Insulin Receptor Substrate Proteins

Publication Title: 
The Journal of Biological Chemistry

Cell culture work suggests that signaling to polymerize cortical filamentous actin (F-actin) represents a required pathway for the optimal redistribution of the insulin-responsive glucose transporter, GLUT4, to the plasma membrane. Recent in vitro study further suggests that the actin-regulatory neural Wiskott-Aldrich syndrome protein (N-WASP) mediates the effect of insulin on the actin filament network. Here we tested whether similar cytoskeletal mechanics are essential for insulin-regulated glucose transport in isolated rat epitrochlearis skeletal muscle.

Author(s): 
Brozinick, Joseph T.
Hawkins, Eric D.
Strawbridge, Andrew B.
Elmendorf, Jeffrey S.
Publication Title: 
Diabetes

OBJECTIVE: Human adenovirus type 36 (Ad-36) increases adiposity but improves insulin sensitivity in experimentally infected animals. We determined the ability of Ad-36 to increase glucose uptake by human primary skeletal muscle (HSKM) cells. RESEARCH DESIGN AND METHODS: The effect of Ad-36 on glucose uptake and cell signaling was determined in HSKM cells obtained from type 2 diabetic and healthy lean subjects. Ad-2, another human adenovirus, was used as a negative control. Gene expression and proteins of GLUT1 and GLUT4 were measured by real-time PCR and Western blotting.

Author(s): 
Wang, Zhong Q.
Cefalu, William T.
Zhang, Xian H.
Yu, Yongmei
Qin, Jianhua
Son, Leslie
Rogers, Pamela M.
Mashtalir, Nazar
Bordelon, Justin R.
Ye, Jianping
Dhurandhar, Nikhil V.
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. Increased phospho-IRS-1 is found in AD brain and insulin-resistant tissues from diabetics.

Author(s): 
Ma, Qiu-Lan
Yang, Fusheng
Rosario, Emily R.
Ubeda, Oliver J.
Beech, Walter
Gant, Dana J.
Chen, Ping Ping
Hudspeth, Beverly
Chen, Cory
Zhao, Yongle
Vinters, Harry V.
Frautschy, Sally A.
Cole, Greg M.
Publication Title: 
American Journal of Physiology. Endocrinology and Metabolism

Skeletal muscle insulin sensitivity improves with a moderate reduction in caloric intake. We studied possible mechanisms in calorie-restricted [CR: 60% ad libitum (AL) intake] compared with AL rats, utilizing a time-matched feeding protocol (3, 5, 10, or 20 days). Visceral fat mass was lower for CR vs. AL at 10 and 20 days, but insulin-stimulated muscle 3-O-methylglucose transport was higher in CR vs. AL rats only at 20 days. Fructose 6-phosphate (precursor for the hexosamine biosynthetic pathway, which has inverse relationship with insulin sensitivity) was reduced only at 3 days of CR.

Author(s): 
Davidson, Robert T.
Arias, Edward B.
Cartee, Gregory D.
Publication Title: 
The Journal of Biological Chemistry

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of beta-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2(-/-) mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial.

Author(s): 
Suzuki, Ryo
Tobe, Kazuyuki
Aoyama, Masashi
Inoue, Atsushi
Sakamoto, Kentaro
Yamauchi, Toshimasa
Kamon, Junji
Kubota, Naoto
Terauchi, Yasuo
Yoshimatsu, Hironobu
Matsuhisa, Munehide
Nagasaka, Shoichiro
Ogata, Hitomi
Tokuyama, Kumpei
Nagai, Ryozo
Kadowaki, Takashi
Publication Title: 
The Journal of Clinical Investigation

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus.

Author(s): 
Kubota, Naoto
Terauchi, Yasuo
Tobe, Kazuyuki
Yano, Wataru
Suzuki, Ryo
Ueki, Kohjiro
Takamoto, Iseki
Satoh, Hidemi
Maki, Toshiyuki
Kubota, Tetsuya
Moroi, Masao
Okada-Iwabu, Miki
Ezaki, Osamu
Nagai, Ryozo
Ueta, Yoichi
Kadowaki, Takashi
Noda, Tetsuo
Publication Title: 
Diabetes

OBJECTIVE: Caloric restriction (CR) has been shown to retard aging processes, extend maximal life span, and consistently increase insulin action in experimental animals. The mechanism by which CR enhances insulin action, specifically in higher species, is not precisely known. We sought to examine insulin receptor signaling and transcriptional alterations in skeletal muscle of nonhuman primates subjected to CR over a 4-year period. RESEARCH DESIGN AND METHODS: At baseline, 32 male adult cynomolgus monkeys (Macaca fascicularis) were randomized to an ad libitum (AL) diet or to 30% CR.

Author(s): 
Wang, Zhong Q.
Floyd, Z. Elizabeth
Qin, Jianhua
Liu, Xiaotuan
Yu, Yongmei
Zhang, Xian H.
Wagner, Janice D.
Cefalu, William T.
Publication Title: 
Free Radical Biology & Medicine

Calorie restriction is a dietary intervention known to improve redox state, glucose tolerance, and animal life span. Other interventions have been adopted as study models for caloric restriction, including nonsupplemented food restriction and intermittent, every-other-day feedings. We compared the short- and long-term effects of these interventions to ad libitum protocols and found that, although all restricted diets decrease body weight, intermittent feeding did not decrease intra-abdominal adiposity.

Author(s): 
Cerqueira, Fernanda M.
da Cunha, Fernanda M.
Caldeira da Silva, Camille C.
Chausse, Bruno
Romano, Renato L.
Garcia, Camila C. M.
Colepicolo, Pio
Medeiros, Marisa H. G.
Kowaltowski, Alicia J.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Sirt3 is a member of the sirtuin family of protein deacetylases that is localized in mitochondria and regulates mitochondrial function. Sirt3 expression in skeletal muscle is decreased in models of type 1 and type 2 diabetes and regulated by feeding, fasting, and caloric restriction. Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling.

Author(s): 
Jing, Enxuan
Emanuelli, Brice
Hirschey, Matthew D.
Boucher, Jeremie
Lee, Kevin Y.
Lombard, David
Verdin, Eric M.
Kahn, C. Ronald
Publication Title: 
Metabolism: Clinical and Experimental

OBJECTIVE: The cellular effects of restricting fat versus carbohydrate during a low-calorie diet are unclear. The aim of this study was to examine acute effects of energy and macronutrient restriction on skeletal muscle insulin signalling in obesity.

Author(s): 
Wang, Cecilia C. L.
Adochio, Rebecca L.
Leitner, J. Wayne
Abeyta, Ian M.
Draznin, Boris
Cornier, Marc-Andre

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