Pathophysiology
Clinical meaning
Understanding the detailed biochemistry of ketogenesis and osmotic diuresis is essential for the NP to anticipate clinical findings, guide management decisions, and recognize treatment complications. KETOGENESIS IN DKA: In the absence of insulin, hormone-sensitive lipase in adipose tissue is uninhibited, releasing massive quantities of free fatty acids (FFAs) into the bloodstream. FFAs are transported to hepatic mitochondria where they undergo beta-oxidation, producing acetyl-CoA. Normally, acetyl-CoA enters the citric acid cycle (TCA cycle), but in DKA, the TCA cycle is overwhelmed because oxaloacetate is diverted to gluconeogenesis (insulin deficiency de-represses PEPCK). The excess acetyl-CoA is shunted into the ketogenic pathway: 1. Two acetyl-CoA molecules condense to form acetoacetyl-CoA 2. HMG-CoA synthase (rate-limiting enzyme of ketogenesis, upregulated by glucagon and downregulated by insulin) converts acetoacetyl-CoA to HMG-CoA 3. HMG-CoA lyase cleaves HMG-CoA to acetoacetate (the first ketone body) 4. Acetoacetate is reversibly reduced to beta-hydroxybutyrate (the predominant ketone body, ratio 3:1 to 10:1 in DKA) or spontaneously decarboxylated to acetone (volatile — exhaled through the lungs, producing fruity breath) Beta-hydroxybutyrate and acetoacetate are strong organic acids (pKa ~4.7) that dissociate completely at...