Primary Cause of Acidosis in Diabetic Ketoacidosis
The acidosis in DKA is caused by the accumulation of ketone bodies (β-hydroxybutyrate and acetoacetate) produced through uncontrolled hepatic fatty acid oxidation, which results from the combination of absolute insulin deficiency and elevated counterregulatory hormones triggering unrestrained lipolysis. 1
Pathophysiologic Mechanism
The fundamental metabolic derangement driving acidosis in DKA involves a specific hormonal cascade:
Insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone) triggers the release of free fatty acids from adipose tissue through accelerated lipolysis 1, 2
These free fatty acids undergo unregulated hepatic β-oxidation, producing excessive ketone bodies—primarily β-hydroxybutyrate and acetoacetate—which accumulate in the blood and cause metabolic acidosis 1, 3
β-hydroxybutyrate is the strongest and most prevalent acid in DKA, though standard nitroprusside testing only detects acetoacetate and acetone, not β-hydroxybutyrate 1
Biochemical Characteristics of the Acidosis
The metabolic acidosis in DKA has specific laboratory features:
Arterial pH ranges from <7.0 to 7.30, with serum bicarbonate ≤18 mEq/L 4
The anion gap is elevated (>10-12 mEq/L) due to accumulation of ketoacids 4
Urine and serum ketones are strongly positive, reflecting the unregulated ketogenesis from severe insulin deficiency 4
Important Clinical Caveat: Mixed Acid-Base Disorders
A critical pitfall is assuming all DKA presents with simple metabolic acidosis:
Nearly half of DKA cases (51.1%) present with mixed acid-base disorders, including DKA with mild acidemia (pH 7.3-7.4) or even diabetic ketoalkalosis (pH >7.4) 5
In diabetic ketoalkalosis, concurrent metabolic alkalosis (47.2% of cases) and respiratory alkalosis (81.1% of cases) can mask the underlying ketoacidosis, yet 34% still have severe ketoacidosis requiring standard DKA treatment 5
Hydration status significantly influences acid-base presentation: better-hydrated patients may develop concurrent hyperchloremic acidosis, while severely dehydrated patients with vomiting can develop concurrent metabolic alkalosis 6
Contrast with Hyperosmolar Hyperglycemic State
Understanding why HHS lacks significant acidosis clarifies DKA's mechanism:
HHS is characterized by residual beta-cell function providing enough insulin to suppress lipolysis and prevent ketogenesis, but remaining inadequate to control hyperglycemia 4, 3
In HHS, arterial pH remains >7.30 with serum bicarbonate >15 mEq/L, and ketones are small or negative 4
This demonstrates that ketone body production—not hyperglycemia itself—is the direct cause of acidosis in DKA 1, 4
Special Consideration: Euglycemic DKA
A dangerous diagnostic pitfall involves SGLT2 inhibitor-associated DKA:
SGLT2 inhibitors are now a leading cause of DKA, including euglycemic DKA with glucose levels <250 mg/dL, through mechanisms involving reduced insulin doses, increased glucagon-driven lipolysis, and decreased renal ketone clearance 2, 7
Euglycemic DKA can delay diagnosis if clinicians rely solely on glucose thresholds rather than checking ketone levels in at-risk patients 4, 7