What is the pathophysiology and management of Diabetic Ketoacidosis (DKA)?

Pathophysiology of Diabetic Ketoacidosis

DKA results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), leading to accelerated lipolysis, excess fatty acid production, beta-oxidation, and ketogenesis with subsequent metabolic acidosis. 1, 2

Core Metabolic Derangements

The fundamental pathophysiology involves two parallel processes driven by the altered insulin-to-glucagon ratio:

Hyperglycemia Pathway

• Reduced insulin action prevents peripheral glucose uptake by muscle and fat tissues while counterregulatory hormones stimulate hepatic glucose production through glycogenolysis and gluconeogenesis 2
• Plasma glucose typically exceeds 250 mg/dL (though euglycemic DKA with glucose <200 mg/dL can occur with recent insulin use, decreased caloric intake, alcohol consumption, or SGLT2 inhibitor use) 1, 3
• Osmotic diuresis from glucosuria leads to profound volume depletion and electrolyte losses 4

Ketoacidosis Pathway

• Insulin deficiency combined with elevated catecholamines triggers accelerated lipolysis in adipose tissue, releasing excessive free fatty acids into circulation 2
• These fatty acids undergo hepatic beta-oxidation and ketogenesis, producing acetoacetate and beta-hydroxybutyrate (ketone bodies) 5
• Ketone accumulation overwhelms buffering capacity, causing metabolic acidosis with arterial pH <7.30 and serum bicarbonate <18 mEq/L 1
• The anion gap becomes elevated (>10-12 mEq/L) due to unmeasured ketoacid anions 1

Key Distinguishing Feature from HHS

DKA differs from hyperosmolar hyperglycemic state because complete insulin absence permits uninhibited lipolysis and ketogenesis, whereas HHS retains sufficient residual beta-cell function to prevent significant ketone formation but not hyperglycemia. 1, 2

Clinical Consequences of Pathophysiology

Acid-Base Disturbance

• Metabolic acidosis severity ranges from mild (pH 7.25-7.30, bicarbonate 15-18 mEq/L) to severe (pH <7.00, bicarbonate <10 mEq/L) 6, 1
• Compensatory Kussmaul respirations develop as the body attempts to eliminate CO2 1

Electrolyte Shifts

• Total body potassium is severely depleted despite normal or elevated initial serum levels, as acidosis drives intracellular potassium into extracellular space 7
• Insulin therapy and acidosis correction cause rapid potassium shift back into cells, creating risk for life-threatening hypokalemia and cardiac arrhythmias (including atrial flutter) 7
• Volume depletion causes hemodynamic stress that further increases arrhythmia risk 7

Osmotic Effects

• Effective serum osmolality increases (though typically <320 mOsm/kg, unlike HHS) 1
• Mental status changes range from alert to stupor/coma, correlating with acidosis severity 1

Precipitating Factors

The most common triggers that unmask or worsen insulin deficiency include:

• Infection (most common precipitant) 1, 4
• Insulin omission (especially in recurrent DKA, often related to psychiatric illness, depression, eating disorders, single-parent homes, or inadequate insurance) 6, 4
• New diagnosis of diabetes (presenting DKA) 4
• SGLT2 inhibitor use (promotes ketogenesis through altered insulin/glucagon ratio and increased physiological stress) 6, 4

Special Pathophysiologic Considerations

SGLT2 Inhibitor-Associated DKA

• SGLT2 inhibitors lower glucose concentrations, changing the insulin/glucagon ratio and predisposing to ketosis 6
• Physiological stress triggers counterregulatory hormones that drive rapid hyperketonaemia (>3.0 mmol/L) and pH drop (<7.3) 6
• Euglycemic ketoacidosis can occur even in patients without diabetes, as SGLT2 inhibitors prevent sufficient insulin concentrations needed to block ketogenesis 6

Checkpoint Inhibitor-Associated Diabetes

• Autoimmune beta-cell destruction from immunotherapy causes acute insulin deficiency mimicking type 1 diabetes 6
• Presents with acute polyuria, polydipsia, weight loss, and lethargy with rapid progression to DKA 6

Timeline and Mortality

• DKA typically develops rapidly within 24 hours (unlike HHS which evolves over days to weeks) 1
• Mortality remains 3.4-5% in experienced centers, with higher rates (up to 15%) in developing countries 6, 1, 2, 4
• Prognosis worsens with age >65 years, coma, hypotension, and severe acidosis (pH <7.0) 1, 2

Critical Monitoring Requirements

• Continuous cardiac monitoring is essential in severe DKA (pH <7.0, bicarbonate <10 mEq/L) to detect arrhythmias early 7
• Electrolytes, especially potassium, require monitoring every 2-4 hours during treatment to prevent hypokalemia-induced arrhythmias 7
• Potassium replacement must begin once serum levels fall below 5.5 mEq/L 7