Is type 2 diabetes due to a deficiency of FAD-linked glycerophosphate dehydrogenase in pancreatic islets?
The mitochondrial enzyme FAD-linked glycerophosphate dehydrogenase (m-GDH) is thought to play a key role in the glucose-sensing mechanism of the insulin-producing B-cell. It catalyses a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets. Its activation by Ca2+ accounts for the preferential stimulation of oxidative glycolysis and, hence, pyruvate oxidation in glucose-stimulated islets. Reduced activity of m-GDH was recently observed in islet, but not liver, homogenates from rats injected with streptozotocin during the neonatal period and in two models of inherited diabetes, i.e. GK rats and db/db mice. In the streptozotocin-injected and GK rats the m-GDH islet defect coincided, in intact islets, with an abnormally low ratio between oxidative and total glycolysis. Decreased activity of m-GDH in T-lymphocytes was also observed in 12 of 32 type 2 (non-insulin-dependent) diabetic patients, but only once among 26 other subjects including 11 healthy volunteers, 9 non-diabetics and 6 patients with either type 1 (insulin-dependent) or symptomatic diabetes. In the T-lymphocytes of type 2 diabetics the m-GDH deficiency occasionally coincided with an abnormally high ratio between glutamate-pyruvate and glutamate-oxaloacetate transaminase activities, as also observed in islets from streptozotocin-injected or GK rats. It is speculated that an islet m-GDH defect could represent a far from uncommon factor contributing to the pathogenesis of type 2 diabetes mellitus.
Malaisse
W J
WJ
Laboratory of Experimental Medicine, Brussels Free University, Erasmus Medical School, Belgium.
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005993:Glycerolphosphate Dehydrogenase / Q000172:deficiency*; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological
D005182:Flavin-Adenine Dinucleotide; D005993:Glycerolphosphate Dehydrogenase