CELLULAR BIOCHEMISTRY 



Insulin 



Less definite statements can be made about the mechanism 

 of insulin action than about that of epinephrine. There is in- 

 direct evidence, obtained by a variety of methods on isolated 

 tissues and on intact animals, that the first step in glucose utili- 

 zation is accelerated by insulin. The same step presumably is 

 inhibited by a substance of pituitary origin which is present in 

 the serum of diabetic animals, which disappears after hypoph- 

 ysectomy and reappears again when the diabetic hypoph- 

 ysectomized rats are injected with growth hormone plus 

 cortisone (3). The diabetic serum was tested on isolated rat 

 diaphragm and the inhibition of glucose uptake could be 

 counteracted by the addition of insulin. A lipoprotein fraction 

 prepared from diabetic plasma and from anterior pituitary pro- 

 duced a strong inhibition of the hexokinase reaction in a cell- 

 free system, but the reversal of this inhibition by insulin was 

 incomplete and did not have the desired degree of reproduci- 

 bility (15). In isolated rat diaphragm the inhibition of glucose 

 uptake produced by a lipoprotein fraction from serum of dia- 

 betic rats was completely reversed by insulin. It should be 

 pointed out that the effect of injection of these lipoprotein frac- 

 tions in intact animals has not so far been reported. 



The severe disturbance in fat metabolism in the liver of the 

 diabetic animal is now regarded as secondary to the inhibited 

 glucose utilization (10). In the reversible series of reactions 

 represented by acetyl CoA^fatty acid, there are two reductive 

 steps in the direction to the right, for each C2 fragment which is 

 added in the lengthening of the fatty acid chain (17). These 

 reductive steps require DPNH which can be supplied by gly- 

 colysis. Whether the DPNH formed during the operations of 

 the Krebs cycle is available for fatty acid synthesis is uncertain. 

 In the absence of sufficient glucose utilization in a liver depleted 

 of its glycogen reserves, the steady-state concentration of DPNH 

 diminishes, and this shifts the equilibrium to the left, i.e., fatty 

 acids are now broken down and ketosis results (12). It should 

 be mentioned that the liver in ketosis responds very sluggishly 



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