Mouse lacking NAD(+)-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle
Mj. Macdonald et Lk. Marshall, Mouse lacking NAD(+)-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle, ARCH BIOCH, 384(1), 2000, pp. 143-153
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.