Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Tzeng, Thing-Fong; Liu, I. M.

doi:10.1007/s00125-005-1791-6

Cited by 25 publications

(16 citation statements)

References 42 publications

(48 reference statements)

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“…This situation imitates the chronic elevation of IL-6 that causes insulin resistance when secreted by adipose tissue in obesity (5,19). This dual behavior of IL-6 in insulin-stimulated glucose uptake has been previously observed in human skeletal muscle cells (40); meanwhile, inhibition of insulin signaling by IL-6 was reported in C2C12 cells (15). Reconciliation of our observation of systemic and muscular insulin resistance in mice treated with IL-6 for 48 h with the maturity-onset obesity and insulin-intolerance phenotype developed by IL-6 -deficient mice (25) is not a simple matter.…”

Section: Il-6 Dual Action On Insulin Sensitivitymentioning

confidence: 53%

“…However, other studies reported a lack of effect or a positive effect of IL-6 on whole-body glucose disposal in rats and humans, respectively (11,12). Alternatively, IL-6 induced insulin resistance in hepatocytes, adipocytes, and myocytes (13)(14)(15)(16). In addition, palmitate-induced IL-6 production led to inhibition of insulin-stimulated glucose uptake in myocytes, as demonstrated by the prevention of these effects with anti-IL-6 or anti-Toll-like receptor-2 antibodies (17,18).…”

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confidence: 99%

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Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle

et al. 2008

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OBJECTIVE-Cytokines are elevated in various insulin-resistant states, including type 2 diabetes and obesity, although the contribution of interleukin-6 (IL-6) in the induction of these diseases is controversial.RESEARCH DESIGN AND METHODS-We analyzed the impact of IL-6 on insulin action in murine primary myocytes, skeletal muscle cell lines, and mice (wild type and proteintyrosine phosphatase 1B [PTP1B] deficient).RESULTS-IL-6 per se increased glucose uptake by activating serine/threonine protein kinase 11 (LKB1)/AMP-activated protein kinase/protein kinase B substrate of 160 kDa (AS160) pathway. A dual effect on insulin action was observed when myotubes and mice were exposed to this cytokine: additive with short-term insulin (increased glucose uptake and systemic insulin sensitivity) but chronic exposure produced insulin resistance (impaired GLUT4 translocation to plasma membrane and defects in insulin signaling at the insulin receptor substrate 1 [IRS-1] level). Three mechanisms seem to operate in IL-6 -induced insulin resistance: activation of c-Jun NH 2 -terminal kinase 1/2 (JNK1/2), accumulation of suppressor of cytokine signaling 3 (socs3) mRNA, and an increase in PTP1B activity. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired phosphorylation of IRS-1 (Ser307), restored insulin signaling, and normalized insulin-induced glucose uptake in myotubes. When using a pharmacological approach, liver X receptor agonists overcome IL-6 -induced insulin resistance by producing downregulation of socs3 and ptp1b gene expression. Finally, the lack of PTP1B confers protection against IL-6 -induced insulin resistance in skeletal muscle in vitro and in vivo, in agreement with the protection against the IL-6 hyperglycemic effect observed on glucose and insulin tolerance tests in adult male mice. CONCLUSIONS-These findings indicate the important role of IL-6 in the pathogenesis of insulin resistance and further implicate PTP1B as a potential therapeutic target in the treatment of type 2 diabetes. Diabetes 57:3211-3221, 2008

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Section: Il-6 Dual Action On Insulin Sensitivitymentioning

confidence: 53%

mentioning

confidence: 99%

Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle

et al. 2008

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“…This effect is mediated by p38 MAPK [114]. In cultured muscle cells, incubation with IL-6 results in phosphorylation of serine 318 on IRS-1 and a decrease in IR autophosphorylation [115], although it is not known whether the IR is directly serine-phosphorylated. JAK/STAT activation of MAPK pathways likely mediates the phosphorylation of IRS-1 on serine 318 by IL-6 incubation [116].…”

Section: Inhibition Of Ir Autophosphorylation By Post-translational Mmentioning

confidence: 99%

Regulation of insulin receptor function

Youngren¹

2007

Cell. Mol. Life Sci.

167

118

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Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article.

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“…Loperamide has been shown to improve insulin sensitivity [2] by reducing the levels of inflammatory cytokines such as tumor necrosis factor-␣ and interleukin-6 [3,4] . Moreover, ␤ -endorphin has been shown to increase insulin sensitivity via the activation of -opioid receptors [5] .…”

Section: Introductionmentioning

confidence: 99%

Activation of Peripheral Opioid µ-Receptors in Blood Vessel May Lower Blood Pressure in Spontaneously Hypertensive Rats

Chen

Shieh²,

Chung

et al. 2011

Pharmacology

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Background/Aims: The role of opioid receptors in the regulation of vascular function remains unclear. In the current study, we evaluated the ability of loperamide, a peripheral opioid receptor agonist, to regulate blood pressure in spontaneously hypertensive rats (SHRs) and examined the mechanism(s) by which loperamide exerts its effects. Methods: In male SHRs, mean arterial pressure (MAP) was measured and hemodynamic analysis was recorded. Additionally, the isometric tension of aortic rings isolated from SHRs was determined. Results: Loperamide dose-dependently decreased MAP in SHRs but not in the normal group of Wistar-Kyoto rats. This reduction of MAP in conscious SHRs was abolished by the selective opioid µ-receptor antagonist cyprodime, but not by naloxonazine, the µ₁-opioid receptor antagonist. However, cardiac output was not altered by loperamide in anesthetized SHRs. Moreover, loperamide-induced relaxation in isolated aortic rings precontracted with phenylephrine or vasopressin. This relaxation was abolished by cyprodime, but not by naloxonazine. Loperamide-induced relaxation was also attenuated by glibenclamide, an ATP-sensitive potassium (K_ATP) channel blocker. Additionally, vasodilatation by loperamide was reduced by an inhibitor of protein kinase A (PKA) and enhanced by an inhibitor of phosphodiesterases. Conclusion: We suggest that loperamide can lower MAP in SHRs via µ₂-opioid receptor-dependent cAMP-PKA pathway that induces vascular relaxation by opening K_ATP channels.

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Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Cited by 25 publications

References 42 publications

Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle

Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle

Regulation of insulin receptor function

Activation of Peripheral Opioid µ-Receptors in Blood Vessel May Lower Blood Pressure in Spontaneously Hypertensive Rats

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