Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

Abstract

Aims/hypothesis Chronic hyperglycaemia aggravates insulin resistance, at least in part, by increasing the formation of advanced glycation end-products (AGEs). Methylglyoxal (MGO) is the most reactive AGE precursor and its abnormal accumulation participates in damage in various tissues and organs. Here we investigated the ability of MGO to interfere with insulin signalling and to affect beta cell functions in the INS-1E beta cell line. Methods INS-1E cells were incubated with MGO and then exposed to insulin or to glucose. Western blotting was used to study signalling pathways, and real-time PCR to analyse gene expression; insulin levels were determined by radioimmunoassay.Results Non-cytotoxic MGO concentrations inhibited insulin-induced IRS tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway activation independently from reactive oxygen species (ROS) production. Concomitantly, formation of AGE adducts on immunoprecipitated IRS was observed. Aminoguanidine reversed MGO inhibitory effects and the formation of AGE adducts on IRS. Further, the insulin-and glucose-induced expression of Ins1, Gck and Pdx1 mRNA was abolished by MGO. Finally, MGO blocked glucoseinduced insulin secretion and PI3K/PKB pathway activation. These MGO effects were abolished by LiCl, which inhibits glycogen synthase kinase-3 (GSK-3). Conclusions/interpretation MGO exerted major damaging effects on INS-1E cells impairing both insulin action and secretion. An important actor in these noxious MGO effects appears to be GSK-3. In conclusion, MGO participates not only in the pathogenesis of the debilitating complications of type 2 diabetes, but also in worsening of the diabetic state by favouring beta cell failure.

Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibit Insulin Secretion and Action in Pancreatic β Cells*

“…This could be attributed, at least in part, to the inhibition of IRS-2 function, which is a known mediator of GSIS (49). Indeed, as shown here and consistent with previous observations (38), a short term (1-h) inhibition of Tyr phosphorylation of IRS-2 is sufficient to impair GSIS. IRS-2 promotes transcription of Pdx1, a transcription factor activated once its repressor FOXO1 is inhibited through Akt phosphorylation and nuclear exclusion (50,51).…”

“…Unlike sertraline, treatment with paroxetine at 75 M failed to exert an inhibitory effect on murine islets (data not shown). (14,38). Therefore, we examined whether sertraline affects glucose-stimulated insulin secretion.…”

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…Yet, we cannot rule out the involvement of others toxic compounds, particularly during NAFPD progression. Indeed, some studies suggest a possible causal relationship between NAFLD/ NAFPD-related disorders with chronic intermittent hypoxia elicited by obstructive sleep apnea [165,166], bacterial endotoxin [167][168][169], glyceraldehyde [170], methylglyoxal [171][172][173], advanced glycation end products (AGE)s [174], receptor for advanced glycation end products (RAGE) [175], nitric oxide/peroxynitrite [176], and lipid peroxidation end products [177,178].…”

Antiglycative and Antioxidative Properties of Ethyl Acetate Fraction of Chinese Purple Yam (<i>Dioscorea alata</i> L.) Extracts

“…Despite the low physical concentration of MGO, under experimental conditions, considerably higher concentrations have to be utilized to achieve certain effects than those in vivo as a compensation for the short reaction time. Fiory et al (2011) used 1 mM MGO to investigate the ability of MGO to affect insulin signaling and cell functions in the INS-1E beta cell line. Li et al (2013) evaluated MGO-induced injury in cultured human brain microvascular endothelial cells with a concentration of 2 mM.…”

“…Besides, MGO can also impair insulin signaling and insulin action in the pancreatic beta cell line INS-1E (Fiory et al, 2011).…”