If metabolism were an unregulated engine it would overheat in times of plenty and shut down in times of starvation. Instead it attempts to smooth its activity.
The first step in this smoothing process is to measure metabolic rate. Cells do so, say Dachun Yao, Michael Brownlee (Albert Einstein College of Medicine, Bronx, NY), and colleagues, by using the glycolysis degradation product methylglyoxal to modify the structure and action of transcription factors. Overactivation of this sensing pathway by hyperglycemia may explain some diabetic symptoms.
Brownlee's group earlier found high methylglyoxal in endothelial cells bathed in high glucose. Methylglyoxal is a precursor of advanced glycation end-product (AGE) formation, a kind of covalent fouling-up of the cellular machinery. But the current finding is more specific. Methylglyoxal attaches to the transcriptional corepressor mSin3A; this brings in a sugar to modify the Sp3 factor so the corepressor complex departs. The result is more angiopoietin 2 (Ang-2) transcription. Too much Ang-2 can cause endothelial cell death and blood vessel regression, a process that occurs in the eyes of many diabetics.
Methylglyoxal is a better target for cells to monitor than glucose alone, because it integrates different metabolic inputs. If metabolic fluxes are high, adjustments at promoters other than Ang-2 might prevent cellular overheating. The same mechanism may also link metabolic flux to behavior, as increased brain glyoxylase expression has recently been shown to increase anxiety-related behaviors in mice.
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