Hormonal and Metabolic Mechanisms Underlying Diabetic Ketoacidosis

Hormonal Derangements

DKA is driven by a combination of insulin deficiency and elevated counter‑regulatory hormones (glucagon, catecholamines, cortisol, growth hormone), which together promote uncontrolled lipolysis, ketogenesis, and hyperglycemia【1】.
The core pathophysiology involves two simultaneous hormonal abnormalities: (1) reduced net effective insulin action (relative or absolute deficiency) and (2) elevation of counter‑regulatory hormones in response to stress or illness【1】【2】.

Counter‑regulatory hormone excess stimulates hepatic and renal glucose production through increased gluconeogenesis and glycogenolysis【1】.
Impaired insulin signaling in peripheral tissues leads to reduced glucose uptake and utilization【1】.
Resulting hyperglycemia raises extracellular osmolality, producing osmotic shifts that contribute to dehydration【1】.

Insulin deficiency together with elevated stress hormones triggers intense lipolysis, releasing free fatty acids from adipose tissue into the circulation【1】【2】.
The liver oxidizes these free fatty acids without normal insulin‑mediated inhibition, generating large amounts of ketone bodies (β‑hydroxybutyrate and acetoacetate)【1】.
Accumulation of ketone bodies overwhelms buffering capacity, producing a high‑anion‑gap metabolic acidosis characteristic of DKA【1】.
In hyperosmolar hyperglycemic state (HHS), residual insulin may be sufficient to suppress lipolysis and ketogenesis despite inadequate glucose control; however, supporting evidence is weak【1】.

When plasma glucose exceeds the renal threshold, glucose appears in the urine (glycosuria)【1】.
Urinary glucose creates an osmotic diuresis that draws water, sodium, potassium, and other electrolytes into the urine【1】.
Ongoing osmotic diuresis leads to progressive dehydration, which can progress to hypotension and shock if untreated【1】.

DKA typically develops rapidly, often within 24 hours, whereas HHS evolves over days to weeks【1】【2】.
Mortality in experienced centers is approximately 5%; risk is higher in very young or elderly patients and in those presenting with coma or hypotension【1】.