What is the pathophysiology 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), which together trigger three core metabolic derangements: uncontrolled hyperglycemia, metabolic acidosis, and increased total body ketone concentration. 1, 2

Core Metabolic Mechanisms

Insulin Deficiency and Counterregulatory Hormone Excess

• The fundamental pathophysiologic defect is reduced effective insulin action paired with elevated counterregulatory hormones, creating a catabolic state that drives all downstream metabolic abnormalities. 1, 3

• This hormonal imbalance affects three major metabolic pathways simultaneously: carbohydrate, protein, and fat metabolism. 3, 2

Hyperglycemia Development

• Insulin deficiency impairs glucose utilization in peripheral tissues (muscle, adipose) while counterregulatory hormones stimulate both hepatic and renal glucose production through glycogenolysis and gluconeogenesis. 1

• The resulting hyperglycemia (typically >250 mg/dL) creates an osmotic diuresis leading to profound dehydration and electrolyte losses. 4, 5

• However, euglycemic DKA (glucose <250 mg/dL) can occur, particularly with SGLT2 inhibitor use, pregnancy, reduced food intake, or alcohol use, making hyperglycemia a less reliable diagnostic criterion than previously thought. 4

Ketogenesis and Metabolic Acidosis

• Elevated counterregulatory hormones combined with insulin deficiency trigger uncontrolled lipolysis in adipose tissue, releasing massive amounts of free fatty acids into circulation. 1

• These free fatty acids undergo unregulated hepatic oxidation and ketone body production (β-hydroxybutyrate and acetoacetate), driven by intrahepatic enzymic processes that are normally suppressed by insulin. 1, 6

• The accumulation of these ketoacids overwhelms the body's buffering capacity, resulting in high anion gap metabolic acidosis (pH <7.3, bicarbonate <18 mEq/L, anion gap >10-12 mEq/L). 4, 2

• β-hydroxybutyrate is the predominant ketone in DKA and should be measured for diagnosis and monitoring, as traditional nitroprusside-based tests do not detect it. 4

SGLT2 Inhibitor-Specific Pathophysiology

• SGLT2 inhibitors create a unique pathophysiologic scenario by reducing insulin doses due to improved glycemic control, increasing glucagon levels that enhance lipolysis and ketone production, and decreasing renal clearance of ketones. 1

• This mechanism can precipitate DKA in both diabetic and non-diabetic patients, particularly with reduced caloric intake or acute illness. 1

• The body's compensatory response to SGLT2 inhibitor-induced glucose depletion involves counterregulatory hormone release, glycogenolysis, and gluconeogenesis, but these protective mechanisms paradoxically worsen ketogenesis. 1

Clinical Manifestations of Pathophysiology

Osmotic Diuresis and Dehydration

• Hyperglycemia exceeds the renal threshold for glucose reabsorption, causing osmotic diuresis with massive losses of water and electrolytes (sodium, potassium, chloride, phosphate, magnesium). 3, 2

• This manifests clinically as polyuria, polydipsia, poor skin turgor, tachycardia, and hypotension. 4

Acidosis-Related Symptoms

• Metabolic acidosis triggers compensatory Kussmaul respirations (deep, labored breathing) to eliminate CO2 and partially correct pH. 4

• Acidosis also causes nausea, vomiting, and abdominal pain, with up to 25% experiencing coffee-ground emesis. 4

Altered Mental Status

• Mental status changes ranging from full alertness to profound lethargy or coma result from hyperosmolarity, acidosis, and cerebral dehydration. 4, 7

• The degree of mental status impairment correlates with severity of metabolic derangements, particularly effective serum osmolality. 7

Distinction from Hyperosmolar Hyperglycemic State (HHS)

• DKA and HHS represent two extremes in the spectrum of decompensated diabetes, with DKA characterized by prominent insulin deficiency and ketoacidosis, while HHS has residual insulin action sufficient to prevent significant ketogenesis but inadequate to control hyperglycemia. 7, 3

• DKA typically evolves rapidly (within 24 hours), whereas HHS develops over days to weeks. 4, 7

• Up to one-third of patients may present with mixed features of both DKA and HHS, requiring tailored therapeutic approaches. 3

Common Pitfalls in Understanding DKA Pathophysiology

• Temperature is unreliable in DKA patients—they can be normothermic or even hypothermic despite serious infection, with hypothermia being a poor prognostic sign. 1, 4

• Leukocytosis in DKA represents a stress response with left shift and does not necessarily indicate infection; procalcitonin is more specific for bacterial infection. 1

• Phosphorus deficiency is common and becomes manifest within 4-12 hours of treatment initiation as insulin drives phosphate intracellularly, potentially impairing oxygen delivery to tissues through depletion of erythrocyte 2,3-diphosphoglycerate. 6