• Title, Summary, Keyword: IRS

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IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1-/- Mice Mediated by miR-33

  • Tang, Chen-Yi;Man, Xiao-Fei;Guo, Yue;Tang, Hao-Neng;Tang, Jun;Zhou, Ci-La;Tan, Shu-Wen;Wang, Min;Zhou, Hou-De
    • Molecules and Cells
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    • v.40 no.2
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    • pp.123-132
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    • 2017
  • Insulin signaling is coordinated by insulin receptor substrates (IRSs). Many insulin responses, especially for blood glucose metabolism, are mediated primarily through Irs-1 and Irs-2. Irs-1 knockout mice show growth retardation and insulin signaling defects, which can be compensated by other IRSs in vivo; however, the underlying mechanism is not clear. Here, we presented an Irs-1 truncated mutated mouse ($Irs-1^{-/-}$) with growth retardation and subcutaneous adipocyte atrophy. $Irs-1^{-/-}$ mice exhibited mild insulin resistance, as demonstrated by the insulin tolerance test. Phosphatidylinositol 3-kinase (PI3K) activity and phosphorylated Protein Kinase B (PKB/AKT) expression were elevated in liver, skeletal muscle, and subcutaneous adipocytes in Irs-1 deficiency. In addition, the expression of IRS-2 and its phosphorylated version were clearly elevated in liver and skeletal muscle. With miRNA microarray analysis, we found miR-33 was down-regulated in bone marrow stromal cells (BMSCs) of $Irs-1^{-/-}$ mice, while its target gene Irs-2 was up-regulated in vitro studies. In addition, miR-33 was down-regulated in the presence of Irs-1 and which was up-regulated in fasting status. What's more, miR-33 restored its expression in re-feeding status. Meanwhile, miR-33 levels decreased and Irs-2 levels increased in liver, skeletal muscle, and subcutaneous adipocytes of $Irs-1^{-/-}$ mice. In primary cultured liver cells transfected with an miR-33 inhibitor, the expression of IRS-2, PI3K, and phosphorylated-AKT (p-AKT) increased while the opposite results were observed in the presence of an miR-33 mimic. Therefore, decreased miR-33 levels can up-regulate IRS-2 expression, which appears to compensate for the defects of the insulin signaling pathway in Irs-1 deficient mice.

Insulin Receptor Substrate Proteins and Diabetes

  • Lee Yong Hee;White Morris F.
    • Archives of Pharmacal Research
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    • v.27 no.4
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    • pp.361-370
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    • 2004
  • The discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades is a key step to understanding insulin and insulin-like growth factor (IGF) action. Moreover, IRS-proteins coordinate signals from the insulin and IGF receptor tyrosine kinases with those generated by proinflammatory cytokines and nutrients. The IRS2-branch of the insulin/IGF signaling cascade has an important role in both peripheral insulin response and pancreatic $\beta$-cell growth and function. Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during peripheral insulin resistance. IRS protein signaling is down regulated by serine phosphorylation or protea-some-mediated degradation, which might be an important mechanism of insulin resistance during acute injury and infection, or chronic stress associated with aging or obesity. Under-standing the regulation and signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal new strategies to prevent or cure diabetes and other metabolic diseases.

Metabolic Syndrome and Insulin Resistance Syndrome among Infertile Women with Polycystic Ovary Syndrome: A Cross-Sectional Study from Central Vietnam

  • Le, Minh Tam;Nguyen, Vu Quoc Huy;Truong, Quang Vinh;Le, Dinh Duong;Le, Viet Nguyen Sa;Cao, Ngoc Thanh
    • Endocrinology and Metabolism
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    • v.33 no.4
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    • pp.447-458
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    • 2018
  • Background: Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies among reproductive-age women. Its metabolic features often overlap with those associated with metabolic syndrome (MS) and insulin resistance syndrome (IRS). The objective of this study was to determine the prevalence and predictors of MS and IRS in infertile Vietnamese women with PCOS. Methods: A cross-sectional study was conducted at a tertiary fertility centre at Hue University Hospital from June 2016 to November 2017. A total of 441 infertile women diagnosed with PCOS based on the revised 2003 Rotterdam consensus criteria were enrolled. MS and IRS were defined based on the National Heart, Lung, and Blood Institute/American Heart Association Adult Treatment Panel III 2005 and American College of Endocrinology IRS 2003 criteria, respectively. Complete clinical and biochemical measurements of 318 women were available for analysis. Independent predictors of MS and IRS were identified using multivariate logistic regression. Results: The overall prevalence of MS and IRS in women with PCOS was 10.4% and 27.0%, respectively. We identified older age (>30 years) and obesity as independent predictors of MS and IRS. Elevated anti-$M{\ddot{u}}llerian$ hormone levels increased the risk of IRS, but not that of MS. Conclusion: MS and IRS are prevalent disorders among infertile Vietnamese women with PCOS. PCOS is not solely a reproductive problem. Screening and early intervention for MS and/or IRS based on anthropometric, metabolic, and reproductive hormone risk factors should be an integral part of fertility care.

Comparison of Lifestyle and Nutrient Intake by Number of Components of Insulin Resistance Syndrome in the Daegu Community (대구지역 인슐린저항성증후군의 생활습관 및 영양섭취상태 비교)

  • 이희자;윤진숙
    • Korean Journal of Community Nutrition
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    • v.6 no.3
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    • pp.317-330
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    • 2001
  • The purpose of this study was to figure out the characteristics of dietary habits and lifestyles related to the development of insulin resistance syndrome(IRS). The participants in this study were 595 adults with one or more abnormal data from a health examination and 215 normal adults. When IRS was defined as a condition in which the subjects have 2 or more abnormalities among obesity, hyperlipidemia, hypertension and hyperglycemia, the prevalence rate was 37.8%. We classified the 595 adults by the number of components of IRS components they had, the higher age and obesity index they had. Total cholesterol and glucose levels in the blood were also positively related to the number of IRS components. IRS subjects tended to practice less habitual drinking and more exercise and weight control. Coffee consumption and dining out frequency were also lower in the IRS group. An analysis of food habits by odds ratio indicated that total food score was better in the IRS group. However, it appeared that food habits such as \"frequent snacking\" and \"never rejecting offered foods\" need to be improved in IRS subjects. Other undesirable food habits were related to the consumption of eggs, dairy products, fried foods, garlic and onion. Dietary intake of Ca, Fe, riboflavin, Vit A, and energy were less than 75% of the Korean recommended allowance for more than half of the subjects. Nutrient intake was lower, Ca/P ratio from food intake was worse in the IRS group. Our results indicated that nutrition counseling for IRS need to be focused on balanced food intake to supply sufficient amount of each nutrient.nt of each nutrient.

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High-resolution ALMA Study of the Proto-Brown-Dwarf Candidate L328-IRS

  • Lee, Chang Won;Kim, Gwanjeong;Myers, Philip C.;Saito, Masao;Kim, Shinyoung;Kwon, Woojin;Lyo, A-Ran;Soam, Archana;Kim, Mi-Ryang
    • The Bulletin of The Korean Astronomical Society
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    • v.43 no.2
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    • pp.39.1-39.1
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    • 2018
  • We present our observational attempts to precisely measure the central mass of a proto-brown dwarf candidate, L328-IRS, in order to investigate whether L328-IRS is in the substellar mass regime. Observations were made for the central region of L328-IRS with the dust continuum and CO isotopologue line emission at ALMA band 6, discovering the detailed outflow activities and a deconvolved disk structure of a size of ${\sim}87AU{\times}{\sim}37AU$. We investigated the rotational velocities as a function of the disk radius, finding that its motions between 130 AU and 60 AU are partially fitted with a Keplerian orbit by a stellar object of ${\sim}0.30M_{\odot}$, while the motions within 60 AU do not follow any Keplerian orbit at all. This makes it difficult to lead a reliable estimation of the mass of L328-IRS. Nonetheless, our ALMA observations were useful enough to well constrain the inclination angle of the outflow cavity of L328-IRS as ${\sim}66^{\circ}$ degree, enabling us to better determine the mass accretion rate of ${\sim}8.9{\times}10^{-7}M_{\odot}yr-1$.From assumptions that the internal luminosity of L328-IRS is mostly due to this mass accretion process in the disk, or that L328-IRS has mostly accumulated the mass through this constant accretion rate during its outflow activity, its mass was estimated to be ${\sim}0.012-0.023M_{\odot}$, suggesting L328-IRS to be a substellar object. However, we leave our identification of L328-IRS as a proto-brown dwarf to be tentative because of various uncertainties especially regarding the mass accretion rate.

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Telmisartan increases hepatic glucose production via protein kinase C ζ-dependent insulin receptor substrate-1 phosphorylation in HepG2 cells and mouse liver

  • Cho, Kae Won;Cho, Du-Hyong
    • Yeungnam University Journal of Medicine
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    • v.36 no.1
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    • pp.26-35
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    • 2019
  • Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

"Dust, Ice, and Gas In Time" (DIGIT) Herschel observations of GSS30-IRS1

  • Je, Hyerin;Lee, Jeong-Eun
    • The Bulletin of The Korean Astronomical Society
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    • v.38 no.2
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    • pp.66.2-66.2
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    • 2013
  • As part of the DIGIT key program, we observed GSS30-IRS1, a Class I object located in Ophiuchus (d=125 pc), with Herschel-PACS. More than 70 lines were detected in 50-200 micron band including CO, OH, H2O, and [OI]. All lines, except for [OI], were detected only at the central spaxel of $9.4^{{\prime}{\prime}}{\times}9.4^{{\prime}{\prime}}$ while the [OI] emission is extended along the NE-SW direction. One interesting feature in GSS30-IRS1 is that the continuum is extended beyond PSF, unlike line emission. It suggests that the external heating is important in GSS30-IRS1. For detail analysis of line fluxes, we apply the non-LTE LVG model, RADEX as well as simple rotational diagrams. We also use the Monte Carlo radiative transfer package, RADMC-3D to understand the heating mechanism of dust grains around GSS30-IRS1. We will discuss about heating and cooling processes associated with GSS30-IRS1.

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Retinoid X Receptor α Overexpression Alleviates Mitochondrial Dysfunction-induced Insulin Resistance through Transcriptional Regulation of Insulin Receptor Substrate 1

  • Lee, Seung Eun;Koo, Young Do;Lee, Ji Seon;Kwak, Soo Heon;Jung, Hye Seung;Cho, Young Min;Park, Young Joo;Chung, Sung Soo;Park, Kyong Soo
    • Molecules and Cells
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    • v.38 no.4
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    • pp.356-361
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    • 2015
  • Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor ${\alpha}$ ($RXR{\alpha}$) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether $RXR{\alpha}$ activation or overexpression can restore IRS1 expression. Both IRS1 and $RXR{\alpha}$ protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of $RXR{\alpha}$ agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. $RXR{\alpha}$ overexpression also increased IRS1 transcription and mitochondrial function. Because $RXR{\alpha}$ overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that $RXR{\alpha}$ directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that $RXR{\alpha}$ bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor ${\delta}$ ($PPAR{\delta}$). These results suggest that $RXR{\alpha}$ overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

Patterns of Insulin Resistance Syndrome in the Taegu Community for the Development of Nutritional Service Improvement Programs (영양서비스 개발을 위한 대구지역의 인슐린저항성증후군 패턴의 인구학적 특성 분석)

  • 이희자;윤진숙;신동훈
    • Korean Journal of Community Nutrition
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    • v.6 no.1
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    • pp.97-107
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    • 2001
  • The clustering of insulin resistance with hypertension, glucose intolerance, hyperinsulinemia, increased triglyceride and decreased HDL cholesterol levels, and central and overall obesity has been called syndrome X, or the insulin resistance syndrome(IRS). To develop a nutrition service for IRS, this study was performed to evaluate the prevalence of each component of the metabolic abnormalities of IRS and analyze the clustering pattern of IRS among subjects living in the Taegu community. Participants in this study were 9234(mean age ; M/F 48/40yrs);63.5% were men, 24.4% were obese, 13.3% had hypertension. 3.7% had hyperglycemia, and 32.4% had hyperlipidemia. The IRS was defined as the coexistence of two or more components among metabolic abnormalities; obesity, hypertension. hyperglucemia and hyperlipidemia. The prevalence of IRS in Taegu was 19.2%(M/F:20.8%/16.4%), the clustering of these fisk variables was higher in advanced age group. Among the subjects of IRS having two of more diseases, 75.6% were obese, the pattern were similar in men and women. The younger, the higher the prevalence of obesity associated clustering patterns. The prevalence of obesity associated patterns among the hyperglycemia associated clustering patterns was 44.5%. The samples of the representative clustering patterns were obesity and hyperlipidemia (8.0%), hypertension and hyperlipidemia(3.2%), hypertension, obesity and hyperlipiemia(3.1%), hypertension and obesity(2.3%), and hyperglycemia and hyperlipidemia(0.8%). The clustering of obesity and hyperlipidemia until 50 year old groups, and the clustering of hypertension and hyperlipidemia in the 60 and 70 age groups were the most prevalent. We concluded that insulin resistance syndrome was a relatively common disorder in the Taegu community, and prevalence and the characteristics of the intervention strategies for IRS are desired, an effective improvement will be achieved.

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