Paths of carbon in gluconeogenesis and lipogenesis: the role of mitochondria in supplying precursors of phosphoenolpyruvate.

Gluconeogenesis-the synthesis of glucose and glucose-containing polysaccharide from compounds other than hexoses-is a process of considerable magnitude in normal animals and one that is subject to grave alterations in certain disease states. In mammals gluconeogenesis occurs mainly, if not exclusively, in liver and kidney.2 Carbohydrate is synthesized by these tissues from lactate and pyruvate during periods of heavy muscular work, and the glucose formed is returned to muscle to serve as a glycolytic energy source (Cori cycle). During long intervals between meals, and especially during fasting, amino acids from tissue proteins serve as a source of carbon for gluconeogenesis. In the absence of adrenal corticosteroids, protein reserves are not converted to carbohydrate sufficiently rapidly to maintain normal blood sugar levels3 while in the diabetic this conversion is so rapid as to elevate blood sugar above the renal threshold.4 The main pathway of carbon in gluconeogenesis differs from the reverse of the glycolytic sequence at 3 steps5 and consequently gluconeogenesis is subject to some controls that are without effect on carbohydrate degradation. One of these steps-the formation of phosphoenolpyruvate from pyruvate-seemed likely to be a site at which metabolic control of gluconeogenesis would be effected6 since it is at the point where pyruvate from either lactate or amino acid residues enters the route to hexose formation. Pyruvate enters the gluconeogenic route by being carboxylated to a dicarboxylic acid.7 This is accomplished by the pyruvate carboxylase (reaction 1) of Utter and Keech which is located predominantly in the mitochondria of liver cells:8-11