138 Essays in Biochemistry 



It is of interest to speculate about the defect in such "diabetic" 

 extracts which can readily degrade fatty acids but not accomplish the 

 reverse process. The addition of glycogen, hexose diphosphate, or a 

 number of glycolytic intermediates, produces a marked stimulating 

 effect upon the incorporation of labeled acetate or pyruvate into long- 

 chain fatty acids. 19 In fact, the addition of hexose diphosphate and 

 ADP restores such lipogenic activity nearly to normal. It is significant 

 that glucose is ineffective, whereas fructose has some stimulating effect- 

 Such results are consistent with the data obtained by Chernick et al. 20 

 who demonstrated that fructose is well utilized by liver slices of dia- 

 betic animals. It appears likely therefore that fructokinase and the 

 remaining glycolytic enzymes are relatively intact in the diabetic state. 

 One is therefore tempted to speculate that the diabetic and fasting 

 states may involve a deficiency of glycolytic intermediates. If this is 

 so, then the addition of phosphorylated intermediates of glycolysis to 

 cell-free systems prepared from diabetic animals should be stimulatory. 

 If this concept is correct, then the failure of the diabetic to synthesize 

 fat 21 can in large measure be ascribed to diminished glycolysis result- 

 ing from the failure to utilize glucose. 



It is attractive to attempt to explain physiological events in terms 

 of chemical reactions, even though the field is still in a primitive state. 

 The fatty livers associated with the diabetic state cannot obviously 

 be ascribed to accelerated lipogenesis, since such livers cannot syn- 

 thesize fat. Nor can this accumulation of fat be due to a diminished 

 catabolism of fat by the liver since there is abundant evidence to the 

 contraiy. It is apparent that this phenomenon must be explained 

 primarily on the basis of accelerated mobilization and transport of fat 

 from the periphery to the liver. 



The ketosis of diabetes is understandable if one pictures an over- 

 production of acetyl CoA from fatty acids in the face of a limited 

 supply of oxalacetate. Conversely the antiketogenic effect of carbo- 

 hydrate can be explained if one assumes that there is a resulting 

 increased production of malate and oxalacetate for condensation with 

 acetyl CoA to form citrate. On this basis, pyruvate which forms 

 acetyl CoA, and should therefore possess some ketogenic activity, fails 

 to do so since it can also provide its own oxalacetate (reactions involv- 

 ing fixation of CO2) . 



That acetoacetate is not readily metabolized in liver is consistent 

 with the absence of an effective activating system in liver. The 

 succinyl CoA transferase system occurs elsewhere 8 and is capable of 

 effectively transferring CoA to acetoacetate. Another reaction of acetyl 



