CARL F. CORI 



to insulin, since it takes some time until secondary changes are 

 repaired. That the normal liver responds rapidly to insulin, as 

 do other tissues, follows from observations made on normal and 

 diabetic subjects with the hepatic vein catheterization technique 

 (2). On injection of insulin the hepatic output of glucose dimin- 

 ishes within a short time. Another secondary disturbance is an 

 increased glucose-6-phosphatase activity in the liver, which re- 

 sults in increased dephosphorylations (1). This nullifies to some 

 extent the beneficial effect of fructose in diabetes. This sugar is 

 phosphorylated to fructose- 1 -phosphate by a separate enzyme 

 and so is able to bypass the metabolic block at the glucose level, 

 but in its metabolic transformations fructose- 1 -phosphate is in 

 equilibrium with glucose-6-phosphate, and thus is converted to 

 glucose by the increased activity of the phosphatases. 



There are some cells which are not influenced by insulin. 

 The ascites tumor cells which were discussed earlier have been 

 tested under a great variety of conditions, but a clear-cut effect 

 of insulin on the rate of sugar uptake could not be shown. The 

 conditions which make a cell respond to insulin are therefore 

 not clearly defined. In general, an enzymatic step, such as that 

 mediated by phosphorylase or hexokinase, which is at the be- 

 ginning of a series of consecutive reactions, cannot, by being 

 speeded up, increase the rate of the over-all reaction unless it is 

 the rate-limiting step. It has been shown by several methods 

 that phosphorylase is the rate-limiting step for glucose formation 

 in the liver (19). The first step may be rate-limiting under the 

 following conditions which, if changed, will permit an increase 

 in the over-all rate. (7) Part of the enzyme is present in an 

 inactive form. This is the condition under which epinephrine 

 is able to exert its eflfect, by converting an inactive form of phos- 

 phorylase to an active form. (2) The substrate concentration is 

 below that which saturates the enzyme. (3) Product inhibition 

 occurs because a subsequent enzymatic step in a reversible chain 

 of reactions is relatively slow. (4) The enzyme is not fully active 

 because it is combined with an inhibitor. Conditions (2) and 

 {4) have each been suggested as the condition under which 



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