Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by α-lipoic acid in 3T3-L1 adipocytes

Yaworsky, Karen; Somwar, Romel; Ramlal, Toolsie; Tritschler, Hans; Klip, Amira

doi:10.1007/s001250050047

Cited by 120 publications

(110 citation statements)

References 52 publications

(43 reference statements)

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“…Interestingly, PI3-kinase or AKT inhibition resulted in an approximately equivalent effect against glucose-induced visfatin secretion as co-incubation with insulin alone. This effect of PI3-kinase inhibition is consistent with results by others on glucose signal transduction [20,21], and comparable results have been obtained for the activation of AKT [22]. The time required for visfatin release during glucose incubation indicates that upregulation of protein synthesis is an underlying mechanism of elevated plasma concentrations, which was confirmed by visfatin mRNA analysis.…”

Section: Discussionsupporting

confidence: 91%

The release of the adipocytokine visfatin is regulated by glucose and insulin

et al. 2006

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Aims/hypothesis The novel insulin-mimetic adipocytokine visfatin has been linked to the metabolic syndrome, but its regulation has not been characterised to date. Since insulinmimetic actions of visfatin may be part of the feedback regulation of glucose homeostasis, we hypothesised that visfatin concentrations are influenced by glucose or insulin blood levels in humans. Subjects, materials and methods In this randomised, doubleblind, placebo-controlled crossover study, nine healthy male subjects (age 26±6 years) attended three different study days. On each day, systemic glucose concentrations of 5.0, 8.3 and 11.1 mmol/l were attained by stepwise increases in i.v. infusions of glucose, representing fasting and postprandial conditions. Visfatin plasma concentrations were studied during concomitant exogenous hyperinsulinaemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control. Additionally, human adipocytes were cultured to study visfatin release and mRNA expression in vitro.Results Glucose concentrations of 8.3 and 11.1 mmol/l increased circulating visfatin from baseline concentrations of 0.5±0.0 ng/ml to 0.9±0.1 and 2.1±0.3 ng/ml, respectively (p<0.01). Glucose-induced elevation of visfatin was prevented by co-infusion of insulin or somatostatin (p<0.05). Cultured subcutaneous and visceral adipocytes released an equivalent amount of visfatin upon glucose-concentrationand time-dependent stimulation. Visfatin secretion involved the phosphatidylinositol 3-kinase (PI3-kinase) and protein kinase B (AKT) pathways. The mRNA expression pattern of visfatin was consistent with this altered protein release. Conclusions/interpretation Circulating visfatin concentrations are increased by hyperglycaemia. This effect is suppressed by exogenous hyperinsulinaemia or somatostatin infusion. Glucose signalling for visfatin release in adipocytes involves the PI3-kinase/AKT pathway.

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Section: Discussionsupporting

confidence: 91%

The release of the adipocytokine visfatin is regulated by glucose and insulin

et al. 2006

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“…In agreement with Klip et al (11,19), wortmannin, a relatively specific inhibitor of PI 3-kinase, abrogated the ability of R-LA to stimulate glucose transport indicating that PI 3-kinase mediates the stimulation of glucose transport by R-LA. However, in spite of the reported millimolar amounts used in these studies (11,19), our investigations show that the concentration of R-LA required to stimulate glucose transport is in the micromolar range, which is comparable with its plasma level after intravenous or oral 388 administration of 200 -600 mg of LA (36,37). R-LA was shown to be more potent than the S isoform in its ability to improve insulin-stimulated glucose uptake in skeletal muscles from obese Zucker rats or to stimulate glucose transport in L6 myotubes and 3T3-L1 adipocytes (7,11,19).…”

Section: T3-l1 Adipocytes Possess a Low Capacity To Reduce R-␣-lipoisupporting

confidence: 88%

“…Consistent with the stimulation of glucose transport, S-LA was found to be less effective in facilitating IR autophosphorylation. The basis for relatively lower efficacy of S-LA observed in this and previous studies (7,11,19) is not known. Since sodium orthovanadate, a potent inhibitor of protein tyrosine phosphatases, was present in the phosphorylation buffer, the observed effect of LA on IR autophosphorylation is not due to the oxidative inactivation of protein tyrosine phosphatases, which might be brought down during the immunoprecipitation of IR.…”

Section: Insulin Receptor As a Target Of R-la Actioncontrasting

confidence: 53%

“…However, in spite of the reported millimolar amounts used in these studies (11,19), our investigations show that the concentration of R-LA required to stimulate glucose transport is in the micromolar range, which is comparable with its plasma level after intravenous or oral 388 administration of 200 -600 mg of LA (36,37). R-LA was shown to be more potent than the S isoform in its ability to improve insulin-stimulated glucose uptake in skeletal muscles from obese Zucker rats or to stimulate glucose transport in L6 myotubes and 3T3-L1 adipocytes (7,11,19). In the present study, although S-LAstimulated glucose uptake was lower than that elicited by R-LA, it did not reach significance, whereas racemic LA was found significantly more effective than S-LA.…”

Section: T3-l1 Adipocytes Possess a Low Capacity To Reduce R-␣-lipoimentioning

confidence: 57%

“…Activation of PI 3-kinase was shown to be necessary for insulin-stimulated translocation of glucose transporter-4 (GLUT4) from a sequestered intracellular pool to the plasma membrane (17,18). Using L6 myotubes and 3T3-L1 adipocytes as a model of muscle and fat cells in culture, R-LA was shown to increase tyrosine phosphorylation of IR and IRS-1, to enhance PI 3-kinase and Akt1 activities, to elevate GLUT4 content in the plasma membranes, and to increase glucose uptake into the cells (19,20). Although these findings have substantially increased our understanding of LA action on the insulin signaling pathway, the basis for the ability of R-LA to activate the elements of this pathway, its mode of action and molecular target (s) are not yet known.…”

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confidence: 99%

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R-α-Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes

Moini

Tirosh

Park

et al. 2002

Archives of Biochemistry and Biophysics

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The insulin signaling pathway has been reported to mediate R-␣-lipoic acid-(R-LA-)-stimulated glucose uptake into 3T3-L1 adipocytes and L6 myotubes. We investigated the role of the thiol antioxidant dihydrolipoic acid (DHLA) and intracellular glutathione (GSH) in R-LA-stimulated glucose transport and explored the hypothesis that R-LA could increase glucose uptake into 3T3-L1 adipocytes in an oxidant-mimetic manner. R-LA pretreatment of 3T3-L1 cells stimulated glucose transport at early time points (30 min-6 h), whereas it inhibited glucose uptake at later time points. Analysis of the oxidized and reduced content of LA in cells and medium showed that >90% of lipoic acid present was in its oxidized form. Furthermore, all oxidized forms of LA (S-, R-, and racemic LA) stimulated glucose uptake, whereas the reduced form, dihydrolipoic acid, was ineffective. Intracellular GSH levels were not changed at the early time points (before 12 h), while longer preincubation (24 -48 h) of cells with R-LA significantly increased intracellular GSH. Pretreatment of adipocytes with R-LA increased intracellular peroxide levels at early time points (30 min-6 h), after which it was decreased (12-48 h). R-LA also increased tyrosine phosphorylation of immunoprecipitated insulin receptors from 3T3-L1 adipocytes. These results indicate that (i) 3T3-L1 adipocytes have a low capacity to reduce R-LA and the oxidized form of lipoic acid is responsible for stimulating glucose uptake, (ii) R-LA modulates glucose uptake by changing the intracellular redox status, and (iii) the insulin receptor is a potential cellular target for R-LA action.

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New Drugs for the Treatment of Diabetes Mellitus

Bailey

2004

International Textbook of Diabetes Mellitus

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This chapter reviews agents other than insulin that are being considered or recently introduced for the treatment of hyperglycemia. These include agents that lower blood glucose by delaying the intestinal digestion and absorption of carbohydrates, increase insulin concentrations, or potentiate insulin action. Other agents under investigation act independently of insulin to enhance glucose utilization, reduce glucose production, decrease obesity, or increase glucose elimination. Intestinal carbohydrate digestion is delayed by fiber supplements and by agents that competitively inhibit α‐glucosidase enzymes (e.g., miglitol and voglibose), thereby decreasing postprandial glucose excursions. Several insulin secretagogues have been designed to rapidly and transiently close ATP‐sensitive potassium channels in the pancreatic B‐cells (e.g., novel meglitinides and imidazolines). Analogues of the intestinal incretin glucagon‐like peptide 1 (GLP‐1) (7‐36 amide), which are more stable and longer acting than the native peptide, act predominantly via the cAMP pathway within the B‐cells to potentiate nutrient‐induced insulin secretion, and enhance insulin biosynthesis. Additionally these agents delay gastric emptying, promote satiety, and, most interestingly, appear to increase formation of new B‐cells. Inhibitors of the circulating enzyme dipeptidyl peptidase 4 augment the effects of GLP‐1 by slowing the degradation of GLP‐1. Non‐peptide compounds have been identified that can activate insulin receptor signaling and prevent normal deactivation of insulin receptor signaling (e.g., inhibitors of certain protein tyrosine phosphatases). Several new thiazolidinedione and non‐thiazolidinedione peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists are in development, along with dual PPAR‐γ and ‐α agonists to address both hyperglycemia and dyslipidemia. Various anti‐obesity agents have been shown to benefit glycemic control, including new β 3 ‐adrenoceptor agonists to stimulate thermogenesis. The amylin analogue pramlintide, which acts centrally to reduce appetite, suppress glucagon secretion, and slow gastric emptying offers an adjunct to insulin therapy, without causing weight gain. Further agents are being considered to antagonize glucagon receptors, reduce the metabolic effects of glucocorticoids, and directly stimulate glucose uptake and metabolism by muscle. Approaches to reduce hepatic glucose output include compounds that inhibit glycogen phosphorylase, glucose‐6‐phosphatase, or other enzymes of gluconeogenesis. Increased glucose elimination is being considered by inhibiting renal glucose reabsorption.

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Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by α-lipoic acid in 3T3-L1 adipocytes

Cited by 120 publications

References 52 publications

The release of the adipocytokine visfatin is regulated by glucose and insulin

The release of the adipocytokine visfatin is regulated by glucose and insulin

R-α-Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes

New Drugs for the Treatment of Diabetes Mellitus

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