Etiologia

In diabetic ketoacidosis (DKA), there is a reduction in the effective circulating concentration of insulin, accompanied by elevated levels of counter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). These hormonal alterations drive the severe metabolic derangements characteristic of DKA. The two most common precipitating factors are infection (particularly urinary tract infections and pneumonia) and discontinuation or inadequate administration of insulin therapy.[1][18]​​​ Underlying medical conditions that provoke the release of counter-regulatory hormones, such as myocardial infarction, stroke, or pancreatitis, may also precipitate DKA in individuals with diabetes.[18]​ Additionally, drugs that affect carbohydrate metabolism, including corticosteroids, thiazide diuretics, sympathomimetics, atypical antipsychotics, immune checkpoint inhibitors, cocaine, and cannabis may contribute to the development of DKA.[1]​​[19][20][21]​​​​[22][6][23]​​​​ The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and the dual SGLT1/SGLT2 inhibitor sotagliflozin has also been implicated in the development of DKA, including the atypical presentation of euglycaemic ketoacidosis, in both type 1 and type 2 diabetes.[1]​​[24][25]​​​​[26][27][28][29]​​​[30]​ The incidence, however, remains low, with only a modest incremental absolute risk. SGLT2 inhibitor cardiovascular outcome trials have reported DKA rates of 0.1% to 0.6% compared with <0.1% to 0.3% in placebo groups.[31]

Pathophysiology

Reduced insulin concentration or action, together with increased levels of counter-regulatory hormones, leads to the hyperglycaemia, volume depletion, and electrolyte imbalance that underlie the pathophysiology of diabetic ketoacidosis.[18]​ These hormonal alterations lead to hepatic and renal gluconeogenesis, glycogenolysis, and impaired glucose utilisation in peripheral tissues, resulting in hyperglycaemia and hyperosmolarity. Insulin deficiency also promotes lipolysis, releasing free fatty acids from adipose tissue, which undergo hepatic oxidation to form the ketone bodies beta-hydroxybutyrate and acetoacetate, leading to ketonaemia and metabolic acidosis.[18]​ Studies have demonstrated elevations in pro-inflammatory cytokines and inflammatory biomarkers (e.g., C-reactive protein), as well as markers of oxidative stress, lipid peroxidation, and cardiovascular risk, during hyperglycaemic crises.[32]​ These abnormalities typically normalise within 24 hours of initiating insulin and fluid replacement therapy.[32]​ Similar elevations in pro-inflammatory cytokines and oxidative stress markers have been observed in people without diabetes during insulin-induced hypoglycaemia.[33] The pro-inflammatory and pro-coagulant states seen in both hyperglycaemic crises and hypoglycaemia may reflect adaptive responses to acute physiological stress rather than direct effects of altered blood glucose levels.​[33][32]​​ 

[Figure caption and citation for the preceding image starts]: Pathogenesis of DKA and HHS; triggers include stress, infection, and insufficient insulin. FFA: free fatty acid; HHS: hyperosmolar hyperglycaemic stateFrom: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43; used with permission [Citation ends].Pathogenesis of DKA and HHS; triggers include stress, infection, and insufficient insulin. FFA: free fatty acid; HHS: hyperosmolar hyperglycaemic state

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