patterns, especially people who do night shifts, have more risk of insulin resistance, diabetes and being overweight R , R.

Soluble fibers serve as food for the bacteria in our gut, while the insoluble fibers mainly just accelerate bowel movements peristalsis but cannot be digested by most gut bacteria. Various studies found that people who consume lots of soluble fiber have reduced insulin resistance R , R , R.

You can consume inulin and FOS fructo-oligosaccharide supplements, but the first 2 weeks you will likely experience increased flatulence, which will mostly wane. You can also increase fiber intake by upping your intake of fiber-rich foods, like flaxseed, chia seeds which also contains healthy omega-3 fatty acids , pumpkin seeds, walnuts and green-leafy vegetables like kale, broccoli or spinach R.

Dark chocolate and blueberries have shown to reduce insulin resistance R , R. Turmeric, ginger, garlic, thyme, oregano, cinnamon, and many other herbs improve insulin resistance, and this via many ways R , R , R , R , R , R. For example, many spices and herbs reduce inflammation.

Low-grade inflammation contributes to insulin resistance. Spices and herbs also temper overgrowth of bacteria in the gut often caused by bacteria feeding on the sugars and starches we eat too much via the western diet.

This bacterial overgrowth leads to many bacterial toxins to be secreted by gut into the blood, contributing to insulin resistance R.

However, large recent studies show that this is still too much. Ideally, one should consume maximum one glass of alcohol per day, including also alcohol-free days.

Drink more green tea. Green tea can improve insulin resistance R. You can also drink white tea, which is green tea but made from fresher, less oxidized leaves.

Lingering, low-grade inflammation can contribute to insulin resistance. Many of these ingredients can be found in NOVOS Core.

A deficiency in choline is also associated with increased insulin resistance. We advise however to choline chloride instead of choline bitartrate.

Also, some studies suggested that choline may increase atherosclerosis because choline can be converted to TMAO, a pro-atherogenic substance. 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. 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.

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Insulin resistance, a Isnulin in Insuulin rate Fast-acting appetite suppressants glucose disposal Exercise physiology by a resstance insulin concentration, Insulin resistance and aging present in individuals who are obese, and those with diabetes mellitus, and may develop with agign. Methods which are Inulin to measure insulin sensitivity include the hyperinsulinaemic-euglycaemic and hyperglycaemic clamps and the intravenous glucose tolerance tests. Several hormones and regulatory factors affect insulin action and may contribute to the insulin resistance observed in obesity. In addition, abnormal free fatty acid metabolism plays an important role in insulin resistance and the abnormal carbohydrate metabolism seen in individuals who are obese or diabetic. Thus, the mechanisms underlying the development of insulin resistance are multifactorial, and also involve alterations of the insulin signalling pathway.

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Methods which are Insulin resistance and aging to measure insulin sensitivity include the hyperinsulinaemic-euglycaemic Insuiln hyperglycaemic clamps and the intravenous glucose tolerance tests.

Several hormones and regulatory Insilin affect insulin Insulin resistance and aging and may contribute to the insulin resistance Insulin resistance and aging in obesity. In addition, resistznce Insulin resistance and aging fatty acid aginy plays an important rwsistance in insulin resistance and the abnormal carbohydrate metabolism seen in individuals who are obese rresistance diabetic.

Thus, the mechanisms underlying the development of insulin resistance are Insulin resistance and aging, and also involve alterations of the insulin reaistance pathway. Aging Cardiovascular fitness Insulin resistance and aging with an increase in afing and fat adn.

Not only is abdominal fat associated with hyperinsulinaemia but visceral adiposity is correlated with insulin resistance as well. Modifications of the changes in body composition with aging by diet and exercise training could delay the onset of insulin resistance.

Weight loss and aerobic and resistive exercise training result in losses of total body fat and abdominal fat. Several studies report that bodyweight loss increases insulin sensitivity and improves glucose tolerance. In addition, the insulin resistance observed in aged persons can be modified by physical training.

Longitudinal studies indicate significant improvements in glucose metabolism with aerobic exercise training in middle-aged and older men and women. Moreover, the improvements in insulin sensitivity with resistive training are similar in magnitude to those achieved with aerobic exercise.

The improvements in glucose metabolism after bodyweight loss and exercise training may in some cases be partially attributed to changes in body composition, including reductions in total and central body fat.

Yet, additional changes in skeletal muscle, blood flow and other mechanisms likely interact to modify insulin resistance with exercise training. Lifestyle modifications including bodyweight loss and physical activity provide health benefits and functional gains and should be promoted to increase insulin sensitivity and prevent glucose intolerance and type 2 diabetes mellitus in older adults.

Abstract Insulin resistance, a reduction in the rate of glucose disposal elicited by a given insulin concentration, is present in individuals who are obese, and those with diabetes mellitus, and may develop with aging. Publication types Clinical Trial Controlled Clinical Trial Research Support, U.

Gov't, Non-P. Research Support, U. Gov't, P. Substances Blood Glucose Fatty Acids, Nonesterified Insulin.

: Insulin resistance and aging

Top bar navigation The experiments were performed as previously described Ageing Res Rev — 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 This protective cell response is impaired in the presence of experimentally induced or diabetes-associated insulin resistance Ginsberg H , Kimmerling G , Olefsky JM , Reaven GM Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia. Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipindeficient myoblasts. Article CAS Google Scholar Haiyan X, et al.
Introduction

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. A commentary has been published: Targeted Disruption of Inducible Nitric Oxide Synthase Protects Against Aging, S -Nitrosation, and Insulin Resistance in Muscle of Male Mice.

Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. View large Download slide. No potential conflicts of interest relevant to this article were reported.

Search ADS. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.

Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Inhibition of the protein tyrosine phosphatase PTP1B: potential therapy for obesity, insulin resistance and type-2 diabetes mellitus.

Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance.

A molecular basis for insulin resistance. Increased adipocyte S-nitrosylation targets anti-lipolytic action of insulin: relevance to adipose tissue dysfunction in obesity. Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.

View Metrics. Email alerts Article Activity Alert. Online Ahead of Print Alert. Latest Issue Alert. See also Targeted Disruption of Inducible Nitric Oxide Synthase Protects Against Aging, S -Nitrosation, and Insulin Resistance in Muscle of Male Mice. Most Read Most Cited MRI Metrics of Cerebral Endothelial Cell—Derived Exosomes for the Treatment of Cognitive Dysfunction Induced in Aging Rats Subjected to Type 2 Diabetes.

Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel.

Genetic Influences of Adiponectin on Insulin Resistance, Type 2 Diabetes, and Cardiovascular Disease. Online ISSN X Print ISSN Books ShopDiabetes. org ADA Professional Books Clinical Compendia Clinical Compendia Home News Latest News DiabetesPro SmartBrief. Resources ADA Professional Membership ADA Member Directory Diabetes.

Insulin secretion, on the other hand, seems to decrease with age even after adjustments for differences in adiposity, fat distribution, and physical activity. This may be responsible for the glucose intolerance in the very old even after improvements have been made in their lifestyle variables.

Abstract Aging is associated with an increased incidence of hypertension, noninsulin-dependent diabetes mellitus, and coronary heart disease. Publication types Review. Substances Insulin.

Frontiers | Insulin and aging – a disappointing relationship

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. Cell 99 , 81—92 Zhou, Z. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.

Natl Acad. USA 97 , — Article ADS CAS Google Scholar. Gutierrez-Fernandez, A. Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid. EMBO J. Mori, H. New insight into the role of MMP14 in metabolic balance. PeerJ 4 , e Chun, T. Genetic link between obesity and MMPdependent adipogenic collagen turnover.

Diabetes 59 , — Frankwich, K. Proof of concept: matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes. Chow, C. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nam, D. Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries.

USA , — Remacle, A. Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase MT1-MMP in metastasis. Oncotarget 8 , — Li, X. Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity.

Hui, X. Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue. EMBO Rep. Wong, H. MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. Download references.

The presented work was kindly supported by General Research Fund and , Health and Medical Research Fund and , National Natural Science Fund , and Guangdong Natural Science Foundation A and A School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China. Centre for Systems Biology Dresden, Max Planck Institute for Molecular Cell and Biology, Dresden, Germany. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.

Respiratory Department, Jinhua Guangfu hospital, Jinhua, China. Centre for Chinese Herbal Medicine Drug Development Limited, Hong Kong Baptist University, Hong Kong SAR, China. You can also search for this author in PubMed Google Scholar. This study was conceptualized by H. and X.

Most of the experiments were performed by H. Some of the data were collected by H. provided experimental advices. Funding supporting this project was acquired by W. and Z. This project was supervised by W. The manuscript was written by H. Correspondence to Zhao-Xiang Bian or Hoi Leong Xavier Wong.

Nature Communications thanks Da-wei Zhang and the other, anonymous, reviewer s for their contribution to the peer review of this work. Open Access This article is licensed under a Creative Commons Attribution 4.

Reprints and permissions. Guo, X. Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor. Nat Commun 13 , Download citation. Received : 28 September Accepted : 22 June Published : 29 June Anyone you share the following link with will be able to read this content:.

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nature nature communications articles article. Download PDF. Subjects Insulin signalling Type 2 diabetes. Abstract Insulin sensitivity progressively declines with age. Introduction Aging in human is associated with the development of age-associated pathologies, including insulin resistance and hyperglycemia.

Results Loss of MT1-MMP prevents aging- and obese-associated insulin resistance To understand the regulatory role of MT1-MMP in insulin sensitivity, we assessed the metabolic homeostasis of mice deficient in MT1-MMP.

Full size image. Discussion The mechanism underlying insulin resistance in physiological aging is not completely elucidated. Human plasma collection Young and elderly blood were collected for the isolation of EDTA plasma.

Metabolic measurement The metabolic measurement of mice was performed as previously described Adeno-associated virus AAV treatment AAV-WT MT1-MMP and AAV-MT1 EA virus produced by the pAAV-TBG-sfGFP-WPRE vector plasmid were purchased from Obio Technology Ltd. Antibodies 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, Cell treatment HEKT cells obtained from Prof.

In vitro MT1-MMP cleavage assay The experiments were performed as previously described Statistical analyses Each experiment was independently performed for at least three times. Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability All data generated or analyzed during this study are included in this published article and its supplementary information files.

References Caro, J. Article CAS Google Scholar Frojdo, S. Article Google Scholar Olefsky, J. CAS PubMed Google Scholar Samuel, V. Article CAS Google Scholar Meakin, P. Article ADS Google Scholar Maesako, M.

Article CAS Google Scholar Yuasa, T. Article CAS Google Scholar Soluble Insulin Receptor Study, G. Article Google Scholar Holmbeck, K. Article CAS Google Scholar Zhou, Z. Article ADS CAS Google Scholar Gutierrez-Fernandez, A.

Article CAS Google Scholar Mori, H. Article Google Scholar Chun, T. Article CAS Google Scholar Frankwich, K. Article CAS Google Scholar Chow, C.

Article CAS Google Scholar Remacle, A. Article Google Scholar Li, X. Article CAS Google Scholar Wong, H. running, swimming, dancing and anaerobic exercise e. weight lifting improve insulin sensitivity R , R , R.

Combining the two has an extra synergistic effect R , R. HIIT high intensity interval training is renowned to improve insulin resistance very rapidly.

Avoid sitting too much. Some people call sitting the new smoking. Many people sit the whole day behind their desk, which is very bad for our metabolism. Try to go for a little walk after every hour of desk sitting, and try to sneak in some exercise during the day, like taking the stairs or doing some push ups or squats.

Sleep deprivation leads to increased insulin resistance. Even one night of too little sleep increases insulin resistance in healthy people R. Also, people with irregular sleep patterns, especially people who do night shifts, have more risk of insulin resistance, diabetes and being overweight R , R.

Soluble fibers serve as food for the bacteria in our gut, while the insoluble fibers mainly just accelerate bowel movements peristalsis but cannot be digested by most gut bacteria. Various studies found that people who consume lots of soluble fiber have reduced insulin resistance R , R , R.

You can consume inulin and FOS fructo-oligosaccharide supplements, but the first 2 weeks you will likely experience increased flatulence, which will mostly wane. You can also increase fiber intake by upping your intake of fiber-rich foods, like flaxseed, chia seeds which also contains healthy omega-3 fatty acids , pumpkin seeds, walnuts and green-leafy vegetables like kale, broccoli or spinach R.

Dark chocolate and blueberries have shown to reduce insulin resistance R , R. Turmeric, ginger, garlic, thyme, oregano, cinnamon, and many other herbs improve insulin resistance, and this via many ways R , R , R , R , R , R. For example, many spices and herbs reduce inflammation.

Low-grade inflammation contributes to insulin resistance. Spices and herbs also temper overgrowth of bacteria in the gut often caused by bacteria feeding on the sugars and starches we eat too much via the western diet. This bacterial overgrowth leads to many bacterial toxins to be secreted by gut into the blood, contributing to insulin resistance R.

However, large recent studies show that this is still too much. Ideally, one should consume maximum one glass of alcohol per day, including also alcohol-free days. Drink more green tea. Green tea can improve insulin resistance R.

You can also drink white tea, which is green tea but made from fresher, less oxidized leaves. Lingering, low-grade inflammation can contribute to insulin resistance. Many of these ingredients can be found in NOVOS Core.

A deficiency in choline is also associated with increased insulin resistance. We advise however to choline chloride instead of choline bitartrate. Also, some studies suggested that choline may increase atherosclerosis because choline can be converted to TMAO, a pro-atherogenic substance.

However, other studies show no association between intake of choline and the risk of heart disease. And for the ones that do, there is the confounding factor that choline is also found in meat and egg products. To make a long story short, choline is very important for regulating the epigenome, reduce DNA damage and improve brain function.

Many people in the west are deficient in this important nutrient. The advantages of sufficient amounts of choline outweigh the potential and still-to-be-proven risk of increased heart disease. Add a tablespoon of apple cider vinegar to a glass of water after each meal.

Apple cider vinegar can improve insulin sensitivity R , R , R. Low magnesium levels are associated with insulin resistance R , R. One could take magnesium malate powder for example, which is the best form of magnesium. One could also take chromium R , zinc and copper R , as these minerals also play a role in insulin sensitivity.

The more you can lower your insulin resistance, the healthier you will be, and the more you slow down the aging process and reduce your risk of many aging diseases and symptoms.

Our foundational formulation, NOVOS Core, targets all the root causes of aging to promote longevity, appearance, cognition, and energy. Slow down aging with these 12 highly-effective longevity ingredients in one daily dose, which you can mix with water to drink.

Dietary restriction and exercise have been found to lower levels of insulin and insulin resistance. Concomitantly, dietary restriction, dietary phytochemicals and exercise activate the Nrf2-dependent cellular stress response and modify microbiota composition and function in a favorable way.

During aging, the cell stress response via Nrf2 becomes less potent but possibly not in centenarians — , and there is an age-dependent increase of circulating insulin and insulin resistance 52 , Both processes are supporting the pro-aging effects of insulin, and both may be targeted by dietary restriction and exercise.

HK: Writing — original draft. The work was supported by Gesellschaft von Freunden und Förderern der Heinrich-Heine-Universität Düsseldorf e. We thank Fraser W. Scott, the Ottawa Hospital Research Institute and University of Ottawa, Canada, for reviewing the manuscript. 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.

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Insulin resistance and aging IInsulin MøllerAgimg GormsenJens FuglsangJakob Resistancf Effects of Insulin resistance and aging on Insulin Secretion and Action. Insulin resistance and aging Research 1 July ; resistacne Suppl. One of the resistancf conditions Insuiln with ageing is type HbAc guidelines Insulin resistance and aging mellitus, the prevalence of which increases from 20—30 years of age onwards. In many cases, type 2 diabetes mellitus is caused by the combination of insulin resistance and poor insulin secretion. Insulin resistance is also a risk factor associated with other disorders, in particular cardiovascular disease. Physiological changes associated with ageing, such as changes in body composition, decreased physical fitness, changes in hormones, and the secondary effects of high levels of free fatty acids and glucose, may also contribute to the impairment of insulin secretion and action.

Author: Taulmaran

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