Etiology/Pathophysiology

• Lack of or insufficient insulin replacement therapy

  • Undiagnosed, untreated diabetes mellitus

  • Treatment failure in known diabetics:

    • Insulin pump failure

    • Forgotten insulin injection

    • Poor adherence to insulin therapy

    • Inability to afford treatment

• Increased insulin demand

  • Stress: infections, surgery, trauma, myocardial infarction, burns, heatstroke

  • Drugs: glucocorticoid therapy, cocaine use, alcohol abuse

DKA, often precipitated by infection (e.g., pneumonia, urinary tract infection), is a common initial manifestation of type 1 diabetes mellitus (∼ 30% of cases).

Osmotic diuresis and hypovolemia

• Insulin normally elevates cellular uptake of glucose from the blood.

• In the insulin-deficient state of DKA, hyperglycemia occurs.

• Hyperglycemia, in turn, leads to progressive volume depletion via osmotic diuresis.

• Insulin deficiency → hyperglycemia → hyperosmolality → osmotic diuresis and loss of electrolytes → hypovolemia

Hypovolemia resulting from DKA can lead to acute kidney injury (AKI) due to decreased renal blood flow! Hypovolemic shock may also develop.

• Insulin deficiency also increases fat breakdown (lipolysis).

• Metabolic acidosis develops as the free fatty acids generated by lipolysis become ketones, two of which are acidic (acetoacetic acid and beta-hydroxybutyric acid).

• Serum bicarbonate is consumed as a buffer for the acidic ketones. Metabolic acidosis with an elevated anion gap is therefore characteristic of DKA.

• Insulin deficiency → ↑ lipolysis → ↑ free fatty acids → hepatic ketone production (ketogenesis) → ketosis → bicarbonate consumption (as a buffer) → anion gap metabolic acidosis

• As a result of hyperglycemic hyperosmolality, potassium shifts along with water from inside cells to the extracellular space and is lost in the urine.

• Insulin normally promotes cellular potassium uptake but is absent in DKA, compounding the problem.

• A total body potassium deficit develops in the body, although serum potassium may be normal or even paradoxically elevated.

• Insulin deficiency → hyperosmolality → K+ shift out of cells + lack of insulin to promote K+ uptake → intracellular K+depleted → total body K+ deficit despite normal or even elevated serum K+

• Primarily affects patients with type 2 diabetes

• The pathophysiology of HHS is similar to that of DKA.

• However, in HHS, there are still small amounts of insulin being secreted by the pancreas, and this is sufficient to prevent DKA by suppressing lipolysis and, in turn, ketogenesis.

• HHS is characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycemia and osmotic diuresis.