Development of diabetic ketoacidosis: some observations on and deductions about the sources of acid.

Abstract

Abstract. The carboxylic acid balance of perfused livers from normal and streptozotocin diabetic rats (in insulin treatment or deprived of insulin for various time intervals) was determined by measurement of FFA, lactate, pyruvate and in ketone bodies in input and output medium. In livers from fed rats of either type of treatment, the carboxylic acid balance was close to zero, and the same was true for livers from 48‐hour fasting rats after 6 hours or more of insulin deprivation. Thus, when livers were perfused with a medium containing 1 mM of lactate and of FFA, the diabetic state did not turn the liver into a state of net acid production. Addition of a high concentration of glucose to the medium inhibited the rate of ketogenesis significantly in livers from fasting diabetic animals perfused for 6 hours after discontinuation of insulin treatment. In this way a high glucose concentration caused an increased net uptake of carboxylic acid in such livers. A decrease in the liver blood flow to one‐third of the normal invariably turned livers into a state of net acid production due to (a) a strongly diminished uptake of lactate in livers perfused with a medium containing no glucose and (b) by a large net lactate production in livers perfused with 20 mM glucose. On the basis of these observations and of data from available literature it is suggested that the pathogenesis of the diabetic ketoacidosis in humans can be divided into two phases: 1) An initial phase (pH 7.4 to 7.1) distinguished by a gradually increasing accumulation of acid equivalents in the body largely caused by accumulation of the keto acids (3‐hydroxybutyrate and acetoacetate) and of non‐carbonic acid equivalents originating from the excretion in the urine of ketone bodies as bases, i.e. with sodium and potassium as the corresponding cations which ensure electroneutrality. 2) A late phase (π <7.1) distinguished by severely impaired capacity for renal excretion of acid equivalents, of an impaired capacity for respiratory compensation of the metabolic acidosis and by a changed hepatic metabolism of lactate: from a net lactate clearing function the liver is turned into a net lactate producing function due to a low perfusion flow and a high glucose concentration. Thus, in the late phase the organism has lost any possibility to eliminate acid. On the basis of pKa values for the second acid group of organic phosphates and inorganic phosphate the estimate is given that net hydrolysis of organic phosphates, which takes place during the development of diabetic ketoacidosis, will rather cause a net removal than a net supply of non‐carbonic acid to the body fluids.