The anomeric malaise: a manifestation of B-cell glucotoxicity.
In non-insulin-dependent diabetic subjects and in various animal models of spontaneous or experimental chronic hyperglycaemia, the secretory response of the pancreatic B-cell to a rapid rise in extracellular D-glucose concentration is characterized by a paradoxical, early and transient fall in insulin output and/or an altered anomeric specificity. These two features of B-cell glucotoxicity may be accounted for by the accumulation of glycogen in the B-cell and the interference of changes in glycogenolysis with the hexose-induced increase in glycolytic flux. The inhibitory action of D-glucose upon glycogenolysis displaying alpha-stereospecificity, the metabolic and secretory response to alpha-D-glucose is expected to be more severely affected than that evoked by the beta-anomer. Such a preferential alteration of the response to alpha-D-glucose was indeed documented in diabetic subjects, BB rats, duct-ligated rabbits, and adult rats either injected with streptozotocin during the neonatal period or rendered hyperglycaemic by the repeated administration of diazoxide. In these experimental models, the attenuation, suppression or even reversal of the anomeric preference in insulin release appeared related to the severity and duration of the hyperglycaemic state. A clear distinction ought to be made between these features of B-cell glucotoxicity and other etiopathogenic factors of B-cell dysfunction, such as the long term deleterious effect of streptozotocin upon the activity of key mitochondrial dehydrogenases.
Malaisse
W J
WJ
Laboratory of Experimental Medicine, Brussels Free University, Belgium.
D000818:Animals; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005947:Glucose / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology; D013012:Sorbitol / Q000378:metabolism
D007328:Insulin; D013012:Sorbitol; D006003:Glycogen; D005947:Glucose