STUDY OF DISEASE 



glands. An example of this situation is the finding of an increase 

 in gluconeogenesis observed in alloxan-diabetic animals (7). 

 These animals have enlarged adrenal cortices, and it is possible 

 that this effect is not directly attributable to hypoinsulinism but 

 is rather a consequence of a secondary hyperadrenalism. 



It is generally agreed today that the major effect upon blood 

 glucose of hypoinsulinism is a decrease in glucose utilization by 

 such tissues as liver and muscle. Conversely the primary effect 

 of hyperinsulinism is an enhancement of glucose utilization in 

 these tissues. Many of the complex consequences of diabetes 

 may be explained upon this basis alone, in that, with the genera- 

 tion of intracellular glucose-6-phosphate impeded, all products 

 derived from glucose-6-phosphate, such as lactate, pyruvate, or 

 CO2, will not be formed from glucose at normal rate. Other 

 reactions, which are coupled to those of glycolysis less directly, 

 such as peptide bond synthesis (8) and fatty acid synthesis 

 (19,4), will also be retarded. There is ample experimental 

 evidence that these effects are observed in the diabetic organism 

 and are reversed by administration of insulin. 



Many diabetic patients require dosages of insulin far in 

 excess of what is generally considered the production of the 

 normal pancreas, and in various situations, most strikingly in 

 severe ketosis, the insulin tolerance may increase enormously. 

 Under these circumstances one must suppose that an "antag- 

 onist" to insulin is present in undue amount in the blood (12) 

 or tissues. Whether this antagonist is in the nature of a pituitary 

 hormone (2), an antibody (1), or a specific destructive enzyme 

 (insulinase) (13) remains to be determined. 



The last fate of glucose to be discussed is urinary loss. The 

 normal operation of renal tubular reabsorption of glucose may 

 be overwhelmed by excessively high concentrations of glucose 

 in the blood. This may occur secondary to a variety of dis- 

 turbances which interfere with glucose utilization, such as 

 insulin deficit, or which cause excessive glucose production, such 

 as excessive epinephrine or excessive corticosteroid. Further, 

 the mechanism of tubular reabsorption may itself be defective 



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