Mouse lacking NAD(+)-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle

We surveyed the BALB/cHeA mouse, which lacks cytosolic glycerol phosphate d ehydrogenase an enzyme that catalyzes a reaction in the glycerol phosphate shuttle. The other enzyme of this shuttle, mitochondrial glycerol phosphate dehydrogenase, is abundant in skeletal muscle and pancreatic islets sugges ting that the shuttle's activity is high in these tissues. Levels of glycer ol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle. Intermediates situated before the triose phosphates in the glycolysis pathway were increased and t hose after the triose phosphates were generally low, depending on the tissu e. The lactate/pyruvate ratio in muscle was low signifying a low cytosolic NAD/NADH ratio. This suggests that a nonfunctional glycerol phosphate shutt le caused a block in glycolysis at the step catalyzed by glyceraldehyde pho sphate dehydrogenase. When exercised, mice were unable to maintain normal A TP levels in skeletal muscle. Blood glucose, serum insulin levels, and panc reatic islet mass were normal. In isolated pancreatic islets insulin releas e, glucose metabolism and ATP levels were normal, but lactate levels and la ctate/pyruvate ratios with a glucose load were slightly abnormal. The BALB/ cHeA mouse can maintain NAD/NADH ratios sufficient to function normally und er most conditions, but the redox state is not normal. Glycerol phosphate i s apparently formed at a slow rate. Skeletal muscle is severely affected pr obably because it is dependent on the glycerol phosphate shuttle more than other tissues. It most likely utilizes glycerol phosphate rapidly and, due to the absence of glycerol kinase in muscle, is unable to rapidly form glyc erol phosphate from glycerol. Glycerol kinase is also absent in the pancrea tic insulin cell, but this cell's function is essentially normal probably b ecause of redundancy of NAD(H) shuttles. (C) 2000 Academic Press.