scholarly journals Maternal Food Restriction Enhances Insulin-Induced GLUT-4 Translocation and Insulin Signaling Pathway in Skeletal Muscle from Suckling Rats

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3368-3378 ◽  
Author(s):  
M. L. Gavete ◽  
M. A. Martín ◽  
C. Alvarez ◽  
F. Escrivá
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Food Restriction ◽  
Glycogen Synthase ◽  
Suckling Rats ◽  
Thrifty Phenotype ◽  
Glut 4 ◽  
Glut 4 Translocation

Abstract Restriction of protein calories during stages of immaturity has a major influence on glucose metabolism and increases the risk of type 2 diabetes in adulthood. However, it is known that reduction of food intake alleviates insulin resistance. We previously demonstrated an improved insulin-induced glucose uptake in skeletal muscle of chronically undernourished adult rats. The purpose of this work was to investigate whether this condition is present during suckling, a period characterized by physiological insulin resistance as well as elucidate some of the underlying mechanisms. With this aim, 10-d-old pups from food-restricted dams were studied. We showed that undernourished suckling rats are glucose normotolerants, despite their depressed insulin secretion capacity. The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. These changes suggest an improved insulin-induced glucose uptake associated with undernutrition. Insulin receptor content as well as that of both regulatory and catalytic phosphoinositol 3-kinase subunits was increased by food restriction. Insulin receptor substrate-1-associated phosphoinositol 3-kinase activity after insulin was enhanced in undernourished rats, as was phospho-glycogen synthase kinase-3, in line with insulin hypersensitivity. Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. These adaptations to a condition of severely limited nutritional resources might result in changes in the development of key tissues and be detrimental later in life, when a correct amount of nutrients is available, as the thrifty phenotype hypothesis predicts.

scholarly journals Functional Studies of Akt Isoform Specificity in Skeletal Muscle in Vivo; Maintained Insulin Sensitivity Despite Reduced Insulin Receptor Substrate-1 Expression

2007 ◽  
Vol 21 (1) ◽  
pp. 215-228 ◽  
Author(s):  
Mark E. Cleasby ◽  
Tracie A. Reinten ◽  
Gregory J. Cooney ◽  
David E. James ◽  
Edward W. Kraegen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Short Hairpin

Abstract The phosphoinositide 3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has been shown to be dysregulated in insulin resistance. However, the specific roles of and signaling pathways triggered by Akt isoforms have not been fully assessed in muscle in vivo. We overexpressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and, after 1 wk, assessed the roles of each isoform on glucose metabolism and fiber growth. We achieved greater than 2.5-fold increases in total Ser473 phosphorylation in muscles expressing ca-Akt-1 and ca-Akt-2, respectively. Both isoforms caused hypertrophy of muscle fibers, consistent with increases in p70S6kinase phosphorylation, and a 60% increase in glycogen accumulation, although only Akt-1 increased glycogen synthase kinase-3β phosphorylation. Akt-2, but not Akt-1, increased basal glucose uptake (by 33%, P = 0.004) and incorporation into glycogen and lipids, suggesting a specific effect on glucose transport. Consistent with this, short hairpin RNA-mediated silencing of Akt-2 caused reductions in glycogen storage and glucose uptake. Consistent with Akt-mediated insulin receptor substrate 1 (IRS-1) degradation, we observed approximately 30% reductions in IRS-1 protein in muscle overexpressing ca-Akt-1 or ca-Akt-2. Despite this, we observed no decrease in insulin-stimulated glucose uptake. Furthermore, a 68% reduction in IRS-1 levels induced using short hairpin RNAs targeting IRS-1 also did not affect glucose disposal after a glucose load. These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in the development of insulin resistance in skeletal muscle in vivo.

scholarly journals Sphingomyelinase has an insulin-like effect on glucose transporter translocation in adipocytes

1998 ◽  
Vol 274 (5) ◽  
pp. R1446-R1453 ◽  
Author(s):  
T. S. David ◽  
P. A. Ortiz ◽  
T. R. Smith ◽  
J. Turinsky
Keyword(s):  
Plasma Membrane ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Insulin Signaling Pathway ◽  
Glut 1 ◽  
Glut 4 ◽  
Glut 4 Translocation

Rat epididymal adipocytes were incubated with 0, 0.1, and 1 mU sphingomyelinase/ml for 30 or 60 min, and glucose uptake and GLUT-1 and GLUT-4 translocation were assessed. Adipocytes exposed to 1 mU sphingomyelinase/ml exhibited a 173% increase in glucose uptake. Sphingomyelinase had no effect on the abundance of GLUT-1 in the plasma membrane of adipocytes. In contrast, 1 mU sphingomyelinase/ml increased plasma membrane content of GLUT-4 by 120% and produced a simultaneous decrease in GLUT-4 abundance in the low-density microsomal fraction. Sphingomyelinase had no effect on tyrosine phosphorylation of either the insulin receptor β-subunit or the insulin receptor substrate-1, a signaling molecule in the insulin signaling pathway. It is concluded that the incubation of adipocytes with sphingomyelinase results in insulin-like translocation of GLUT-4 to the plasma membrane and that this translocation does not occur via the activation of the initial components of the insulin signaling pathway.

Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation

2007 ◽  
Vol 293 (5) ◽  
pp. E1358-E1364 ◽  
Author(s):  
Andrew J. Hoy ◽  
Clinton R. Bruce ◽  
Anna Cederberg ◽  
Nigel Turner ◽  
David E. James ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glucose Infusion ◽  
Metabolic Effects ◽  
Synthesis Rate ◽  
Muscle Sample

Hyperglycemia is a defining feature of Type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance, and our group (Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB. Am J Physiol Endocrinol Metab Endocrinol Metab 290: E471–E479, 2006) has recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5 h but not after 3 h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (∼10 mM) was produced in cannulated male Wistar rats for up to 5 h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5 h (by 25%, P < 0.0001 at 5 h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%; P < 0.05) and glycogen synthesis rate (52%; P < 0.001) were reduced after 5 h compared with after 3 h of infusion. Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3β] over the same time course. In isolated soleus strips taken from control or 1- or 5-h glucose-infused animals, insulin-stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5-h muscle sample (68% vs. 1-h sample; P < 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5 h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than to a defect in insulin signaling or glucose transport.

From Insulin Receptor Signalling to Glut 4 Translocation Abnormalities in Obesity and Insulin Resistance

1999 ◽  
Vol 19 (1-4) ◽  
pp. 217-228 ◽  
Author(s):  
Y. Le Marchand-Brustel ◽  
J-F. Tanti ◽  
M. Cormont ◽  
J-M. Ricort ◽  
T. Grémeaux ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glut 4 ◽  
Receptor Signalling ◽  
Insulin Receptor Signalling ◽  
Glut 4 Translocation

scholarly journals Interleukin-1β-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 241-251 ◽  
Author(s):  
Jennifer Jager ◽  
Thierry Grémeaux ◽  
Mireille Cormont ◽  
Yannick Le Marchand-Brustel ◽  
Jean-François Tanti
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Protein Kinase B ◽  
Transcriptional Level ◽  
Insulin Receptor Substrate ◽  
Down Regulation ◽  
Glut 4

Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1β level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1β to alter insulin signaling and action remains to be explored. We demonstrated that IL-1β slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1β treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1β slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1β-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1β reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1β is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.

Insulin signalling, exercise and cellular integrity

2003 ◽  
Vol 31 (6) ◽  
pp. 1281-1285 ◽  
Author(s):  
J.P. Kirwan ◽  
L.F. del Aguila
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
Eccentric Exercise ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Marathon Running ◽  
Glut 4 ◽  
Tnf Α

Although the effects of exercise on insulin sensitivity are generally positive, eccentric exercise presents a paradox because it induces a transient state of insulin resistance that persists for up to 48 h after the exercise bout. Excessive eccentric contractions, such as prolonged downhill running, or marathon running, causes muscle damage and disruption of the integrity of the cell. Down-regulation of insulin receptor tyrosine phosphorylation and subsequent steps in the insulin signalling pathway, including insulin receptor substrate-1 (IRS-1)-associated phosphoinositide 3-kinase (PI3K), Akt kinase serine phosphorylation and activity and glucose transporter (GLUT-4) protein content, are evident in skeletal muscle after eccentric exercise. Furthermore, increased tumour necrosis factor α (TNF-α) secretion from monocytes is associated with the decrease in PI3K activity after this type of exercise. Recent studies have shown that TNF-α can increase IRS-1 serine/threonine phosphorylation, which impairs IRS-1 docking to the insulin receptor, and this inhibits insulin signalling. Thus a unifying hypothesis to explain insulin resistance after eccentric exercise may include inflammation arising from the disruption of muscle-cell integrity, leading to an acute-phase response that includes TNF-α, with the latter inhibiting insulin signalling and subsequent metabolic events. In contrast, exercise training increases insulin signalling and GLUT-4 expression, decreases TNF-α expression in skeletal muscle, and is associated with enhanced insulin sensitivity. These observations highlight the complexity of the cellular and molecular adaptations to exercise. Understanding these adaptations is essential in order to establish a sound theoretical basis for recommending exercise as a therapeutic intervention for insulin resistance and type 2 diabetes.

Glucose uptake and glucose transporter proteins in skeletal muscle from undernourished rats

2001 ◽  
Vol 281 (5) ◽  
pp. E1101-E1109 ◽  
Author(s):  
María Agote ◽  
Luis Goya ◽  
Sonia Ramos ◽  
Carmen Alvarez ◽  
M. Lucía Gavete ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Subcellular Fractionation ◽  
Phosphatidylinositol 3 Kinase ◽  
Glut 4 ◽  
Gastrocnemius Muscles ◽  
Glucose Transporter Proteins ◽  
And Control

Undernutrition in rats impairs secretion of insulin but maintains glucose normotolerance, because muscle tissue presents an increased insulin-induced glucose uptake. We studied glucose transporters in gastrocnemius muscles from food-restricted and control anesthetized rats under basal and euglycemic hyperinsulinemic conditions. Muscle membranes were prepared by subcellular fractionation in sucrose gradients. Insulin-induced glucose uptake, estimated by a 2-deoxyglucose technique, was increased 4- and 12-fold in control and food-restricted rats, respectively. Muscle insulin receptor was increased, but phosphotyrosine-associated phosphatidylinositol 3-kinase activity stimulated by insulin was lower in undernourished rats, whereas insulin receptor substrate-1 content remained unaltered. The main glucose transporter in the muscle, GLUT-4, was severely reduced albeit more efficiently translocated in response to insulin in food-deprived rats. GLUT-1, GLUT-3, and GLUT-5, minor isoforms in skeletal muscle, were found increased in food-deprived rats. The rise in these minor glucose carriers, as well as the improvement in GLUT-4 recruitment, is probably insufficient to account for the insulin-induced increase in the uptake of glucose in undernourished rats, thereby suggesting possible changes in other steps required for glucose metabolism.

Activity of insulin receptor kinase and glycogen synthase in skeletal muscle from patients with chronic renal failure

1989 ◽  
Vol 121 (5) ◽  
pp. 744-750 ◽  
Author(s):  
Jens F. Bak ◽  
Ole Schmitz ◽  
Søren S. Sørensen ◽  
Jens Frøkjær ◽  
Torben Kjær ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Insulin Receptors ◽  
Receptor Function ◽  
Uremic Patients ◽  
Glycogen Synthase Activity

Abstract. To examine subcellular mechanisms behind the pathogenesis of peripheral insulin resistance in chronic uremic patients, insulin receptor function and glycogen synthase activity were studied in biopsies of skeletal muscle obtained during renal transplant surgery in 9 non-diabetic uremic patients. The results were compared with values obtained in an age- and sex-matched group of subjects with normal renal function, undergoing surgery for urological or gynecological diseases. The recovery of solubilized, wheat germ agglutinin-purified insulin receptors from skeletal muscle was increased among the uremic patients: 49.3 ± 6.1 vs 31.4 ± 2.8 fmol/100 mg muscle in healthy controls (p < 0.03). Basal as well as insulin-stimulated kinase activities of the insulin receptors, expressed as phosphorylation of the synthetic peptide poly(Glu-Tyr(4:1)) were similar. In addition, the maximal activity of the glycogen synthase was enhanced in uremic muscle: 26.6 ± 2.8 vs 19.5 ± 1.8 nmol · (mg protein)−1 · min−1 (p < 0.05), whereas the half-maximal activation constant for glucose-6-phosphate was identical in the two groups. Likewise, the muscle glycogen concentrations were similar in the uremic patients and the normal controls. In conclusion, our data suggest that neither impaired insulin receptor function nor a reduced maximal glycogen synthase activity of skeletal muscle are involved in the pathogenesis of the insulin resistance of patients with chronic renal failure.

Sign in / Sign up

Export Citation Format

Share Document