What is the pathophysiology of diabetic ketoacidosis?

Pathophysiology of Diabetic Ketoacidosis

DKA results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), which together trigger three core metabolic derangements: uncontrolled lipolysis with ketogenesis, impaired peripheral glucose utilization with increased hepatic glucose production, and profound osmotic diuresis leading to severe dehydration. 1

Core Hormonal Abnormalities

The pathophysiologic cascade begins with two fundamental hormonal defects that must occur simultaneously 1, 2:

• Insulin deficiency (absolute or relative) prevents glucose uptake by peripheral tissues and removes the brake on lipolysis 1
• Excess counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone) actively drive metabolic decompensation 1, 2

Prevention of either hormonal abnormality will prevent DKA development entirely 3

Metabolic Consequences: The Three-Pronged Attack

1. Hyperglycemia and Osmotic Diuresis

• Reduced insulin action impairs glucose utilization in muscle and adipose tissue while simultaneously increasing hepatic and renal glucose production 1
• Plasma glucose typically exceeds 250 mg/dL (though SGLT2 inhibitor-induced DKA can present with glucose as low as 177-180 mg/dL) 1, 4
• Hyperglycemia causes glycosuria once the renal threshold is exceeded, triggering massive osmotic diuresis with loss of water and electrolytes (sodium, potassium) 3

2. Ketogenesis and Metabolic Acidosis

• Insulin deficiency combined with elevated catecholamines triggers accelerated lipolysis, releasing massive amounts of free fatty acids from adipose tissue 1, 2
• These free fatty acids undergo hepatic β-oxidation to generate excess ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone 1
• Hyperglucagonemia in the setting of insulin deficiency further augments ketogenesis 5
• Accumulation of ketone bodies (organic acids) overwhelms buffering capacity, producing metabolic acidosis with pH <7.30 and bicarbonate <18 mEq/L 4
• The anion gap is elevated (>10-12 mEq/L) due to unmeasured ketoacid anions 4

Critical distinction: Overproduction of ketone bodies is the primary mechanism initiating and maintaining hyperketonaemia throughout DKA, whereas hyperglycemia is initially driven by overproduction but maintained largely by impaired glucose utilization 5

3. Protein Catabolism and Gluconeogenesis

• Net increase in protein breakdown delivers amino acids from muscle to the liver as gluconeogenic precursors 3
• Blood pyruvate and lactate concentrations rise, contributing additional substrate for hepatic glucose production 3

Metabolic Profile Characteristics

DKA has a distinctive metabolic signature 6:

• β-hydroxybutyrate to acetoacetate ratio: typically 3:1 (lower than alcoholic ketoacidosis) 6
• Lactate to pyruvate ratio: typically 11:1 6
• Both serum and urine ketones are strongly positive 4

Clinical Tempo and Progression

• DKA typically develops rapidly, evolving within 24 hours (in contrast to HHS which develops over days to weeks) 4
• Children and adolescents progress fastest because β-cell destruction is most rapid in this age group; DKA can evolve from modest hyperglycemia to severe crisis within hours, especially with infection or other stressors 1
• Insulin pump failure creates absolute insulin deficiency and can precipitate DKA within 4-10 hours depending on insulin formulation 1

Why DKA Differs from HHS

The key pathophysiologic distinction between DKA and hyperosmolar hyperglycemic state (HHS) lies in residual insulin activity 4, 2:

• In DKA: Complete lack of insulin permits unrestrained lipolysis and ketogenesis 2
• In HHS: Residual β-cell function provides enough insulin to prevent significant lipolysis and ketogenesis but remains inadequate to control hyperglycemia 4, 2

This explains why HHS presents with much higher glucose (>600 mg/dL), absent or minimal ketones, and higher osmolality (>320 mOsm/kg) but less acidosis (pH >7.30) 4

Common Precipitating Mechanisms

Understanding precipitants clarifies how the pathophysiologic cascade is triggered 1:

• Infection (30-50% of cases): Stress hormones increase insulin requirements while reducing effective insulin action 1
• Insulin omission: Removes the primary brake on lipolysis and ketogenesis 1, 2
• SGLT2 inhibitors: Reduce insulin doses due to improved glycemia, increase glucagon levels enhancing lipolysis, and decrease renal ketone clearance—creating euglycemic DKA even in non-diabetics 1
• Acute illness (MI, stroke, pancreatitis, trauma): Elevates counterregulatory hormones 1
• Medications: Corticosteroids, thiazides, and sympathomimetics (dobutamine, terbutaline) disturb glucose metabolism and elevate stress hormones 1

Critical Pitfall

Never discontinue basal insulin, even when glucose appears normal, because stopping basal insulin markedly increases the risk of rapid ketosis and DKA within 4-10 hours 1. This is especially dangerous with insulin pump therapy where only rapid-acting insulin is used, providing no depot effect 1.