Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes

2013 ◽  
Vol 304 (1) ◽  
pp. E1-E13 ◽  
Author(s):  
Katharina Timper ◽  
Jean Grisouard ◽  
Nadine S. Sauter ◽  
Tanja Herzog-Radimerski ◽  
Kaethi Dembinski ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mrna Expression ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Hormone Sensitive Lipase ◽  
Human Adipocytes ◽  
Chemotactic Protein ◽  
Fatty Acid Release ◽  
Glucose Transporter Glut4

Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1β, and the IL-1 receptor antagonist IL-1Ra, whereas TNFα, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-κB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1β, and TNFα. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-κB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-κB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.

scholarly journals Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs

2013 ◽  
Vol 24 (16) ◽  
pp. 2544-2557 ◽  
Author(s):  
L. Amanda Sadacca ◽  
Joanne Bruno ◽  
Jennifer Wen ◽  
Wenyong Xiong ◽  
Timothy E. McGraw
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Receptor Activation ◽  
Glut4 Translocation ◽  
Insulin Stimulation ◽  
Transport Vesicles ◽  
Glucose Transporter Glut4

Adipocyte glucose uptake in response to insulin is essential for physiological glucose homeostasis: stimulation of adipocytes with insulin results in insertion of the glucose transporter GLUT4 into the plasma membrane and subsequent glucose uptake. Here we establish that RAB10 and RAB14 are key regulators of GLUT4 trafficking that function at independent, sequential steps of GLUT4 translocation. RAB14 functions upstream of RAB10 in the sorting of GLUT4 to the specialized transport vesicles that ferry GLUT4 to the plasma membrane. RAB10 and its GTPase-activating protein (GAP) AS160 comprise the principal signaling module downstream of insulin receptor activation that regulates the accumulation of GLUT4 transport vesicles at the plasma membrane. Although both RAB10 and RAB14 are regulated by the GAP activity of AS160 in vitro, only RAB10 is under the control of AS160 in vivo. Insulin regulation of the pool of RAB10 required for GLUT4 translocation occurs through regulation of AS160, since activation of RAB10 by DENND4C, its GTP exchange factor, does not require insulin stimulation.

scholarly journals Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signaling pathways in vitro and in vivo

2021 ◽  
Author(s):  
Zhenyu Jiao ◽  
Yingqun Chen ◽  
Yang Xie ◽  
Yanbing Li ◽  
Zhi Li
Keyword(s):  
Insulin Resistance ◽  
Uric Acid ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Mouse Model ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Abnormal Glucose Metabolism ◽  
Insulin Tolerance

Abstract BackgroundHigh uric acid (HUA) is associated with insulin resistance and abnormal glucose metabolism in cardiomyocytes. Metformin is a recognized agonist of AMP-activated protein kinase (AMPK) and an antidiabetic drug widely used for type 2 diabetes. It can play a cardioprotective role in many pathways. We investigated whether metformin protects against HUA-induced insulin resistance and abnormal glucose metabolism in cardiomyocytes.MethodsWe exposed primary cardiomyocytes to HUA, and cellular glucose uptake was quantified by measuring the uptake of 2-NBDG, a fluorescent glucose analog, after insulin excitation.ResultsTreatment with metformin (10 µmol/L) protected against HUA-inhibited glucose uptake induced by insulin in primary cardiomyocytes, as shown by fluorescence microscopy and flow cytometry analysis. HUA directly inhibited the phosphorylation of Akt and the translocation of glucose transporter type 4 (GLUT4) induced by insulin, which was blocked by metformin. Metformin promoted phosphorylation of AMPK, renewed HUA-inhibited glucose uptake induced by insulin and protected against insulin resistance in cardiomyocytes. As a result of these effects, in a mouse model of acute hyperuricemia, metformin improved insulin tolerance and glucose tolerance, accompanied by increased AMPK phosphorylation, Akt phosphorylation and translocation of GLUT4 in myocardial tissues. As expected, AICAR, another AMPK activator, had equivalent effects to metformin, demonstrating the important role of AMPK activation in protecting against insulin resistance induced by HUA in cardiomyocytes. Metformin protects against insulin resistance induced by HUA in cardiomyocytes and improves insulin tolerance and glucose tolerance in an acute hyperuricemic mouse model, along with the activation of AMPK.ConclusionsConsequently, metformin may be an important potential new treatment strategy for hyperuricemia-related cardiovascular disease.

Locally and systemically active glucocorticosteroids modify intestinal absorption of sugars in rats

2003 ◽  
Vol 94 (2) ◽  
pp. 583-590 ◽  
Author(s):  
A. Thiesen ◽  
G. E. Wild ◽  
M. Keelan ◽  
M. T. Clandinin ◽  
A. B. R. Thomson
Keyword(s):  
Clinical Practice ◽  
Food Intake ◽  
Mrna Expression ◽  
Glucose Uptake ◽  
Intestinal Mucosa ◽  
Glucose Transporter ◽  
Male Rats ◽  
Adult Rats ◽  
Glucose Transporter 1

Glucocorticosteroids enhance digestive and absorptive functions of the intestine of weaning and adult rats. This study was undertaken to assess the influence of treatment of weaning male rats with budesonide (Bud), prednisone (Pred), or control vehicle on the in vitro jejunal and ileal uptake of glucose and fructose. Bud and Pred had no effect on the uptake ofd-glucose by sodium glucose transporter-1. In contrast, the uptake of d-fructose by GLUT-5 was similarly increased with Bud and with Pred. The increases in the uptake of fructose were not due to variations in the weight of the intestinal mucosa, food intake, or in GLUT-5 protein or mRNA expression. There were no steroid-associated changes in mRNA expression of c- myc, c- jun, c- fos, proglucagon, or selected cytokines. However, the abundance of ileal ornithine decarboxylase mRNA was increased with Pred. Giving postweaning rats 4 wk of Bud or Pred in doses equivalent to those used in clinical practice increases fructose but not glucose uptake. This enhanced uptake of fructose was likely regulated by posttranslational processes.

scholarly journals Pro-inflammatory cytokines and adipose tissue

2001 ◽  
Vol 60 (3) ◽  
pp. 349-356 ◽  
Author(s):  
Simon W. Coppack
Keyword(s):  
Adipose Tissue ◽  
Insulin Receptor ◽  
Mrna Expression ◽  
Glucose Transporter ◽  
Uncoupling Protein ◽  
The Body ◽  
Hormone Sensitive Lipase ◽  
Whole Body ◽  
Peroxisome Proliferator

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor a (TNF-a) and several interleukins (IL), notably IL-1b and IL-6. Other adipocyte products with ‘immunological’ actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-a and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-a mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual ‘inflammatory‘ stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-a. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-a and IL-6 inhibit lipoprotein lipase, and TNF-a additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-a also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more ‘trophic’, and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor g). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of b3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-a is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-a is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.

scholarly journals Attenuation of Free Fatty Acid (FFA)-Induced Skeletal Muscle Cell Insulin Resistance by Resveratrol is Linked to Activation of AMPK and Inhibition of mTOR and p70 S6K

2020 ◽  
Vol 21 (14) ◽  
pp. 4900
Author(s):  
Danja J. Den Hartogh ◽  
Filip Vlavcheski ◽  
Adria Giacca ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Specific Proteins ◽  
P70 S6k

Insulin resistance, a main characteristic of type 2 diabetes mellitus (T2DM), is linked to obesity and excessive levels of plasma free fatty acids (FFA). Studies indicated that significantly elevated levels of FFAs lead to skeletal muscle insulin resistance, by dysregulating the steps in the insulin signaling cascade. The polyphenol resveratrol (RSV) was shown to have antidiabetic properties but the exact mechanism(s) involved are not clearly understood. In the present study, we examined the effect of RSV on FFA-induced insulin resistance in skeletal muscle cells in vitro and investigated the mechanisms involved. Parental and GLUT4myc-overexpressing L6 rat skeletal myotubes were used. [3H]2-deoxyglucose (2DG) uptake was measured, and total and phosphorylated levels of specific proteins were examined by immunoblotting. Exposure of L6 cells to FFA palmitate decreased the insulin-stimulated glucose uptake, indicating insulin resistance. Palmitate increased ser307 (131% ± 1.84% of control, p < 0.001) and ser636/639 (148% ± 10.1% of control, p < 0.01) phosphorylation of IRS-1, and increased the phosphorylation levels of mTOR (174% ± 15.4% of control, p < 0.01) and p70 S6K (162% ± 20.2% of control, p < 0.05). Treatment with RSV completely abolished these palmitate-induced responses. In addition, RSV increased the activation of AMPK and restored the insulin-mediated increase in (a) plasma membrane GLUT4 glucose transporter levels and (b) glucose uptake. These data suggest that RSV has the potential to counteract the FFA-induced muscle insulin resistance.

scholarly journals Glucose-transporter (GLUT4) protein content in oxidative and glycolytic skeletal muscles from calf and goat

1995 ◽  
Vol 305 (2) ◽  
pp. 465-470 ◽  
Author(s):  
J F Hocquette ◽  
F Bornes ◽  
M Balage ◽  
P Ferre ◽  
J Grizard ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Skeletal Muscles ◽  
Glucose Transporter ◽  
Transporter Protein ◽  
Rat Muscle ◽  
Glucose Transporter Glut4

It is well accepted that skeletal muscle is a major glucose-utilizing tissue and that insulin is able to stimulate in vivo glucose utilization in ruminants as in monogastrics. In order to determine precisely how glucose uptake is controlled in various ruminant muscles, particularly by insulin, this study was designed to investigate in vitro glucose transport and insulin-regulatable glucose-transporter protein (GLUT4) in muscle from calf and goat. Our data demonstrate that glucose transport is the rate-limiting step for glucose uptake in bovine fibre strips, as in rat muscle. Insulin increases the rate of in vitro glucose transport in bovine muscle, but to a lower extent than in rat muscle. A GLUT4-like protein was detected by immunoblot assay in all insulin-responsive tissues from calf and goat (heart, skeletal muscle, adipose tissue) but not in liver, brain, erythrocytes and intestine. Unlike the rat, bovine and goat GLUT4 content is higher in glycolytic and oxido-glycolytic muscles than in oxidative muscles. In conclusion, using both a functional test (insulin stimulation of glucose transport) and an immunological approach, this study demonstrates that ruminant muscles express GLUT4 protein. Our data also suggest that, in ruminants, glucose is the main energy-yielding substrate for glycolytic but not for oxidative muscles, and that insulin responsiveness may be lower in oxidative than in other skeletal muscles.

Ready, set, internalize: mechanisms and regulation of GLUT4 endocytosis

2008 ◽  
Vol 29 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Costin N. Antonescu ◽  
Michelangelo Foti ◽  
Nathalie Sauvonnet ◽  
Amira Klip
Keyword(s):  
Insulin Resistance ◽  
Muscle Contraction ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Cells ◽  
Fat Cells ◽  
Intracellular Membrane ◽  
Membrane Compartments ◽  
Glucose Transporter Glut4

The facilitative glucose transporter GLUT4, a recycling membrane protein, is required for dietary glucose uptake into muscle and fat cells. GLUT4 is also responsible for the increased glucose uptake by myofibres during muscle contraction. Defects in GLUT4 membrane traffic contribute to loss of insulin-stimulated glucose uptake in insulin resistance and Type 2 diabetes. Numerous studies have analysed the intracellular membrane compartments occupied by GLUT4 and the mechanisms by which insulin regulates GLUT4 exocytosis. However, until recently, GLUT4 internalization was less well understood. In the present paper, we review: (i) evidence supporting the co-existence of clathrin-dependent and independent GLUT4 internalization in adipocytes and muscle cells; (ii) the contrasting regulation of GLUT4 internalization by insulin in these cells; and (iii) evidence suggesting regulation of GLUT4 endocytosis in muscle cells by signals associated with muscle contraction.

Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes

2010 ◽  
Vol 18 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Jean Grisouard ◽  
Elisa Bouillet ◽  
Katharina Timper ◽  
Tanja Radimerski ◽  
Kaethi Dembinski ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Inflammatory Cytokines ◽  
Lipolytic Activity ◽  
Hormone Sensitive Lipase ◽  
Low Grade ◽  
Human Adipocytes ◽  
Glycerol Release ◽  
Cellular Mechanisms ◽  
Pro Inflammatory Cytokines

High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold ( P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level ( P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.

scholarly journals Peripheral insulin resistance in ILK-depleted mice by reduction of GLUT4 expression

2017 ◽  
Vol 234 (2) ◽  
pp. 115-128 ◽  
Author(s):  
Marco Hatem-Vaquero ◽  
Mercedes Griera ◽  
Andrea García-Jerez ◽  
Alicia Luengo ◽  
Julia Álvarez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Chow Diet ◽  
Peripheral Tissues ◽  
Akt Phosphorylation ◽  
Glut4 Expression

The development of insulin resistance is characterized by the impairment of glucose uptake mediated by glucose transporter 4 (GLUT4). Extracellular matrix changes are induced when the metabolic dysregulation is sustained. The present work was devoted to analyze the possible link between the extracellular-to-intracellular mediator integrin-linked kinase (ILK) and the peripheral tissue modification that leads to glucose homeostasis impairment. Mice with general depletion of ILK in adulthood (cKD-ILK) maintained in a chow diet exhibited increased glycemia and insulinemia concurrently with a reduction of the expression and membrane presence of GLUT4 in the insulin-sensitive peripheral tissues compared with their wild-type littermates (WT). Tolerance tests and insulin sensitivity indexes confirmed the insulin resistance in cKD-ILK, suggesting a similar stage to prediabetes in humans. Under randomly fed conditions, no differences between cKD-ILK and WT were observed in the expression of insulin receptor (IR-B) and its substrate IRS-1 expressions. The IR-B isoform phosphorylated at tyrosines 1150/1151 was increased, but the AKT phosphorylation in serine 473 was reduced in cKD-ILK tissues. Similarly, ILK-blocked myotubes reduced their GLUT4 promoter activity and GLUT4 expression levels. On the other hand, the glucose uptake capacity in response to exogenous insulin was impaired when ILK was blocked in vivo and in vitro, although IR/IRS/AKT phosphorylation states were increased but not different between groups. We conclude that ILK depletion modifies the transcription of GLUT4, which results in reduced peripheral insulin sensitivity and glucose uptake, suggesting ILK as a molecular target and a prognostic biomarker of insulin resistance.

scholarly journals Leucaena leucocephalaFruit Aqueous Extract Stimulates Adipogenesis, Lipolysis, and Glucose Uptake in Primary Rat Adipocytes

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Umah Rani Kuppusamy ◽  
Bavani Arumugam ◽  
Nooriza Azaman ◽  
Chai Jen Wai
Keyword(s):  
Glucose Uptake ◽  
Leucaena Leucocephala ◽  
Glucose Transporter ◽  
Regulatory Element ◽  
Hormone Sensitive Lipase ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Fruit Extract ◽  
Rat Adipocytes

Leucaena leucocephalahad been traditionally used to treat diabetes. The present study was designed to evaluatein vitro“insulin-like” activities ofLeucaena leucocephala(Lam.) deWit. aqueous fruit extract on lipid and glucose metabolisms. The ability of the extract to stimulate adipogenesis, inhibit lipolysis, and activate radio-labeled glucose uptake was assessed using primary rat adipocytes. Quantitative Real-Time RT-PCR was performed to investigate effects of the extract on expression levels of genes (protein kinases B, AKT; glucose transporter 4, GLUT4; hormone sensitive lipase, HSL; phosphatidylinositol-3-kinases, PI3KA; sterol regulatory element binding factor 1, Srebp1) involved in insulin-induced signaling pathways.L. leucocephalaaqueous fruit extract stimulated moderate adipogenesis and glucose uptake into adipocytes when compared to insulin. Generally, the extract exerted a considerable level of lipolytic effect at lower concentration but decreased gradually at higher concentration. The findings concurred with RT-PCR analysis. The expressions of GLUT4 and HSL genes were upregulated by twofold and onefold, respectively, whereas AKT, PI3KA, and Srebp1 genes were downregulated. TheL. leucocephalaaqueous fruit extract may be potentially used as an adjuvant in the treatment of Type 2 diabetes mellitus and weight management due to its enhanced glucose uptake and balanced adipogenesis and lipolysis properties.

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