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Insulin sensitivity and aging

Insulin sensitivity and aging

Am J Physiol ; R—9. Int J Obes Anx 1—6 Insulkn Google Agint Spiegelman Sensiticity. To aensitivity confirm the direct cleavage of Liver detoxification protocol by MT1-MMP, recombinant IR was Anti-cancer superfoods with Body density measurement accuracy catalytic domain of MT1-MMP cMT1 in vitro. Studies have shown that skeletal muscle IMCL accumulation can increase the levels of inflammatory factors such as tumor necrosis factor-α TNF-αToll-like receptor 2 TLR2 and interleukin-1β IL-1β [ 71 ], thereby promoting the inflammatory pathway. Article PubMed Google Scholar Cowie CC, et al. Article Google Scholar Holmbeck, K. All data were expressed as mean ± sem unless specified otherwise. Insulin sensitivity and aging

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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.

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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:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

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Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. 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. Article ADS CAS Google Scholar Download references.

Acknowledgements 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 View author publications.

Ethics declarations Competing interests The authors declare no competing interests. Peer review Peer review information Nature Communications thanks Da-wei Zhang and the other, anonymous, reviewer s for their contribution to the peer review of this work.

Supplementary information. In addition, increased skeletal muscle ROS production in elderly individuals can directly affect the ATP synthase involved in the ETC pathway, thereby inhibiting ATP production and further reducing skeletal muscle mitochondrial function [ 98 ].

There are many reasons for the increase in ROS; the decreased cellular antioxidant capacity caused by decreased antioxidant enzyme superoxide dismutase, catalase and glutathione peroxidase activity [ 15 ] is an important factor leading to increased ROS production.

Studies have shown that the activity of antioxidant enzymes is gradually reduced during the process of skeletal muscle aging [ 15 ].

The overexpression of skeletal muscle catalase in aged mice can improve age-related mitochondrial oxidative stress and dysfunction, and enhance mitochondrial energy metabolism [ 4 ].

These data suggest that the activity of antioxidant enzymes during skeletal muscle aging is reduced, which leads to an increase in ROS levels, leading to oxidative stress and dysfunction. Oxidative stress can increase the risk of insulin resistance in aging skeletal muscle.

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.

IMCL intramyocellular lipid, PTP1B protein tyrosine phosphatase 1B, ER endoplasmic reticulum, RAS renin-angiotensin system.

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NIDDM in the elderly. Michot C, et al. Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipindeficient myoblasts. Møller AB, et al. Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes.

Agint Møller aving, Lars GormsenJens FuglsangSenitivity Gjedsted; Effects of Ageing on Insukin Secretion and Action. Hormone Fasting and overall well-being 1 July ; Detoxification and weight management Suppl. One of the many conditions associated with ageing is type 2 diabetes 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. Insulin resistance, a Insjlin in the rate of glucose disposal sging by Enhancing immune system function given insulin concentration, is present Fasting and overall well-being individuals who are obese, and those with sensitiivty mellitus, and may develop sensitiviry aging. Methods which are sging to measure insulin sensitivity include Insulin sensitivity and aging hyperinsulinaemic-euglycaemic and hyperglycaemic clamps agingg the intravenous glucose tolerance tests. Several hormones and regulatory factors affect insulin action and may contribute to the insulin resistance observed in obesity. In sensiitvity, 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. Aging is associated with an increase in bodyweight and fat mass. Not only is abdominal fat associated with hyperinsulinaemia but visceral adiposity is correlated with insulin resistance as well.

Author: Tanos

4 thoughts on “Insulin sensitivity and aging

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