Effects of Methylglyoxal on Rat Pancreatic β-Cells

Cook, Lynda; Davies, Jamie A.; Yates, Allen P.; Elliott, A.; Lovell, J. M.; Joule, John A.; Pemberton, PW; Thornalley, Paul J.; Best, Leonard

doi:10.1016/s0006-2952(97)00619-9

Cited by 52 publications

(35 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous reports have shown that MGO alters insulin secretion [17,19,21]. Our current study on INS-1E cells further documents the inhibitory effect of MGO on glucoseinduced insulin secretion, but clearly goes beyond by providing decisive insight into the mechanisms involved.…”

Section: Discussionsupporting

confidence: 79%

“…We have also shown that MGO induces insulin resistance in skeletal muscle cells through direct chemical modification of IRS proteins [15]. Finally, MGO is thought to exert deleterious effects on insulin secretion [16][17][18][19][20][21]. However, the molecular mechanisms involved in the effect of MGO on the regulation of insulin release remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Other effects of MG leading to increased excitability are not ruled out and have been described earlier. For example, 300 M MG induced a slowly developing depolarization in cortical neurons (75), whereas a fast depolarization was observed by 1 mM MG in isolated rat pancreatic islet cells (76). However, in human skin, MG is plainly a noxious and irritant compound; intradermal injections caused burning pain for a few minutes and a typical axon reflex flare response indicative of peptidergic nociceptor activation (10 mM; 15 l).…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

Eberhardt

Filipovic

Leffler

et al. 2012

Journal of Biological Chemistry

179

174

View full text Add to dashboard Cite

Background: Methylglyoxal is a reactive metabolite that modifies proteins and accumulates in diabetes and uremia. Results: Methylglyoxal excites nociceptors and releases neuropeptides via activation of TRPA1 channels by modifying their intracellular N-terminal cysteine and lysine residues. Conclusion: Methylglyoxal acting through TRPA1 is a possible cause of painful metabolic neuropathies. Significance: Methylglyoxal and its reaction with TRPA1 are promising targets for medicinal chemistry to fight neurotoxicity.

show abstract

“…An increased generation of glucose metabolites by sulphonylureas and the intracellular accumulation of these metabolites could explain the glucose-dependent beta cell swelling observed in response to tolbutamide, which, in turn, leads to VRAC activation (for discussion of this topic see [34]). Consistent with this possibility, we have previously demonstrated that methylglyoxal, which generates large quantities of D-lactate in islet cells [35], also causes beta cell swelling and VRAC activation [36]. The mechanism by which tolbutamide might influence glucose metabolism and, in particular, whether this effect involves SUR1, remain to be established.…”

Section: Discussionmentioning

confidence: 71%

Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells

2004

View full text Add to dashboard Cite

Aims/hypothesis. Hypoglycaemic sulphonylureas are thought to stimulate insulin release by binding to a sulphonylurea receptor, closing K ATP channels and inducing electrical activity. However, the fact that these drugs stimulate insulin release at high glucose concentrations where K ATP channels are closed suggests additional ionic actions. The aim of this study was to test the hypothesis that sulphonylureas influence the current of the glucose-and volume-regulated anion channel. Methods. Electrical and ion-channel activity were recorded in isolated rat beta cells using the patchclamp technique. 86 Rb + efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique. Results. In the absence of glucose, tolbutamide (100 µmol/l) transiently depolarised the cells. In the presence of glucose (5 mmol/l), tolbutamide evoked a sustained period of electrical activity, whilst at 10 mmol/l glucose, the drug evoked a pronounced 'silent' depolarisation. In the absence of glucose, tolbutamide inhibited 86 Rb + efflux. However, at 10 mmol/l glucose, tolbutamide induced a transient stimulation of efflux. Tolbutamide potentiated the whole-cell volume-regulated anion conductance in a glucose-dependent manner with an EC 50 of 85 µmol/l. In single channel recordings, tolbutamide increased the channel-open probability. Tolbutamide caused beta cell swelling in the presence of glucose, but not in its absence. Conclusions/interpretation. Tolbutamide can induce beta cell electrical activity by potentiating the glucose-and volume-regulated anion channel current. This effect is probably not due to a direct effect of the drug on the channel, but could be secondary to a metabolic action in the beta cell.

show abstract

Effects of Methylglyoxal on Rat Pancreatic β-Cells

Cited by 52 publications

References 21 publications

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

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

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells

Contact Info

Product

Resources

About