| Research Abstract |
We have extensively analyzed molecular basis of glucose signaling in the pancreatic β cell. In relation to glucose toxicity, high plasma glucose was in fact priming the β cell and amelioration of hyperglycemia resulted in β cell suppression rather than β cell recovery. The finding indicates that high glucose primes the β cell under a certain circumstance. We can see β cell glucose toxicity in patients with 'ketosis-onset diabetes and subsequent non-insulin-dependency', which was established as a distinctive clinical entity by us. Characteristics of β cell glucose signaling in mouse with targeted disruption of IRS-1, glucokinase, and mGPDH was delineated. Regarding mediators of KATP channel-independent glucose action, synergism between signals arising from upper glycolytic pathway and mitochondrial metabolism was demonstrated. Furthermore, importance of lipid signal/protein acylation was discovered. Taken together, we reached to a working hypothesis that glucose stimulation of pancreatic β cell is mediated by 'not one but many' signals working in synergy.
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