"Blinding" of AMP-dependent kinase by methylglyoxal: a mechanism that allows perpetuation of hepatic insulin resistance?
AMP-dependent kinase (AMPK) is a regulatory carrefour and a key target for therapeutics. The role of AMPK in regulating cellular energy status (by sensing low energy using [AMP] as its signal) and activating catabolic pathways while inhibiting anabolic routes, places this enzyme at a central control point in maintaining energy homeostasis. The exquisite allosteric sensing of AMP is done by a domain with three arginine residues, which make it very vulnerable to glycation, especially by the alpha-dicarbonyl methylglyoxal (MG). MG accumulates in hyperglycemia, insulin resistance, diabetes and when there is excess flux of reactive oxygen species coming from the mitochondria. We hypothesize that excess MG in the above-mentioned conditions blocks the sensing of AMP by AMPK, thereby favoring gluconeogenesis (thus hepatic glucose output and hyperglycemia) and lipogenesis (hepatic steatosis and high VLDL), hallmarks of insulin resistance and diabetes. Our hypothesis may explain, for instance, the perpetuation of hepatic insulin resistance, as well as part of the action of metformin, which is a potent anti-glycation agent. Future targets for type 2 diabetes treatments will likely be those that can effect beneficial changes in the activity of AMPK, and our theory predicts that anti-glycation agents may become part of that armamentarium.
Gugliucci
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Glycation, Oxidation and Disease Laboratory, Touro University-California, Mare Island Building H-83, 1310, Johnson Lane, Vallejo, CA 94592, USA. alejandro.gugliucci@tu.edu
D000249:Adenosine Monophosphate / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism*
D000249:Adenosine Monophosphate; D011765:Pyruvaldehyde; D011494:Protein Kinases