scholarly journals Muscle Adaptation to Short-Term Fasting in Healthy Lean Humans

2008 ◽  
Vol 93 (7) ◽  
pp. 2900-2903 ◽  
Author(s):  
Maarten R. Soeters ◽  
Hans P. Sauerwein ◽  
Peter F. Dubbelhuis ◽  
Johanna E. Groener ◽  
Mariëtte T. Ackermans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Protein Kinase B ◽  
Muscle Adaptation ◽  
Short Term ◽  
Akt Phosphorylation ◽  
Induce Insulin Resistance ◽  
Before And After ◽  
Muscle Biopsies

Abstract Context: It has been demonstrated repeatedly that short-term fasting induces insulin resistance, although the exact mechanism in humans is unknown to date. Intramyocellular sphingolipids (i.e. ceramide) have been suggested to induce insulin resistance by interfering with the insulin signaling cascade in obesity. Objective: Our objective was to study peripheral insulin sensitivity together with muscle ceramide concentrations and protein kinase B/AKT phosphorylation after short-term fasting. Main Outcome Measures and Design: After 14- and 62-h fasting, glucose fluxes were measured before and after a hyperinsulinemic euglycemic clamp. Muscle biopsies were performed in the basal state and during the clamp to assess muscle ceramide and protein kinase B/AKT. Results: Insulin-mediated peripheral glucose uptake was significantly lower after 62-h fasting compared with 14-h fasting. Intramuscular ceramide concentrations tended to increase during fasting. During the clamp the phosphorylation of protein kinase B/AKT at serine473 in proportion to the total amount of protein kinase B/AKT was significantly lower. Muscle ceramide did not correlate with plasma free fatty acids. Conclusions: Fasting for 62 h decreases insulin-mediated peripheral glucose uptake with lower phosphorylation of AKT at serine473. AKT may play a regulatory role in fasting-induced insulin resistance. Whether the decrease in AKT can be attributed to the trend to higher muscle ceramide remains unanswered.

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.

scholarly journals Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes

2002 ◽  
pp. 419-429 ◽  
Author(s):  
J Buren ◽  
HX Liu ◽  
J Jensen ◽  
JW Eriksson
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Signalling ◽  
Protein Kinase B ◽  
Insulin Binding ◽  
Insulin Receptor Substrate ◽  
Phosphatidylinositol 3 Kinase ◽  
Rat Adipocytes

OBJECTIVE: Glucocorticoid excess leads to insulin resistance. This study explores the effects of glucocorticoids on the glucose transport system and insulin signalling in rat adipocytes. The interaction between glucocorticoids and high levels of insulin and glucose is also addressed. DESIGN AND METHODS: Isolated rat adipocytes were cultured for 24 h at different glucose concentrations (5 and 15 mmol/l) with or without the glucocorticoid analogue dexamethasone (0.3 micromol/l) and insulin (10(4) microU/ml). After the culture period, the cells were washed and then basal and insulin-stimulated glucose uptake, insulin binding and lipolysis as well as cellular content of insulin signalling proteins (insulin receptor substrate-1 (IRS-1), IRS-2, phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB)) and glucose transporter isoform GLUT4 were measured. RESULTS: Dexamethasone in the medium markedly decreased both basal and insulin-stimulated glucose uptake at both 5 and 15 mmol/l glucose (by approximately 40-50%, P<0.001 and P<0.05 respectively). Combined long-term treatment with insulin and dexamethasone exerted additive effects in decreasing basal, and to a lesser extent insulin-stimulated, glucose uptake capacity (P<0.05) compared with dexamethasone alone, but this was seen only at high glucose (15 mmol/l). Insulin binding was decreased (by approximately 40%, P<0.05) in dexamethasone-treated cells independently of surrounding glucose concentration. Following dexamethasone treatment a approximately 75% decrease (P<0.001) in IRS-1 expression and an increase in IRS-2 (by approximately 150%, P<0.001) was shown. Dexamethasone also induced a subtle decrease in PI3-K (by approximately 20%, P<0.01) and a substantial decrease in PKB content (by approximately 45%, P<0.001). Insulin-stimulated PKB phosphorylation was decreased (by approximately 40%, P<0.01) in dexamethasone-treated cells. Dexamethasone did not alter the amount of total cellular membrane-associated GLUT4 protein. The effects of dexamethasone per se on glucose transport and insulin signalling proteins were mainly unaffected by the surrounding glucose and insulin levels. Dexamethasone increased the basal lipolytic rate (approximately 4-fold, P<0.05), but did not alter the antilipolytic effect of insulin. CONCLUSIONS: These results suggest that glucocorticoids, independently of the surrounding glucose and insulin concentration, impair glucose transport capacity in fat cells. This is not due to alterations in GLUT4 abundance. Instead dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 and PKB accompanied by a parallel reduction in insulin-stimulated activation of PKB.

scholarly journals NF-κB-Inducing Kinase (NIK) Mediates Skeletal Muscle Insulin Resistance: Blockade by Adiponectin

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3622-3627 ◽  
Author(s):  
Sanjeev Choudhary ◽  
Sandeep Sinha ◽  
Yanhua Zhao ◽  
Srijita Banerjee ◽  
Padma Sathyanarayana ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Kinase Activity ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Muscle Insulin Resistance ◽  
Akt Phosphorylation ◽  
Skeletal Muscle Insulin Resistance ◽  
Obese Subjects

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.

Regulation of muscle glycogen phosphorylase activity following short-term endurance training

1996 ◽  
Vol 270 (2) ◽  
pp. E328-E335 ◽  
Author(s):  
A. Chesley ◽  
G. J. Heigenhauser ◽  
L. L. Spriet
Keyword(s):  
Endurance Training ◽  
Muscle Glycogen ◽  
Glycogen Phosphorylase ◽  
Citrate Synthase ◽  
Phosphorylase Activity ◽  
Short Term ◽  
Mitochondrial Potential ◽  
Before And After ◽  
Glycogen Phosphorylase Activity ◽  
Muscle Biopsies

The purpose of this study was to examine the regulation (hormonal, substrate, and allosteric) of muscle glycogen phosphorylase (Phos) activity and glycogenolysis after short-term endurance training. Eight untrained males completed 6 days of cycle exercise (2 h/day) at 65% of maximal O2 uptake (Vo2max). Before and after training subjects cycled for 15 min at 80% of Vo2max, and muscle biopsies and blood samples were obtained at 0 and 30 s, 7.5 and 15 min, and 0, 5, 10, and 15 min of exercise. Vo2max was unchanged with training but citrate synthase (CS) activity increased by 20%. Muscle glycogenolysis was reduced by 42% during the 15-min exercise challenge following training (198.8 +/- 36.9 vs. 115.4 +/- 25.1 mmol/kg dry muscle), and plasma epinephrine was blunted at 15 min of exercise. The Phos a mole fraction was unaffected by training. Muscle phosphocreatine utilization and free Pi and AMP accumulations were reduced with training at 7.5 and 15 min of exercise. It is concluded that posttransformational control of Phos, exerted by reductions in substrate (free Pi) and allosteric modulator (free AMP) contents, is responsible for a blunted muscle glycogenolysis after 6 days of endurance training. The increase in CS activity suggests that the reduction of muscle glycogenolysis was due in part to an enhanced mitochondrial potential.

scholarly journals Inhibition of growth-factor-induced phosphorylation and activation of protein kinase B/Akt by atypical protein kinase C in breast cancer cells

2000 ◽  
Vol 352 (2) ◽  
pp. 475-482 ◽  
Author(s):  
Muling MAO ◽  
Xianjun FANG ◽  
Yiling LU ◽  
Ruth LAPUSHIN ◽  
Robert C. BAST ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Protein Kinase B ◽  
Akt Phosphorylation ◽  
Kinase C ◽  
Pkc Inhibitors

The protein kinase B/Akt serine/threonine kinase, located downstream of phosphoinositide 3-kinase (PI-3K), is a major regulator of cellular survival and proliferation. Atypical protein kinase C (aPKC) family members are activated by PI-3K and also contribute to cell proliferation, suggesting that Akt and aPKC might interact to activate signalling through the PI-3K cascade. Here we demonstrate that blocking PKC activity in MDA-MB-468 breast cancer cells increased the phosphorylation and activity of Akt. Functional PI-3K was required for the PKC inhibitors to increase Akt phosphorylation and activation, potentially owing to the activation of specific PKC isoforms by PI-3K. The concentration dependence of the action of the PKC inhibitors implicates aPKC in the inhibition of Akt phosphorylation and activity. In support of a role for aPKC in the regulation of Akt, Akt and PKCζ or PKCλ/ℓ were readily co-precipitated from the BT-549 breast cancer cell line. Furthermore, the overexpression of PKCζ inhibited growth-factor-induced increases in Akt phosphorylation and activity. Thus PKCζ associates physically with Akt and decreases Akt phosphorylation and enzyme activity. The effects of PKC on Akt were transmitted through the PI-3K cascade as indicated by changes in p70 s6 kinase (p70s6k) phosphorylation. Thus PKCζ, and potentially other PKC isoenzymes, regulate growth-factor-mediated Akt phosphorylation and activation, which is consistent with a generalized role for PKCζ in limiting growth factor signalling through the PI-3K/Akt pathway.

scholarly journals Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats

Diabetologia ◽  
2004 ◽  
Vol 47 (11) ◽  
pp. 1879-1887 ◽  
Author(s):  
V. Rotter Sopasakis ◽  
B.-M. Larsson ◽  
A. Johansson ◽  
A. Holm�ng ◽  
U. Smith
Keyword(s):  
Insulin Resistance ◽  
Interleukin 6 ◽  
Insulin Signalling ◽  
Short Term ◽  
Induce Insulin Resistance

scholarly journals CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes

2012 ◽  
Vol 448 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Yeliz Angin ◽  
Laura K. M. Steinbusch ◽  
Peter J. Simons ◽  
Sabrina Greulich ◽  
Nicole T. H. Hoebers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Lipid Accumulation ◽  
Insulin Signalling ◽  
Culture Conditions ◽  
Contractile Dysfunction ◽  
Rat Cardiomyocytes ◽  
Akt Phosphorylation ◽  
Palmitate Uptake

An increased cardiac fatty acid supply and increased sarcolemmal presence of the long-chain fatty acid transporter CD36 are associated with and contribute to impaired cardiac insulin sensitivity and function. In the present study we aimed at preventing the development of insulin resistance and contractile dysfunction in cardiomyocytes by blocking CD36-mediated palmitate uptake. Insulin resistance and contractile dysfunction were induced in primary cardiomyocytes by 48 h incubation in media containing either 100 nM insulin (high insulin; HI) or 200 μM palmitate (high palmitate; HP). Under both culture conditions, insulin-stimulated glucose uptake and Akt phosphorylation were abrogated or markedly reduced. Furthermore, cardiomyocytes cultured in each medium displayed elevated sarcolemmal CD36 content, increased basal palmitate uptake, lipid accumulation and decreased sarcomere shortening. Immunochemical CD36 inhibition enhanced basal glucose uptake and prevented elevated basal palmitate uptake, triacylglycerol accumulation and contractile dysfunction in cardiomyocytes cultured in either medium. Additionally, CD36 inhibition prevented loss of insulin signalling in cells cultured in HP, but not in HI medium. In conclusion, CD36 inhibition prevents lipid accumulation and lipid-induced contractile dysfunction in cardiomyocytes, but probably independently of effects on insulin signalling. Nonetheless, pharmacological CD36 inhibition may be considered as a treatment strategy to counteract impaired functioning of the lipid-loaded heart.

Sign in / Sign up

Export Citation Format

Share Document