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.

scholarly journals Local Cortisol Elevation Contributes to Endometrial Insulin Resistance in Polycystic Ovary Syndrome

2018 ◽  
Vol 103 (7) ◽  
pp. 2457-2467 ◽  
Author(s):  
Jia Qi ◽  
Wangsheng Wang ◽  
Qinling Zhu ◽  
Yaqiong He ◽  
Yao Lu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Implantation Rate ◽  
Insulin Signaling Pathway ◽  
Ovary Syndrome

Abstract Context Endometrial insulin resistance (IR) may account for the endometrial dysfunction in polycystic ovary syndrome (PCOS). The underlying mechanism remains to be elucidated. Objective To investigate whether the abundance of 11β-hydroxysteroid dehydrogenases (11β-HSDs) 1 and 2 and cortisol as well as the insulin signaling pathway are altered in PCOS endometrium and to clarify the relationship between endometrial IR and local cortisol. Design We measured cortisol and cortisone concentrations, 11β-HSD1 and 11β-HSD2, and core insulin signaling molecules in endometrial biopsies collected from non-PCOS and PCOS with or without IR patients on the seventh day after human chorionic gonadotropin injection. We also studied the effects of cortisol on glucose uptake and the insulin signaling pathway in primary cultured endometrial epithelial cells (EECs). Results The cortisol concentration was elevated, whereas 11β-HSD2 expression was diminished in endometrial biopsies obtained from PCOS with IR patients compared with those from non-PCOS and PCOS without IR patients. The implantation rate was relatively impaired and the endometrial insulin signaling pathway was defective in PCOS with IR patients. In addition, cortisol attenuated insulin-stimulated glucose uptake in EECs, which was mediated by inhibition of Akt phosphorylation and glucose transporter type 4 translocation via induction of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Conclusions Decreased oxidation of cortisol and defects of insulin signaling in endometrium were observed in PCOS with IR patients. The excessive cortisol level, derived from the reduction of 11β-HSD2, might contribute to the development of endometrial IR by inhibiting the insulin signaling pathway via induction of PTEN expression in EECs.

Comparative effects of IGF-I and insulin on the glucose transporter system in rat muscle

1994 ◽  
Vol 267 (3) ◽  
pp. E461-E466 ◽  
Author(s):  
S. Lund ◽  
A. Flyvbjerg ◽  
G. D. Holman ◽  
F. S. Larsen ◽  
O. Pedersen ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Acute Effect ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Glut 4 ◽  
Igf I ◽  
Glut 4 Translocation

The acute effect of insulin-like growth factor I (IGF-I) and insulin on glucose uptake and the glucose transport system in in vitro incubated rat soleus muscles was examined using 3-O-methylglucose and the ATB-[3H]BMPA exofacial photolabeling technique. IGF-I and insulin both stimulated 3-O-methylglucose uptake and GLUT-4 translocation in a dose-dependent manner with a maximal effect six- to sevenfold above basal. No additive effects of IGF-I and insulin on maximal 3-O-methylglucose uptake were found. On a molar basis, IGF-I was 13 times less potent than insulin. Receptor binding experiments showed that IGF-I exhibited a much lower affinity for the insulin receptor [half-maximal effective dose (ED50) = 28.5 nM] than that of insulin (ED50 = 0.20 nM). In contrast, IGF-I bound to the partially purified IGF-I receptor with an apparent affinity (ED50 = 3.7 nM) that was similar to the concentrations of IGF-I which caused half-maximal activation of 3-O-methylglucose uptake (ED50 = 2.4 nM) and GLUT-4 translocation (ED50 = 2.5 nM). Our findings suggest that IGF-I exerts its insulin-like effects on glucose uptake primarily through its own specific receptor and that the molecular events underlying IGF-I and insulin actions on glucose uptake in skeletal muscle are similar, namely caused by a translocation of the GLUT-4 transporter from an intracellular pool to the cell surface.

scholarly journals Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson’s Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Szu-Yi Chou ◽  
Lung Chan ◽  
Chen-Chih Chung ◽  
Jing-Yuan Chiu ◽  
Yi-Chen Hsieh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Extracellular Vesicles ◽  
Insulin Signaling ◽  
Clinical Manifestations ◽  
Insulin Signaling Pathway ◽  
Insulin Receptor Substrate ◽  
Neuronal Markers

IntroductionDiabetes increases the risk of Parkinson’s disease (PD). The phosphorylation of type 1 insulin receptor substrate (IRS-1) determines the function of insulin signaling pathway. Extracellular vesicles (EVs) are emerging as biomarkers of human diseases. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs).Research Design and MethodsIn total, there were 94 patients with PD and 63 healthy controls recruited and their clinical manifestations were evaluated. Blood NDEVs were isolated using the immunoprecipitation method, and Western blot analysis was conducted to assess total IRS-1, p-IRS-1, and downstream substrates level in blood NDEVs. Statistical analysis was performed using SPSS 19.0, and p < 0.05 was considered significant.ResultsThe isolated blood EVs were validated according to the presence of CD63 and HSP70, nanoparticle tracking analysis and transmission electron microscopy. NDEVs were positive with neuronal markers. PD patients exerted significantly higher level of p-IRS-1S312 in blood NDEVs than controls. In addition, the p-IRS-1S312 levels in blood NDEVs was positively associated with the severity of tremor in PD patients after adjusting of age, sex, hemoglobin A1c, and body mass index (BMI).ConclusionPD patients exerted altered p-IRS-1S312 in the blood NDEVs, and also correlated with the severity of tremor. These findings suggested the association between dysfunctional insulin signaling pathway with PD. The role of altered p-IRS-1S312 in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.

Additive effect of contractions and insulin on GLUT-4 translocation into the sarcolemma

1994 ◽  
Vol 77 (4) ◽  
pp. 1597-1601 ◽  
Author(s):  
J. Gao ◽  
J. Ren ◽  
E. A. Gulve ◽  
J. O. Holloszy
Keyword(s):  
Plasma Membrane ◽  
Glucose Transport ◽  
Membrane Fraction ◽  
Glucose Transporter ◽  
Subcellular Fractionation ◽  
Muscle Group ◽  
Intracellular Membrane ◽  
Glut 4 ◽  
Incremental Effect ◽  
Glut 4 Translocation

The maximal effects of insulin and muscle contractions on glucose transport are additive. GLUT-4 is the major glucose transporter isoform expressed in skeletal muscle. Muscle contraction and insulin each induce translocation of GLUT-4 from intracellular sites into the plasma membrane. The purpose of this study was to test the hypothesis that the incremental effect of contractions and insulin on glucose transport is mediated by additivity of the maximal effects of these stimuli on GLUT-4 translocation into the sarcolemma. Anesthetized rats were given insulin by intravenous infusion to raise plasma insulin to 2,635 +/- 638 microU/ml. The gastrocnemius-plantaris-soleus group was stimulated to contract via the sciatic nerve by using a protocol that maximally activates glucose transport. After treatment with insulin, contractions, or insulin plus contractions or no treatment, the gastrocnemius-plantaris-soleus muscle group was dissected out and was subjected to subcellular fractionation to separate the plasma membrane and intracellular membrane fractions. Insulin induced a 70% increase and contractions induced a 113% increase in the GLUT-4 content of the plasma membrane fraction. The effects of insulin and contractions were additive, as evidenced by a 185% increase in the GLUT-4 content of the sarcolemmal fraction. This finding provides evidence that the incremental effect of maximally effective insulin and contractile stimuli on glucose transport is mediated by additivity of their effects on GLUT-4 translocation into the sarcolemma.

scholarly journals Effects of Chronic Undernutrition on Glucose Uptake and Glucose Transporter Proteins in Rat Heart

Endocrinology ◽  
2002 ◽  
Vol 143 (11) ◽  
pp. 4295-4303 ◽  
Author(s):  
M. Lucia Gavete ◽  
Maria Agote ◽  
M. Angeles Martin ◽  
Carmen Alvarez ◽  
Fernando Escriva
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Surface Membrane ◽  
Subcellular Fractionation ◽  
High Energy ◽  
Regulatory Subunits ◽  
Glut 1 ◽  
Glut 4 ◽  
Energy Demands ◽  
Glucose Transporter Proteins

Abstract The high energy demands of myocardium are met through the metabolism of lipids and glucose. Importantly, enhanced glucose utilization rates are crucial adaptations of the cardiac cell to some pathological conditions, such as hypertrophy and ischemia, but the effects of undernutrition on heart glucose metabolism are unknown. Our previous studies have shown that undernutrition increases insulin-induced glucose uptake by skeletal muscle. Consequently, we considered the possibility of a similar adaptation in the heart. With this aim, undernourished rats both in the basal state and after euglycemic hyperinsulinemic clamps were used to determine the following parameters in myocardium: glucose uptake, glucose transporter (GLUT) content, and some key components of the insulin signaling cascade. Heart membranes were prepared by subcellular fractionation in sucrose gradients. Although GLUT-4, GLUT-1, and GLUT-3 proteins and GLUT-4/1 mRNAs were reduced by undernutrition, basal and insulin-stimulated 2-deoxyglucose uptake were significantly enhanced. Phosphoinositol 3-kinase activity remained greater than control values in both conditions. The abundance of p85α and p85β regulatory subunits of phosphoinositol 3-kinase was increased as was phospho-Akt during hyperinsulinemia. These changes seem to improve the insulin stimulus of GLUT-1 translocation, as its content was increased at the surface membrane. Such adaptations associated with undernutrition must be crucial to improvement of cardiac glucose uptake.

268 THE EFFECTS OF METFORMIN ON THE INSULIN SIGNALING PATHWAY ON PORCINE GRANULOSA LUTEIN CELLS IN A PRIMARY CULTURE SYSTEM

2007 ◽  
Vol 19 (1) ◽  
pp. 250
Author(s):  
M. S. Hossein ◽  
M. S. Lee ◽  
W. S. Hwang
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Insulin Signaling ◽  
Luciferase Activity ◽  
Insulin Signaling Pathway ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activator Protein ◽  
Nuclear Factor Kb

Metformin (N,N22-dimethylbiguanide) is an oral antihyperglycaemic drug which increases insulin-stimulated glucose uptake as an insulin sensitizing agent (ISA) and has direct effects on ovarian steroidogenesis in human. To investigate the effects of metformin on the insulin signaling pathway on porcine granulosa lutein cells in a primary culture system, we examined mRNA expressions of porcine insulin receptor, insulin-like growth factor-1 receptor, and insulin receptor substrate-1; expressions of downstream targets (Raf, MEK1/2, ERK, PDK1, mTOR, p70, and nuclear factor kB) of the insulin receptor signaling pathway; the luciferase activity of transcription factors activator protein 1; and nuclear factor kB. Granulosa cells were plated in DMEM and 10% fetal bovine serum at a density of 3.5 � 107 in a T-25 tissue culture flask and cultured for 48 h at 37�C in a humidified atmosphere of 5% CO2 and 95% air. Then, porcine granulosa lutein cells (pGLs) were cultured in a serum-free DMEM as a control group or supplemented with 10-5 M metformin, 100 ng mL-1 of insulin, or both for 24 h. The monolayer was collected for RT-PCR and western blot analysis. For transient transfections, porcine granulosa cells were plated in DMEM and 10% FBS at a concentration of 2.5 � 106/well in 24-well culture dishes for 16 h and then transfected with plasmid constructs using FuGene6 Transfection Reagent. Reporter vectors used in these studies were AP-1-luc and NF-κ B-luc. Cells were treated post-transfection with 10-5 M metformin, 100 ng mL-1 insulin, or both for 48 h. The luciferase activity was assayed using the dual luciferase assay kit with a Microlumat LB 96 P luminometer. Metformin with insulin significantly increased mRNA expressions of insulin receptor, insulin-like growth factor-1 receptor, and insulin receptor substrate-1, whereas metformin alone had no significant effect on the expression of genes. Metformin alone and with insulin significantly increased expressions of downstream targets of the insulin receptor signaling pathway except MEK2. Metformin with insulin significantly elicited an induction of luciferase activity in the transfection of activator protein 1 and nuclear factor kB reporter, whereas metformin alone did not. Metformin induced expressions of target molecules in the insulin signaling pathway but had no effect on the luciferase activity of activator protein 1 and nuclear factor kB in porcine granulosa lutein cells. Metformin with insulin increased the luciferase activity of activator protein 1. These results suggest that metformin with insulin could change the function of ovarian granulosa cells induced by activator protein 1 activity.

Effect of diet on insulin- and contraction-mediated glucose transport and uptake in rat muscle

1995 ◽  
Vol 269 (3) ◽  
pp. R544-R551 ◽  
Author(s):  
X. Han ◽  
T. Ploug ◽  
H. Galbo
Keyword(s):  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Fiber Types ◽  
Transport Capacity ◽  
Glut 1 ◽  
Glut 4 ◽  
Red Muscle ◽  
Muscle Glucose Transport ◽  
Stimulation Of

A diet rich in fat diminishes insulin-mediated glucose uptake in muscle. This study explored whether contraction-mediated glucose uptake is also affected. Rats were fed a diet rich in fat (FAT, 73% of energy) or carbohydrate (CHO, 66%) for 5 wk. Hindquarters were perfused, and either glucose uptake or glucose transport capacity (uptake of 3-O-[14C]-methyl-D-glucose (40 mM)) was measured. Amounts of glucose transporter isoform GLUT-1 and GLUT-4 glucose-transporting proteins were determined by Western blot. Glucose uptake was lower (P < 0.05) in hindlegs from FAT than from CHO rats at submaximum and maximum insulin [4 +/- 0.4 vs. 5 +/- 0.3 (SE) mumol.min-1.leg-1 at 150 microU/ml insulin] as well as during prolonged stimulation of the sciatic nerve (4.4 +/- 0.4 vs. 5.6 +/- 0.6 mumol.min-1.leg-1). Maximum glucose transport elicited by insulin (soleus: 1.7 +/- 0.2 vs. 2.6 +/- 0.2 mumol.g-1.5 min-1, P < 0.05) or contractions (soleus: 1.8 +/- 0.2 vs. 2.6 +/- 0.3, P < 0.05) in red muscle was decreased in parallel in FAT compared with CHO rats. GLUT-4 content was decreased by 13-29% (P < 0.05) in the various fiber types, whereas GLUT-1 content was identical in FAT compared with CHO rats. It is concluded that a FAT diet reduces both insulin and contraction stimulation of glucose uptake in muscle and that these effects are associated with diminished skeletal muscle glucose transport capacities and GLUT-4 contents.

scholarly journals Influence ofOreocnide integrifolia(Gaud.) Miq on IRS-1, Akt and Glut-4 in Fat-Fed C57BL/6J Type 2 Diabetes Mouse Model

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Ansarullah ◽  
Selvaraj Jayaraman ◽  
Anandwardhan A. Hardikar ◽  
A. V. Ramachandran
Keyword(s):  
Signaling Pathway ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Therapeutic Potential ◽  
Insulin Signaling Pathway ◽  
High Fat ◽  
Isolated Pancreatic Islets ◽  
Glut 4

Oreocnide integrifolia(OI) leaves are used as folklore medicine by the people of northeast India to alleviate diabetic symptoms. Preliminary studies revealed hypoglycemic and hypolipidemic potentials of the aqueous leaf extract. The present study was carried out to evaluate whether the OI extract induces insulin secretionin vivoandin vitroand also whether it is mediated through the insulin-signaling pathway. The experimental set-up consisted of three groups of C57BL/6J mice strain: (i) control animals fed with standard laboratory diet, (ii) diabetic animals fed with a high-fat diet for 24 weeks and (iii) extract-supplemented animals fed with 3% OI extract along with high-fat diet for 24 weeks. OI-extract supplementation lowered adiposity and plasma glucose and insulin levels. Immunoblot analysis of IRS-1, Akt and Glut-4 protein expressions in muscles of extract-supplemented animals revealed that glucoregulation was mediated through the insulin-signaling pathway. Moreover, immunostaining of pancreas revealed increased insulin immunopositive cells in OI-extract-treated animals. In addition, the insulin secretogogue ability of the OI extract was demonstrated when challenged with high glucose concentration using isolated pancreatic isletsin vitro. Overall, the present study demonstrates the possible mechanism of glucoregulation of OI extract suggestive of its therapeutic potential for the management of diabetes mellitus.

Dexamethasone modulates insulin receptor expression and subcellular distribution of the glucose transporter GLUT 1 in UMR 106-01, a clonal osteogenic sarcoma cell line

1996 ◽  
Vol 17 (1) ◽  
pp. 7-17 ◽  
Author(s):  
D M Thomas ◽  
S D Rogers ◽  
K W Ng ◽  
J D Best
Keyword(s):  
Plasma Membrane ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Insulin Binding ◽  
Receptor Expression ◽  
Glut 1 ◽  
Receptor Mrna ◽  
Insulin Receptor Expression ◽  
Umr 106

ABSTRACT Corticosteroids have profound effects on bone metabolism, though the underlying mechanisms remain unclear. They are also known to alter glucose metabolism, in part by induction of insulin resistance. To determine whether corticosteroids impair glucose metabolism in bone cells, we have examined the actions of dexamethasone (DEX) on glucose transport and insulin receptor expression using osteoblast-like UMR 106-01 cells. DEX was shown to inhibit basal 2-deoxyglucose uptake by up to 30% in a time- and dose-dependent manner. It inhibited insulin-stimulated glucose transport by 13%. By Northern and Western blot analysis, DEX was shown to stimulate insulin receptor mRNA and protein by up to 5·6-fold, but it had no effect on expression of the glucose transporter GLUT 1 mRNA or protein under basal conditions. However, DEX augmented insulin-stimulated GLUT 1 mRNA and protein levels. By Scatchard analysis of labelled insulin binding, DEX increased insulin receptor number per cell by 54%. Subcellular fractionation and Western blot analysis demonstrated that DEX caused a redistribution of immunoreactive GLUT 1 from plasma membrane to intracellular microsomes, resulting in a 21% decrease in GLUT 1 at the plasma membrane. These data suggest that (i) DEX impairs basal glucose transport by post-translational mechanisms in UMR 106-01 cells, (ii) DEX increases insulin receptor mRNA, protein and insulin binding and (iii) the inhibition of glucose transport by DEX dominates its effects on the insulin receptor. It is possible that DEX inhibition of glucose transport in osteoblasts may contribute to steroid-induced osteoporosis.

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