Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction.

Sakoda, Hideyuki; Ogihara, Takehide; Anai, Motonobu; Funaki, Makoto; Inukai, Kouichi; Katagiri, Hideki; Fukushima, Yasushi; Onishi, Yukiko; Ono, Hiraku; Fujishiro, Midori; Kikuchi, Masatoshi; Oka, Yoshitomo; Asano, Tomohiko

doi:10.2337/diabetes.49.10.1700

Cited by 196 publications

(138 citation statements)

References 58 publications

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“…It seems unlikely, therefore, that the combination of dexamethasone and insulin contributed to the rise in serum leptin via an increase in adipocyte glucose utilization. This is in agreement with in vitro data showing that glucocorticoids tend to decrease human adipocyte glucose utilization (24,25).…”

Section: Discussionsupporting

confidence: 82%

A pulse of insulin and dexamethasone stimulates serum leptin in fasting human subjects

Laferrère

Caixàs²,

Fried³

et al. 2002

European Journal of Endocrinology

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Objectives: We have previously shown that dexamethasone increases serum leptin in fed but not in fasted human subjects. We hypothesized that insulin and/or glucose mediated the effect of food intake. The primary aim of this study was to determine whether the administration of a pulse of insulin with dexamethasone was sufficient to increase serum leptin in vivo in fasted human subjects. Whether the presence of transient hyperglycemia and the dose of insulin were important was tested as a secondary aim. Methods: Twenty-nine normal subjects were studied. In experiment 1 (meal-like), a pulse of insulin (0.03 U/kg s.c.) and of dexamethasone (2 mg i.v.) was given, and the blood glucose transiently elevated to 50 mg/dl above baseline for the first 2 h. In experiments 2 and 3 (dose-response), the effect of two doses of insulin (0.03 U/kg in experiment 2 and 0.06 U/kg in experiment 3) was tested in combination with dexamethasone, this time without transient hyperglycemia. Nine subjects were studied under fasting conditions, with or without dexamethasone, as a control experiment. Results: A meal-like transient hyperinsulinemia and hyperglycemia, with a pulse of dexamethasone, increased serum leptin levels from baseline by 54^21% at 9 h ðP ¼ 0:038Þ: In the absence of transient hyperglycemia, leptin increased significantly after doses of both insulin and dexamethasone. The effect of insulin was dose-dependent, with a larger increment of serum leptin at 9 h after the highest dose of insulin ð75:2^15:7% vs 21:3^8:5%; P ¼ 0:013Þ. Fasting, with or without dexamethasone, resulted in a significant 20% decrease in leptin from morning basal levels. Conversely, the administration of a pulse of insulin and glucose, in the absence of dexamethasone, prevented the drop in serum leptin observed during fasting, regardless of the insulin dose or the serum glucose elevation. Conclusions: With the permissive effect of dexamethasone, a single pulse of insulin triggered a rise in serum leptin in humans, even in the absence of transient hyperglycemia. A single pulse of insulin with glucose can prevent the drop in serum leptin normally observed during fasting.

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Section: Discussionsupporting

confidence: 82%

A pulse of insulin and dexamethasone stimulates serum leptin in fasting human subjects

Laferrère

Caixàs²,

Fried³

et al. 2002

European Journal of Endocrinology

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“…It has long been known that glucocorticoids cause insulin resistance in vitro and in vivo (Ward et al 2003). Thus, in 3T3-L1 fat cells, insulin-induced glucose uptake is significantly impaired after chronic treatment with dexamethasone (Sakoda et al 2000, Bazuine et al 2004. However, it is not clear to what extent increased glucocorticoid levels contribute to impaired insulin sensitivity seen in obesity.…”

Section: Discussionmentioning

confidence: 95%

“…However, our data also point to the fact that fat-secreted visfatin is probably not a mediator of glucocorticoid-induced glucose intolerance. Here, other mechanisms including downregulation of insulinsensitizing adiponectin and inhibition of insulin signaling molecules probably contribute (Sakoda et al 2000, Fasshauer & Paschke 2003. Furthermore, since visfatin is not exclusively expressed in fat, visfatin serum levels in patients with hypercortisolism need to be determined to further define its role in states of increased glucocorticoid levels.…”

Section: Figurementioning

confidence: 99%

Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes

Kralisch¹,

Klein²,

Lössner³

et al. 2005

Journal of Endocrinology

146

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Recently, visfatin was characterized as a novel adipocytokine that is upregulated in obesity and exerts insulinmimetic effects in various tissues. To clarify expression and regulation of this adipocytokine, visfatin mRNA was measured by quantitative real-time reverse transcriptionpolymerase chain reaction in 3T3-L1 adipocytes during adipogenesis and after treatment with various hormones known to alter insulin sensitivity. Visfatin expression was about 6-fold higher in 3T3-L1 adipocytes in vitro as compared with epididymal fat in vivo and increased during adipogenic conversion more than 3-fold. Interestingly, 100 nM dexamethasone significantly increased visfatin mRNA by almost 1·5-fold. In contrast, 500 ng/ml growth hormone (GH), 10 ng/ml tumor necrosis factor (TNF) , and 10 µM isoproterenol downregulated visfatin expression by 45%, 36%, and 43% respectively. Insulin did not influence synthesis of this adipocytokine. The effects of dexamethasone, GH, TNF and isoproterenol were time-and dose-dependent. Furthermore, activation of G s -protein-coupled pathways by forskolin and cholera toxin was sufficient to significantly downregulate visfatin mRNA. Taken together, our results show a differential regulation of visfatin mRNA by insulin resistanceinducing hormones, supporting the view that this adipocytokine might be an interesting novel candidate linking core components of the metabolic syndrome such as obesity and insulin resistance.

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“…In fact, dexamethasone did not change GLUT-4 expression levels while decreasing GLUT-4 translocation and glucose uptake in 3T3-L1 cells. 30 Dexamethasone also led to decreased GLUT-4 expression in adipocytes in one study, 31 …”

Section: Discussionmentioning

confidence: 99%

Lactoferrin increases 172ThrAMPK phosphorylation and insulin-induced p473SerAKT while impairing adipocyte differentiation

et al. 2009

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Objective: Lactoferrin is a pleiotropic glycoprotein of the innate immune system with known effects on immunomodulation and cell differentiation. To gain an insight into the interaction among obesity, inflammation and insulin action, we aimed to examine the effects of lactoferrin on adipogenesis and the response to insulin in human hepatocarcinoma (HepG2) and 3T3-L1 cell lines. Design: The cells were cultured with increasing lactoferrin concentration under non-inflammatory, inflammatory and standard conditions. The response to insulin was evaluated through 473Ser AKT phosphorylation. The effects of lactoferrin on adipogenesis were studied through the expression of different lipogenic markers, AMP-activated protein kinase (AMPK) activation, retinoblastoma (Rb) activity and Oil Red O staining in 3T3-L1 cells. Results: Lactoferrin increased dose-dependent insulin-induced 473Ser AKT phosphorylation in both cell lines. Inflammationinduced decreased 473Ser AKT phosphorylation was also rescued by lactoferrin. In addition, lactoferrin led to increased p172Thr AMPK during 3T3-L1 differentiation and to decreased adipogenesis (as shown by decreased expression of fatty acid synthase, acetyl-coenzyme A carboxylase-a and peroxisome proliferator-activated receptor-g in parallel with decreased formation of lipid droplets). Lactoferrin also increased dose-dependent Rb activity (expression and hypophosphorylation) during 3T3-L1 differentiation. Conclusion: Lactoferrin administration increased insulin-induced 473Ser AKT phosphorylation, even in those conditions wherein the response to insulin was downregulated, and led to blunted adipogenesis in the context of increased p172Thr AMPK and Rb activity.

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Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction.

Cited by 196 publications

References 58 publications

A pulse of insulin and dexamethasone stimulates serum leptin in fasting human subjects

A pulse of insulin and dexamethasone stimulates serum leptin in fasting human subjects

Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes

Lactoferrin increases 172ThrAMPK phosphorylation and insulin-induced p473SerAKT while impairing adipocyte differentiation

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