Etiology
In diabetic ketoacidosis (DKA), there is a reduction in the net effective concentration of circulating insulin along with an elevation of counter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). These alterations lead to extreme manifestations of metabolic derangements that can occur in diabetes. The two most common precipitating events are inadequate insulin therapy or infection, particularly urinary tract infections and pneumonia.[1][13] Underlying medical conditions that provoke the release of counter-regulatory hormones, such as myocardial infarction or stroke, may also result in DKA in patients with diabetes.[13] Additionally, drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, pentamidine, sympathomimetic agents (e.g., dobutamine and terbutaline), second-generation antipsychotic agents, and immune checkpoint inhibitors may contribute to the development of DKA.[1][14][15][16] The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, as well as the dual SGLT1/SGLT2 inhibitor sotagliflozin, has also been implicated in the development of DKA, including the atypical presentation of euglycemic ketoacidosis, in patients with both type 1 and type 2 diabetes.[1][17][18][19][20][21][22][23]
Pathophysiology
Reduced insulin concentration or action, along with increased insulin counter-regulatory hormones, leads to the hyperglycemia, volume depletion, and electrolyte imbalance that underlie the pathophysiology of DKA.[13] Hormonal alterations lead to increased gluconeogenesis (hepatic and renal glucose production), glycogenolysis, and impaired glucose utilization in peripheral tissues, which result in hyperglycemia and hyperosmolarity. Insulin deficiency leads to release of free fatty acids from adipose tissue (lipolysis), hepatic fatty acid oxidation, and formation of ketone bodies (beta-hydroxybutyrate and acetoacetate), which result in ketonemia and acidosis.[13] Studies have demonstrated the elevation of proinflammatory cytokines and inflammatory biomarkers (e.g., C-reactive protein [CRP]), markers of oxidative stress, lipid peroxidation, and cardiovascular risk factors with hyperglycemic crises.[24] All of these parameters return to normal within 24 hours of initiation of insulin and hydration therapy.[24] Elevation of proinflammatory cytokines, and markers of lipid peroxidation and oxidative stress, have also been demonstrated in non-diabetic patients with insulin-induced hypoglycemia.[25] The observed proinflammatory and procoagulant states in both hyperglycemic crises and hypoglycemia may be the result of adaptive responses to acute stress and not aberrations in blood glucose per se.[24][25] It has been postulated that ketosis-prone diabetes comprises different syndromes based on autoantibody status, human leukocyte antigen (HLA) genotype, and beta-cell functional reserve.[26][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 hyperglycemic stateFrom: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43; used with permission [Citation ends].
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