What is the cause of acidosis in diabetic ketoacidosis?

[BabcockHall]

When the Krebs' cycle is too slow to consume all of the acetyl CoA from beta-oxidation, some of the acetyl CoA is used to make ketone bodies.  When the three ketone bodies, acetone, acetoacetate, and beta-hydroxybutyrate are in abnormally high concentrations, this is ketosis.    Type I (and occasionally Type II) diabetics suffer from diabetic ketoacidosis, in which the blood pH lowers (there are three grades of severity).  What is unclear to me is the cause of the lowered pH.  My working hypothesis is that the acid may be generated when the fatty acyl esters are oxidized to acetyl CoA (beta-oxidation), because each round should produce one proton.  When I looked at the pathway to produce ketone bodies, I became convinced that the textbook presentations do not always write balanced equations for this pathway.  The attached file is modified from one textbook: I added protons to reactions 2 and 4.  

Ketone_body_pathway_v1.pdf

[CharonY]

Ketoacidosis is primarily caused by the accumulation of beta-hydroxybutyrate and acetoacetate themselves. The accumulation of these acids in the extracellular fluid lead to loss of bicarbonate ions, thus reducing the buffer capacity of blood. Keywords you may want to look up if you want to see the viewpoint from the medical side are the serum anion gap and the delta-delta gap. 

[BabcockHall]

“Anion gap = [Na⁺] – ([Cl^-] + [HCO₃^-])

 “The normal value is about 12 meq/liter (range 8 to 16).  The anion gap estimates the unmeasured anions in the plasma and is normally composed of polyanionic plasma proteins such as albumin (1 g/dL of serum protein possesses negative charge equivalent to 1.7 to 2.4 meq/liter), phosphate, sulfate, lactate, and other organic anions.

 “The anion gap is particularly useful in evaluating metabolic acidosis.  Elevated values indicate that the acidosis is due to ingestion or generation of a fixed acid, stronger than H₂CO₃, at rates that exceed the rate at which the anion can be excreted from the body.  Examples are diabetic ketoacidosis, in which acetoacetic and b-hydroxybutyric acids are generated; lactic acidosis; and renal failure, in which the rate of generation of strong acids is normal but the anions the acids, e.g., phosphate and sulfate, cannot be normally excreted.  Ingestion of methanol, which generates formic acid, ingestion of ethylene glycol, which yields oxalic acid, and salicylate intoxication all produce high anion gap acidosis.”

 p. 188 in Principles of Biochemistry: Mammalian Biochemistry, 7^th ed., Smith E, Hill, RL, Lehman IR, Lefkowitz, RJ, Handler P, White A, McGraw-Hill, 1983

Thank you.  I found the passage above to be helpful.  I have not yet looked into the delta-delta gap.  I have been examining the reactions I wrote out in the pdf (I have not yet figured out how to format them for this thread).  If we take acetyl CoA as the starting material and imagine that only beta-hydroxybutyrate is formed, then no net protons are consumed or produced.  If we instead imagine that only acetoacetate is formed, then one proton is produced.  This is equivalent to four protons per palmitoyl CoA, the precursor to acetyl CoA.  On the other hand, seven protons are produced in the beta-oxidation of one palmitoyl CoA to eight acetyl CoA molecules.

Edited February 13, 2018 by BabcockHall