Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKα-independent manner

Abstract

Aims/hypothesis: Some cyclooxygenase-2 (COX2, also known as prostaglandin-endoperoxide synthase 2 [PTGS2]) inhibitors have been shown to increase insulin sensitivity in man or induce hypoglycaemic episodes when overconsumed or taken in combination with oral hypoglycaemic drugs. These side-effects and their impact on patients are not always recognised in routine clinical practice. We investigated whether these side-effects of COX2 (PTGS2) inhibitors result from stimulation of the glucose transport system in skeletal muscle cells. Materials and methods: L6 myotube cultures were used to study effects of COX2 (PTGS2) inhibitors on the glucose transport system and their relationship to PTGS2 expression, insulin action and AMP-activated protein kinase α (AMPKα) activity. Results: The inhibitors niflumic acid, nimesulide and rofecoxib increased the rate of hexose uptake in L6 myotubes in the absence of insulin and in a dose-and time-dependent manner. They did this by increasing the total cell content of member 4 of the solute carrier family 2 (SCLC2A4, previously known as glucose transporter 4 [GLUT4]) (but not SCLC2A1 [previously known as GLUT1]) mRNA and protein and the amount of it in the plasma membrane. AMPKα was not involved in the latter effect since the inhibitors did not activate it. In addition, none of the inhibitors modulated the rate of hexose transport in vascular endothelial and smooth muscle cells expressing PTGS2 and SCLC2A1. Prostaglandin-endoperoxide synthase 1 (also known as cyclooxygenase 1) inhibitors (acetylsalicylic acid and indomethacin) did not alter the rate of hexose uptake and SCLC2A4 subcellular distribution in L6 myotubes. Conclusions/interpretation: This study suggests that certain COX2 (PTGS2) inhibitors can alter glucose homeostasis in vivo by stimulating glucose uptake in skeletal muscles that express PTGS2.

PTGS-2–PTGER2/4 Signaling Pathway Partially Protects From Diabetogenic Toxicity of Streptozotocin in Mice

“…Modulation of SLC2A2 by PGE 2 has not been studied yet. However, inhibition of PTGS-2 has been shown to augment the rate of hexose transport in myotubes by recruiting the glucose transporter SLC2A4 (40). Whether PTGS-2 inhibition may also affect SLC2A2 needs to be clarified.…”

A gene expression signature for insulin resistance

“…For example, higher-than-conventional doses of NSAIDs have been shown to lower plasma glucose levels in individuals with type 2 diabetes (6, 31). The mechanism(s) of the glucose-lowering action of these compounds are varied and include inhibition of cyclooxygenase (COX) activity and PGE 2 production (indomethacin with a GES score of 6.255; ibuprofen, 0.476) (17,38), free radical scavenger and antioxidant (mesalamine, 2.627) (5), inhibition of NF-B activation (niflumic acid, 0.614) (3,4) and regulation of peroxisome proliferator-activated receptors (PPARs) (indomethacin; dicoflenac, 0.347) (1,24). The beta-blocker propranolol (1.330) has been reported to ameliorate TNF-␣-induced insulin resistance in rats (23).…”

Bilirubin Increases the Expression of Glucose Transporter-1 and the Rate of Glucose Uptake in Vascular Endothelial Cells

“…The [ 3 H]-2-deoxy-D-glucose ([ 3 H]-dGlc) uptake assay in VEC cultures was performed as described [17,18]. A freshly-prepared stock solution of BR (30 mmol/l) in 100 mmol/l NaOH served to prepare serial dilutions of BR in the NaOH solution.…”