Materiały źródłowe

• #1 Adult Diabetic Ketoacidosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560723/

  Diabetic ketoacidosis (DKA) is characterized by uncontrolled hyperglycemia, metabolic acidosis, and increased body ketone concentration. […] DKA is a state of a relative or absolute insulin deficiency that is worsened by hyperglycemia, dehydration, and acidosis. […] In diabetic ketoacidosis, insulin deficiency and increased counter-regulatory hormones can lead to increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization. This will ultimately cause worsening hyperglycemia. […] Insulin deficiency and increased counterregulatory hormones also lead to the release of free fatty acids into circulation from adipose tissue (lipolysis), which undergo hepatic fatty acid oxidation to ketone bodies (beta-hydroxybutyrate and acetoacetate), resulting in ketonemia and metabolic acidosis.

• #1 Diabetic Ketoacidosis – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279146/

  Insulin deficiency, increased insulin counter-regulatory hormones (cortisol, glucagon, growth hormone, and catecholamines) and peripheral insulin resistance lead to hyperglycemia, dehydration, ketosis, and electrolyte imbalance which underlie the pathophysiology of DKA. […] Hyperglycemia of DKA evolves through accelerated gluconeogenesis, glycogenolysis, and decreased glucose utilization all due to absolute insulin deficiency. Of note, diabetes patients who developed DKA while treated with SGLT-2 inhibitors can present without hyperglycemia, i.e., with euglycemic DKA. Due to increased lipolysis and decreased lipogenesis, abundant free fatty acids are converted to ketone bodies: -hydroxybutyrate (-OHB), acetoacetate, and acetone. Hyperglycemia-induced osmotic diuresis, if not accompanied by sufficient oral fluid intake, leads to dehydration, hyperosmolarity, electrolyte loss, and subsequent decrease in glomerular filtration. With decline in renal function, glycosuria diminishes and hyperglycemia/hyperosmolality worsens. With impaired insulin action and hyperosmolality, utilization of potassium by skeletal muscle is markedly diminished leading to intracellular potassium depletion. Also, potassium is lost via osmotic diuresis causing profound total body potassium deficiency. Therefore, DKA patients can present with broad range of serum potassium concentrations. Nevertheless, a normal plasma potassium concentration may indicate that potassium stores in the body are severely diminished and the institution of insulin therapy and correction of hyperglycemia will lead to future hypokalemia.

• #1 Diabetic ketoacidosis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/symptoms-causes/syc-20371551

  Diabetic ketoacidosis usually happens after: An illness. An infection or other illness can cause the body to make higher levels of certain hormones, such as adrenaline or cortisol. These hormones work against the effects of insulin and sometimes cause diabetic ketoacidosis. Pneumonia and urinary tract infections are common illnesses that can lead to diabetic ketoacidosis. […] A problem with insulin therapy. Missed insulin treatments can leave too little insulin in the body. Not enough insulin therapy or an insulin pump that doesn’t work right also can leave too little insulin in the body. Any of these problems can lead to diabetic ketoacidosis. […] Untreated, diabetic ketoacidosis can lead to loss of consciousness and, eventually, death.

• #1 ScholarWorks @ UTRGV – Research Colloquium: Euglycemic Diabetic Ketoacidosis Induced by Jardiance in a 37-Year-Old Female: A Case Report

  https://scholarworks.utrgv.edu/colloquium/2024/talks/13/

  Diabetic ketoacidosis (DKA) is a complication of diabetes, very common throughout the Rio Grande Valley region, can be life threatening and is characterized by hyperglycemia, ketonemia and metabolic acidosis. […] Nevertheless, euglycemic diabetic ketoacidosis (euglycemic DKA) is an atypical presentation in which patients show the classic signs of DKA but with normal or near-normal blood glucose levels. […] The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as Jardiance (empagliflozin), has been associated with an increased risk of euglycemic DKA. […] The mechanism involves an increase in urinary glucose excretion, decreasing plasma glucose levels and thereby promoting ketogenesis, mainly in situations of stress or insulin deficiency. […] This case report highlights the importance of recognizing euglycemic DKA in patients treated with SGLT2 inhibitors such as Jardiance. […] Physicians should have a high index of suspicion for this disease in diabetic patients presenting with unexplained metabolic acidosis and normal glucose levels. Early diagnosis and prompt treatment are crucial to prevent serious outcomes.

• #1 Diabetic ketoacidosis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/symptoms-causes/syc-20371551

  Diabetic ketoacidosis is a serious complication of diabetes. […] The condition develops when the body can’t produce enough insulin. Insulin plays a key role in helping sugar a major source of energy for muscles and other tissues enter cells in the body. […] Without enough insulin, the body begins to break down fat as fuel. This causes a buildup of acids in the bloodstream called ketones. If it’s left untreated, the buildup can lead to diabetic ketoacidosis. […] Sugar is a main source of energy for the cells that make up muscles and other tissues. Insulin helps sugar enter the cells in the body. […] Without enough insulin, the body can’t use sugar to make the energy it needs. This causes the release of hormones that break down fat for the body to use as fuel. This also produces acids known as ketones. Ketones build up in the blood and eventually spill over into the urine.

• #1 Pathophysiology of DKA – RCEMLearning

  https://www.rcemlearning.co.uk/modules/paediatric-diabetic-ketoacidosis/lessons/basic-science-and-pathophysiology-51/topic/pathophysiology-of-dka/

  Insulin […] Consequence of a deliberate or inadvertent failure to take exogenous insulin (known patient) or as part of the initial presentation of T1DM. […] Low levels of insulin stimulate the release of glucagon, ACTH, growth hormone, prolactin and catecholamines. […] Amino acids, lactate and glycerol are converted to glucose within the liver and released into the circulation. […] Breakdown of glycogen stores within the striated muscle and liver release glucose into the circulation. […] Despite the presence of high blood glucose, low levels of insulin inhibit uptake by the peripheral tissues, further exacerbating hyperglycaemia. […] Triglycerides within adipose tissue are broken down due to release of free fatty acids. These are subsequently oxidised to form ketone bodies (acetoacetate and -hydroxybutyrate).

• #1 Diabetic Ketoacidosis in Adults: Part 1. Pathogenesis and Diagnosis

  https://www.southsudanmedicaljournal.com/archive/may-2022/diabetic-ketoacidosis-in-adults-part-1.-pathogenesis-and-diagnosis.html

  At the same time, decreased renal plasma flow causes secondary hyperaldosteronism and additional potassium losses. […] Individuals with DKA are potassium depleted, often with a total body K+ deficit of 400 mmol or more (35 mmol/kg). […] The positive feedback loops caused by volume depletion thus worsen hypokalaemia and hyperglycaemia and are important in the development of DKA. […] Normally, hyperglycaemia should suppress glucagon via insulin release within pancreatic islets. In DKA, glucagon levels may be markedly elevated despite profound hyperglycaemia. […] Elevated glucagon levels increase both hyperglycaemia and ketone production. […] With insulin deficiency and high glucagon levels, the low insulin to glucagon ratio promotes breakdown of triglycerides through activation of hormone sensitive lipase in adipose tissue releasing free fatty acids (FFA) and glycerol.

• #1 Diabetic ketoacidosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Diabetic_ketoacidosis_pathophysiology

  Development of diabetic ketoacidosis (DKA) is the result of a relative or absolute deficiency of insulin and an excess of glucagon. […] Diabetic ketoacidosis (DKA) is the result of insulin deficiency from new-onset diabetes (usually type 1 diabetes), insulin noncompliance, prescription or illicit drug use, and increased insulin need because of any condition. […] The major effect of insulin deficiency is decreased intra-cellular glucose utilization and mobilization of body sources of glucose by counter-regulatory or stress hormones namely, glucagon, catecholamines, cortisol and growth hormone. This eventually leads to a large increase in blood glucose levels and ketonemia. […] Insulin deficiency is the most important regulator of ketogenesis. […] Lipolysis is mediated by hormone-sensitive lipase in adipose tissue. Hormone-sensitive lipase is activated by both insulin deficiency and the rise in counter-regulatory hormones in DKA.

• #1 Diabetic Ketoacidosis in Adults: Part 1. Pathogenesis and Diagnosis

  https://www.southsudanmedicaljournal.com/archive/may-2022/diabetic-ketoacidosis-in-adults-part-1.-pathogenesis-and-diagnosis.html

  FFAs generate acetyl-CoA in the liver (through beta-oxidation) which then enter the Krebs cycle to generate ATP. […] As acetyl-CoA is produced in large quantities under these conditions, the capacity of the Krebs cycle becomes saturated and acetyl-CoA diverts into the ketogenic pathway resulting in the production of ketone bodies (acetoacetate, beta-hydroxybutyrate and acetone). […] Hyperglycaemia, increased glucagon and increased levels of other counter-regulatory hormones such as adrenaline and cortisol all contribute to insulin resistance and decreased glucose uptake in skeletal muscles.

• #1 Diabetic Ketoacidosis | AAFP

  https://www.aafp.org/pubs/afp/issues/2005/0501/p1705.html

  A diagnosis of diabetic ketoacidosis requires the patients plasma glucose concentration to be above 250 mg per dL (although it usually is much higher), the pH level to be less than 7.30, and the bicarbonate level to be 18 mEq per L or less. […] DKA is caused by reduced insulin levels, decreased glucose use, and increased gluconeogenesis from elevated counter regulatory hormones, including catecholamines, glucagon, and cortisol. […] DKA primarily affects patients with type 1 diabetes, but also may occur in patients with type 2 diabetes, and is most often caused by omission of treatment, infection, or alcohol abuse. […] The severity of DKA is determined primarily by the pH level, bicarbonate level, and mental status, and not by the blood glucose measurement. […] Beta-hydroxybutyrate accounts for about 75 percent of ketones in ketoacidosis, and when available it is preferred for monitoring DKA over the nitroprusside method, which only measures acetoacetate.

• #1 Diabetic ketoacidosis

  https://acutecaretesting.org/en/articles/diabetic-ketoacidosis

  The problem in DKA is that the rate at which ketones are produced exceeds the rate at which they can be metabolized/excreted and they accumulate in blood with disastrous results. […] The abnormal accumulation of ketoacids in blood that occurs in DKA overwhelms this buffering system. […] Eventually, a point is reached when buffering fails and hydrogen ion concentration increases, and pH falls below normal. The patient is said to be suffering a metabolic acidosis, and blood gas analysis at this stage reveals reduced pH in combination with a reduced bicarbonate concentration. […] Diabetic ketoacidosis is the extreme and life-threatening metabolic derangement that results from severe insulin deficiency.

• #1 Diabetic ketoacidosis – Wikipedia

  https://en.wikipedia.org/wiki/Diabetic_ketoacidosis

  In various situations such as infection, insulin demands rise but are not matched by the failing pancreas. Blood sugars rise, dehydration ensues, and resistance to the normal effects of insulin increases further by way of a vicious circle. […] As a result of the above mechanisms, the average adult with DKA has a total body water shortage of about 6 liters (or 100 mL/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/L or 250 mg/dL. […] DKA is common in type 1 diabetes as this form of diabetes is associated with an absolute lack of insulin production by the islets of Langerhans. In type 2 diabetes, insulin production is present but is insufficient to meet the body’s requirements as a result of end-organ insulin resistance. Usually, these amounts of insulin are sufficient to suppress ketogenesis. If DKA occurs in someone with type 2 diabetes, their condition is called „ketosis-prone type 2 diabetes”. The exact mechanism for this phenomenon is unclear, but there is evidence both of impaired insulin secretion and insulin action.

• #1 Diabetic Ketoacidosis (DKA) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka

  Serum levels of glycerol and free fatty acids rise because of unrestrained lipolysis. […] Glucagon also stimulates mitochondrial conversion of free fatty acids into ketones. […] Insulin normally blocks ketogenesis by inhibiting the transport of free fatty acid derivatives into the mitochondrial matrix, but ketogenesis proceeds in the absence of insulin. […] The major ketoacids produced, acetoacetic acid and beta-hydroxybutyric acid, are strong organic acids that create metabolic acidosis. […] Hyperglycemia due to insulin deficiency causes an osmotic diuresis that leads to marked urinary losses of water and electrolytes. […] Potassium is also lost in large quantities. […] Despite a significant total body deficit of potassium, initial serum potassium is typically normal or elevated because of the extracellular migration of potassium in response to acidosis. […] If serum potassium is not monitored and replaced as needed, life-threatening hypokalemia may develop.

• #1 Canine diabetic ketoacidosis | Academy EN

  https://vetfocus.royalcanin.com/en/scientific/canine-diabetic-ketoacidosis

  Metabolic acidosis (pH 7.3, bicarbonate 15 mmol/L) in DKA is mainly secondary to KB accumulation, hypovolemia (lactic acidosis, volume-responsive azotemia), hyperchloremia and uremia. […] Up to 70% of DKA patients are in a state of decompensated DM because of concomitant pathologies responsible for increased insulin resistance common comorbidities are acute pancreatitis, bacterial urinary tract infection and hyperadrenocorticism. […] Therefore, once the patient is stable, further investigations (e.g., hematology, biochemistry, urine analysis with culture, pancreatic lipase serology, endocrine tests, imaging) are necessary in order to identify possible triggers. […] Total body potassium is generally depleted in DKA, but levels can vary between patients, and although not as frequent as in human medicine, hyperkalemia can be present.

• #1 Diabetic Ketoacidosis (DKA) – Complications of Diabetes Mellitus, Acute – Glucose Metabolism Disorders – Endocrinology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.13.3.1.

  Diabetic ketoacidosis (DKA) is a life-threatening hyperglycemic emergency requiring prompt recognition, diagnosis, and treatment. […] Regarding the pathogenesis of DKA, extracellular fluid (ECF) volume depletion results from hyperglycemia-induced urinary losses of water and electrolytes, which are caused by absolute or relative insulin deficiency and by increased levels of glucagon and other counterregulatory hormones (catecholamines, cortisol, and growth hormone). These counterregulatory hormones promote hepatic gluconeogenesis. Marked insulin deficiency leads to increased activity of hormone-sensitive lipase, which promotes the breakdown of triglycerides into glycerol and free fatty acids. Free fatty acids are oxidized in the liver to ketone bodies. This process is predominantly stimulated by glucagon and leads to high anion gap metabolic acidosis. Hyperglycemia and hyperketonemia both contribute to osmotic diuresis, resulting in volume depletion and decreased glomerular filtration, thereby further exacerbating hyperglycemia. […] As already mentioned, SGLT-2 inhibitors may increase the risk of DKA. This is related to increased ketogenesis as a result of the increased glucagon to insulin ratio. Patients taking SGLT-2 inhibitors have a 2.6 to 5.3 times increased risk of DKA.

• #1 Diabetic ketoacidosis – Wikipedia

  https://en.wikipedia.org/wiki/Diabetic_ketoacidosis

  Diabetic ketoacidosis arises because of a lack of insulin in the body. The lack of insulin and corresponding elevation of glucagon leads to increased release of glucose by the liver (a process that is normally suppressed by insulin) from glycogen via glycogenolysis and also through gluconeogenesis. High glucose levels spill over into the urine, taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis. This leads to polyuria, dehydration, and polydipsia. The absence of insulin also leads to the release of free fatty acids from adipose tissue (lipolysis), which the liver converts into acetyl CoA through a process called beta oxidation. […] Acetyl CoA is metabolised into ketone bodies under severe states of energy deficiency, like starvation, through a process called ketogenesis, whose final products are aceto-acetate and -Hydroxybutyrate. These ketone bodies can serve as an energy source in the absence of insulin-mediated glucose delivery, and is a protective mechanism in case of starvation. The ketone bodies, however, have a low pKa and therefore turn the blood acidic (metabolic acidosis). The body initially buffers the change with the bicarbonate buffering system, but this system is quickly overwhelmed and other mechanisms must work to compensate for the acidosis. One such mechanism is hyperventilation to lower blood carbon dioxide levels (a form of compensatory respiratory alkalosis). This hyperventilation, in its extreme form, may be observed as Kussmaul respiration.

• #1 Diabetic Ketoacidosis in Adults: Part 1. Pathogenesis and Diagnosis

  https://www.southsudanmedicaljournal.com/archive/may-2022/diabetic-ketoacidosis-in-adults-part-1.-pathogenesis-and-diagnosis.html

  The metabolic derangements that lead to Diabetic Ketoacidosis (DKA) are described. Understanding the pathogenesis is the key to rapid and accurate diagnosis and hence successful management. […] DKA develops either due to absolute insulin deficiency or to relative insulin deficiency associated with an increase in counter-regulatory hormones (especially glucagon, catecholamines and cortisol). […] During conditions of reduced insulin/glucagon ratio, hyperglycaemia exceeding the threshold for renal tubular reabsorption of glucose develops causing a brisk osmotic diuresis with water and electrolyte losses which lead to dehydration and eventually extracellular fluid volume depletion. […] The ensuing plasma volume contraction causes compensatory release of more counter-regulatory hormones (particularly cortisol and catecholamines) which lead to ever worsening hyperglycaemia and volume depletion in a positive feedback loop.

• #1 Adult Diabetic Ketoacidosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560723/

  New data suggests that hyperglycemia leads to a severe inflammatory state and an increase in proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-beta, -6, and -8), C-reactive protein, lipid peroxidation, and reactive oxygen species, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of apparent infection or cardiovascular pathology.

• #1 From Sweet to Sour: SGLT-2-Inhibitor-Induced Euglycemic Diabetic Ketoacidosis

  https://www.mdpi.com/2075-4426/14/7/665

  Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are highly selective, effective, and generally well-tolerated antihyperglycemic agents targeting the SGLT-2 transmembrane protein. […] The primary pathophysiological process behind its multifactorial aetiology comprises glucosuria and osmotic diuresis, which produce a significant carbohydrate deficit, leading to an increase in the glucagon–insulin ratio, thus resulting in accelerated ketogenesis. […] SGLT-2 inhibitors increase the risk of ketoacidosis in several ways; central to these processes is an increase in the glucagon–insulin ratio. […] Reduced reabsorption and glucosuria result in a decrease in blood glucose levels. […] As blood glucose decreases, a carbohydrate deficit develops, resulting in a reduced insulin dose requirement in insulin-treated patients and reduced endogenous insulin secretion from the pancreas.

• #1 A short note on pathophysiology involved in euglycemic diabetic ketoacidosis

  https://www.africanjournalofdiabetesmedicine.com/articles/a-short-note-on-pathophysiology-involved-in-euglycemic-diabetic-ketoacidosis-97765.html

  Euglycaemic Diabetic Ketoacidosis (EDKA) is a clinical syndrome present in both type 1 and type 2 diabetes mellitus, and in the presence of severe metabolic acidosis and ketonemia characterized by euglycemia. […] The overall mechanism is based on general starvation leading to ketosis while maintaining euglycemia. […] The underlying mechanism of EDKA follows carbohydrate starvation, which generally results in decreased serum insulin and excess counter-regulatory hormones such as glucagon, epinephrine and cortisol. Increased glucagon/ insulin ratio leads to increased lipolysis, increased free fatty acids, and ketoacidosis. […] Decreased oral intake, vomiting, and volume depletion due to osmotic diuresis from diabetes aggravate elevated glucagon, cortisol, and epinephrine, impairing lipolysis and ketogenesis.

• #1 From Sweet to Sour: SGLT-2-Inhibitor-Induced Euglycemic Diabetic Ketoacidosis

  https://www.mdpi.com/2075-4426/14/7/665

  Insulin also increases the activity of acetyl-CoA carboxylase, resulting in the production of malonyl-CoA, which is a potent inhibitor of carnitine-palmitoyl transferase I (CPT-I). […] By lowering blood glucose levels, SGLT-2 inhibitors indirectly stimulate glucagon secretion, which inhibits acetyl-CoA carboxylase activity and increases CPT-I activity in the liver, further contributing to increased ketogenesis. […] This combination of decreased insulin and increased glucagon secretion leads to a higher glucagon–insulin ratio which favours ketogenesis. […] Additionally, SGLT-2 inhibitors increase ketone body reabsorption by decreasing sodium reabsorption in the proximal tubule, which increases sodium concentration in the distal tubule, resulting in an electrochemical gradient favouring acetoacetate and β-hydroxybutyrate reabsorption.

• #1 Diabetic Ketoacidosis – Harvard Health

  https://www.health.harvard.edu/a_to_z/diabetic-ketoacidosis-a-to-z

  Diabetic ketoacidosis is a potentially fatal complication of diabetes that occurs when you have much less insulin than your body needs. This problem causes the blood to become acidic and the body to become dangerously dehydrated. […] In diabetic ketoacidosis, ketones build up in the blood, seriously altering the normal chemistry of the blood and interfering with the function of multiple organs. They make the blood acidic, which causes vomiting and abdominal pain. If the acid level of the blood becomes extreme, ketoacidosis can cause falling blood pressure, coma and death. […] Ketoacidosis is always accompanied by dehydration, which is caused by high levels of glucose in the blood. Glucose builds up in the blood if there is not enough insulin to move glucose into your cells. […] Diabetic ketoacidosis requires treatment in a hospital, often in the intensive care unit. You will receive a large volume of fluids intravenously (through a vein) and insulin to lower your blood sugar and to correct the acidosis. Your blood sugar and acid levels will be monitored frequently, and you will be given potassium supplements to restore your body’s supply of this essential mineral. Until your blood chemistry returns to normal, your vital signs (temperature, pulse, respirations, blood pressure) and urine output will be monitored closely. If an infection has triggered your episode of ketoacidosis, antibiotics or other medications will be used to treat the infection.

• #1 Diabetic Ketoacidosis | AAFP

  https://www.aafp.org/pubs/afp/issues/2005/0501/p1705.html

  Studies of patients with a pH level of 6.9 or higher have found no evidence that bicarbonate is beneficial, and some studies have suggested bicarbonate therapy may be harmful for these patients. […] Although the phosphate level frequently is low in patients with DKA, good-quality studies have shown that routine phosphate replacement does not improve outcomes in DKA, and excessive replacement can lead to hypocalcemia. […] Whole body potassium deficits typically are 3 to 5 mEq per L (3 to 5 mmol per L). Acidosis increases potassium levels and glucose administered with insulin lowers them. […] Cerebral edema is a rare but important complication of DKA. Although it can affect adults, it is more common in young patients, occurring in 0.7 to 1.0 percent of children with DKA.

• #1 Diabetic ketoacidosis – Wikipedia

  https://en.wikipedia.org/wiki/Diabetic_ketoacidosis

  The clinical state of DKA is associated, in addition to the above, with the release of various counterregulatory hormones such as glucagon and adrenaline as well as cytokines, the latter of which leads to increased markers of inflammation, even in the absence of infection. […] Cerebral edema, which is the most dangerous DKA complication, is probably the result of a number of factors. Some authorities suggest that it is the result of overvigorous fluid replacement, but the complication may develop before treatment has been commenced. It is more likely in those with more severe DKA, and in the first episode of DKA. Likely factors in the development of cerebral edema are dehydration, acidosis and low carbon dioxide levels; in addition, the increased level of inflammation and coagulation may, together with these factors, lead to decreased blood flow to parts of the brain, which then swells up once fluid replacement has been commenced. The swelling of brain tissue leads to raised intracranial pressure ultimately leading to death.

• #1 Classic diabetic ketoacidosis and the euglycemic variant

  https://consultqd.clevelandclinic.org/classic-diabetic-ketoacidosis-and-the-euglycemic-variant

  The serum potassium value is not an indicator of potassium status in either DKA or EDKA because in each form there is a total potassium deficit due to osmotic diuresis. […] In SGLT-2 inhibitor-related EDKA, the SGLT-2 inhibitor generally lowers the risk of severe hyperkalemia in people with type 2 diabetes. […] The current recommendations are to start subcutaneous insulin when the serum glucose level is less than 200 to 250 mg/dL, the anion gap is less than 12, and the bicarbonate level is greater than 15 mmol/L. […] In SGLT-2 inhibitor-related EDKA, the transition cutoffs need to be tempered because ketosis – and, therefore, a low bicarbonate level – may rebound after intravenous therapy is discontinued due to the persistent effect of the medication. […] Although ketoacidosis has a common pathophysiologic pathway to development, varied etiopathologies initiate the process, chief among them being diabetes. With the extensive use of SGLT-2 inhibitors, it has become clear that the pathophysiology of DKA is different from that of EDKA. Therefore, most importantly, the management strategies for DKA and EDKA are different, as are the surveillance requirements for terminating acute interventions.

• #2 Diabetic Ketoacidosis (DKA) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka

  Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. […] DKA occurs mostly in type 1 diabetes mellitus. […] DKA is diagnosed by detection of hyperketonemia and anion gap metabolic acidosis in the presence of hyperglycemia. […] DKA develops when insulin levels are insufficient to meet the body’s basic metabolic requirements. […] Insulin deficiency can be absolute (eg, during lapses in the administration of exogenous insulin) or relative (eg, when usual insulin doses do not meet metabolic needs during physiologic stress). […] Insulin deficiency and an increase in counterregulatory hormones (glucagon, catecholamines, cortisol) causes the body to metabolize triglycerides and amino acids instead of glucose for energy.

• #2 Diabetic ketoacidosis – Etiology | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/162/aetiology

  In 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. […] 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. Hormonal alterations in DKA lead to increased gluconeogenesis, hepatic and renal glucose production, 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. […] It has also been postulated that ketosis-prone diabetes comprises different syndromes based on autoantibody status, human leukocyte antigen (HLA) genotype, and beta-cell functional reserve.

• #2 Diabetic Ketoacidosis in Adults: Part 1. Pathogenesis and Diagnosis

  https://www.southsudanmedicaljournal.com/archive/may-2022/diabetic-ketoacidosis-in-adults-part-1.-pathogenesis-and-diagnosis.html

  The metabolic derangements that lead to Diabetic Ketoacidosis (DKA) are described. Understanding the pathogenesis is the key to rapid and accurate diagnosis and hence successful management. […] DKA develops either due to absolute insulin deficiency or to relative insulin deficiency associated with an increase in counter-regulatory hormones (especially glucagon, catecholamines and cortisol). […] During conditions of reduced insulin/glucagon ratio, hyperglycaemia exceeding the threshold for renal tubular reabsorption of glucose develops causing a brisk osmotic diuresis with water and electrolyte losses which lead to dehydration and eventually extracellular fluid volume depletion. […] The ensuing plasma volume contraction causes compensatory release of more counter-regulatory hormones (particularly cortisol and catecholamines) which lead to ever worsening hyperglycaemia and volume depletion in a positive feedback loop.

• #2 Diabetic Ketoacidosis (DKA) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka

  Serum levels of glycerol and free fatty acids rise because of unrestrained lipolysis. […] Glucagon also stimulates mitochondrial conversion of free fatty acids into ketones. […] Insulin normally blocks ketogenesis by inhibiting the transport of free fatty acid derivatives into the mitochondrial matrix, but ketogenesis proceeds in the absence of insulin. […] The major ketoacids produced, acetoacetic acid and beta-hydroxybutyric acid, are strong organic acids that create metabolic acidosis. […] Hyperglycemia due to insulin deficiency causes an osmotic diuresis that leads to marked urinary losses of water and electrolytes. […] Potassium is also lost in large quantities. […] Despite a significant total body deficit of potassium, initial serum potassium is typically normal or elevated because of the extracellular migration of potassium in response to acidosis. […] If serum potassium is not monitored and replaced as needed, life-threatening hypokalemia may develop.

• #2 Diabetic ketoacidosis: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000320.htm

  DKA is sometimes the first sign of type 1 diabetes in people who have not yet been diagnosed. It can also occur in someone who has already been diagnosed with type 1 diabetes. Infection, injury, a serious illness, missing doses of insulin shots, or the stress of surgery can lead to DKA in people with type 1 diabetes. […] People with type 2 diabetes can also develop DKA, but it is much less common and less severe. It is usually triggered by prolonged uncontrolled blood sugar, missing doses of medicines, or a severe illness or infection.

• #2 Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-epidemiology-and-pathogenesis

  Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also called hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes. […] The epidemiology and the factors responsible for the metabolic abnormalities of DKA and HHS in adults will be discussed here. […] DKA is characteristically associated with type 1 diabetes. It also occurs in type 2 diabetes under conditions of extreme stress such as serious infection, trauma, cardiovascular or other emergencies, in association with sodium-glucose cotransporter 2 (SGLT2) inhibitor use, or as a presenting manifestation of type 2 diabetes in some populations, a disorder called ketosis-prone diabetes mellitus. […] DKA is more common in younger adults (aged 18 to 44 years). […] Coronavirus disease 2019 (COVID-19) infection has also been associated with greater risk of DKA in both type 1 and type 2 diabetes.

• #2 Diabetic ketoacidosis

  https://acutecaretesting.org/en/articles/diabetic-ketoacidosis

  Disturbance of the mechanisms which maintain normal blood pH is a defining feature of diabetic ketoacidosis (DKA), an acute and life-threatening complication of the chronic metabolic disease, diabetes. […] Diabetic ketoacidosis (DKA), by contrast, is an acute complication of diabetes which evolves over a period of less than 24 hours and results directly from insulin deficiency. It is a medical emergency. […] Since the primary defect in DKA is severe insulin deficiency, an understanding of the pathogenesis of DKA demands, at the very least, outline knowledge of the normal action of insulin. […] In the absence of insulin, glucose in blood cannot enter tissue cells where it is needed to provide energy, and the liver inappropriately continues to release glucose produced from non-carbohydrate sources and breakdown of glycogen to the blood.

• #2 Pulsenotes | DKA notes

  https://app.pulsenotes.com/medicine/diabetes/notes/dka

  Diabetic ketoacidosis (DKA) is a life-threatening diabetic emergency. […] DKA is a severe metabolic complication of diabetes. It is typically seen in those with T1DM as a presenting feature, in patients with poor control or intercurrent illness. […] The condition is characterised by a biochemical triad of hyperglycaemia, ketonaemia and acidosis. […] DKA is a metabolic disorder, which is characterised by hyperglycaemia, ketonaemia and acidosis that is a consequence of absolute or relative insulin deficiency. […] The lack of insulin means the body is unable to utilise glucose. This leads to accumulation of glucose within the blood resulting in hyperglycaemia. […] This is coupled with an increase in counter-regulatory hormone release (e.g. cortisol, glucagon, growth hormone), which exacerbates the hyperglycaemia and drives the production of alternative energy sources.

• #2 Diabetic Ketoacidosis (DKA): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/118361-overview

  The excess acetyl coenzyme A is therefore rerouted to ketogenesis. […] When the accumulated ketones exceed the body’s capacity to extract them, they overflow into urine (ie, ketonuria). […] If the situation is not treated promptly, a greater accumulation of organic acids leads to frank clinical metabolic acidosis (ie, ketoacidosis), with a significant drop in pH and bicarbonate serum levels. […] Ketones/ketoacids/hydroxy acids, in particular, beta-hydroxybutyrate, induce nausea and vomiting that consequently aggravate fluid and electrolyte loss already existing in DKA. […] Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances. […] Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis. […] Many of the underlying pathophysiologic disturbances in DKA are directly measurable by the clinician and need to be monitored throughout the course of treatment.

• #2 Diabetic ketoacidosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Diabetic_ketoacidosis_pathophysiology

  Development of diabetic ketoacidosis (DKA) is the result of a relative or absolute deficiency of insulin and an excess of glucagon. […] Diabetic ketoacidosis (DKA) is the result of insulin deficiency from new-onset diabetes (usually type 1 diabetes), insulin noncompliance, prescription or illicit drug use, and increased insulin need because of any condition. […] The major effect of insulin deficiency is decreased intra-cellular glucose utilization and mobilization of body sources of glucose by counter-regulatory or stress hormones namely, glucagon, catecholamines, cortisol and growth hormone. This eventually leads to a large increase in blood glucose levels and ketonemia. […] Insulin deficiency is the most important regulator of ketogenesis. […] Lipolysis is mediated by hormone-sensitive lipase in adipose tissue. Hormone-sensitive lipase is activated by both insulin deficiency and the rise in counter-regulatory hormones in DKA.

• #2

  https://link.springer.com/article/10.1007/s40138-012-0001-3

  Thus there is both overproduction and underutilization of ketones in an insulin-deficient state. […] Also, glucagon itself will stimulate hormone-sensitive lipase, which in turn mobilizes adipose stores and converts triglycerides to free fatty acids. […] These free fatty acids are then transported across the mitochondrial membrane, and they are eventually used for synthesis of ketones, namely in the form of acetoacetic acid, which is oxidized to form betahydroxybutyrate or decarboxylated to form acetone. […] Unfortunately, with ketone overproduction, peripheral tissues cannot utilize these molecules and ketosis predominates. […] Many of the remaining problems with DKA are from the resultant osmotic diuresis. […] Sodium tends to be low secondary to the fact that glucose is osmotically active and will draw fluids into the extracellular space. […] Potassium is variable based on the degree of acidosis and the time of presentation of the DKA.

• #2 Canine diabetic ketoacidosis | Academy EN

  https://vetfocus.royalcanin.com/en/scientific/canine-diabetic-ketoacidosis

  Baseline blood glucose, electrolytes, acid-base balance and ketonemia/ketonuria analyses are crucial in the diagnosis of diabetic ketoacidosis (DKA). […] When these mechanisms are exacerbated, severe hyperglycemia, ketonemia, electrolyte and acid-base balance abnormalities develop, causing a condition known as diabetic ketoacidosis (DKA). […] In time, blood glucose (BG) can reach the renal threshold (180-220 mg/dL, 10.0-12.2 mmol/L), leading to glycosuria with subsequent fluid and electrolyte losses due to osmotic diuresis. […] The hormone-sensitive lipase stimulates hydrolysis of triglycerides into free fatty acids (FFA); these in turn undergo beta-oxidation in hepatocyte mitochondria into acetyl coenzyme A (Acetyl-CoA). […] In the presence of oxaloacetate, Acetyl-CoA can enter the Krebs cycle and produce energy, but during DKA oxaloacetate is preferentially directed toward gluconeogenesis; therefore, especially when Acetyl-CoA production is excessive, it accumulates and combines to form ketone bodies (KBs): acetoacetate (AcAc), beta-hydroxybutyrate (BHB), and acetone.

• #2 Pulsenotes | DKA notes

  https://app.pulsenotes.com/medicine/diabetes/notes/dka

  The lack of utility of glucose leads to the break down of fats (lipolysis) that increases serum free fatty acids. […] This increases the levels of ketone bodies (acetone, beta-hydroxybutyrate and acetoacetate) within the blood leading to ketonaemia. […] The main ketone body within DKA is 3-beta-hydroxybutyrate. […] Ketone bodies are weak acids, which can lead to significant acidosis and severe illness in increasing quantities. […] As DKA progresses, the raised plasma glucose leads to osmotic diuresis and profound hypovolaemia that is exacerbated by vomiting.

• #2 Canine diabetic ketoacidosis | Academy EN

  https://vetfocus.royalcanin.com/en/scientific/canine-diabetic-ketoacidosis

  After insulin treatment (potassium shift) and fluid therapy (dilutional effect, acidosis correction) true hypokalemia becomes evident. […] Insulin is essential to decrease gluconeogenesis, improve glucose utilization and to both reduce KB production and increase KB metabolism. […] In reducing hyperglycemia (and therefore osmolality), insulin promotes fluid shift from the extra to intracellular space, worsening hypovolemia. […] It also causes electrolyte shifts, unmasking deficiencies, therefore insulin is started once these electrolyte deficiencies (particularly hypokalemia) and hypovolemia are corrected. […] A veterinary study showed that starting insulin within 6 hours of hospital admission reduces time for DKA resolution (based on ketonuria) and does not increase the complication rate. […] Once ketoacidosis is resolved (AG 10-12 mEq/L, BHB 0.6 mmol/L, pH 7.3), glucose levels are well controlled, and patient is eating (or would eat at home) and drinking, long-acting insulin is started.

• #2 Management of Diabetic Ketoacidosis | AAFP

  https://www.aafp.org/pubs/afp/issues/1999/0801/p455.html

  Diabetic ketoacidosis is a triad of hyperglycemia, ketonemia and acidemia, each of which may be caused by other conditions. […] The therapeutic regimen, which consists of replacing fluid and electrolyte losses and administering low-dose insulin, is based on an understanding of the pathogenesis of the condition. […] Major components of the pathogenesis of diabetic ketoacidosis are reductions in effective concentrations of circulating insulin and concomitant elevations of counterregulatory hormones (catecholamines, glucagon, growth hormone and cortisol). […] These hormonal alterations bring about three major metabolic events: (1) hyperglycemia resulting from accelerated gluconeogenesis and decreased glucose utilization, (2) increased proteolysis and decreased protein synthesis and (3) increased lipolysis and ketone production. […] Hyperglycemia initially causes the movement of water out of cells, with subsequent intracellular dehydration, extra-cellular fluid expansion and hyponatremia. […] The net result of all these alterations is hyperglycemia with metabolic acidosis and an increased plasma anion gap.

• #2 Pathogenesis – GPnotebook

  https://gpnotebook.com/pages/diabetes-and-endocrinology/diabetic-ketoacidosis/pathogenesis

  In diabetic ketoacidosis, insulin deficiency and high counter regulatory hormone concentrations leads to […] increase lipolysis and ketogenesis and cause ketonemia and subsequent metabolic acidosis […] the rate at which ketone bodies are formed may exceed the rate at which acetoacetic acid and beta-hydroxybutyric acid can be utilised by muscles and other tissues. Ketogenic amino acids aggravate the derangements in lipid metabolism. Ketogenesis thus increases, leading to ketonaemia and ketonuria. If the urinary excretion is compromised by dehydration, the plasma hydrogen ion concentration increases, and systemic metabolic ketoacidosis results. […] These changes will further worsen hyperglycemia and hyperketonemia by stimulating further stress hormone production. Exogenous insulin plus fluid and electrolyte therapy is needed to interrupt this cycle which otherwise will result in fatal dehydration and metabolic acidosis.

• #2 Canine diabetic ketoacidosis | Academy EN

  https://vetfocus.royalcanin.com/en/scientific/canine-diabetic-ketoacidosis

  In order to maintain serum electrical neutrality, negatively charged KBs are excreted in the kidneys along with positive ions, causing osmotic diuresis and electrolyte deficiencies. […] Excessive KB production and severe hyperglycemia are further promoted by the insulin-resistance action of so-called counter-regulatory hormones (glucagon, cortisol, growth hormone, adrenaline), which increase with stressful conditions and comorbidities. […] Moreover, hyperglycemia itself is recognized as a pro-inflammatory state that promotes cytokine release and development of reactive oxygen species, further promoting insulin resistance. […] The DKA acronym acts as a reminder that the condition is characterized by hyperglycemia (D) (as in diabetes mellitus), ketonemia/ketonuria (K), and metabolic acidosis (A).

• #2 Euglycemic diabetic ketoacidosis: A missed diagnosis

  https://www.wjgnet.com/1948-9358/full/v12/i5/514.htm

  Euglycemic diabetic ketoacidosis (DKA) is an acute life-threatening metabolic emergency characterized by ketoacidosis and relatively lower blood glucose (less than 11 mmol/L). […] The pathophysiology of euglycemic DKA involves a relative or absolute carbohydrate deficit, milder degree of insulin deficiency or resistance and increased glucagon/insulin ratio. […] The hormonal imbalance causes hyperglycemia by increasing glycogenolysis, hepatic gluconeogenesis and decreased peripheral utilization of glucose. […] Carbohydrate deficit has a pivotal role in the pathophysiology of euglycemic DKA, while insulin deficit or insulin resistance is relatively minor and secondary. […] The three common causes of euglycemic DKA are SGLT-2 inhibitors, pregnancy and prolonged fasting. […] The exact mechanism that can precipitate DKA in susceptible individuals includes, osmotic diuresis along with glucosuria (causing a state of carbohydrate deficit), volume depletion and dehydration.

• #2 Classic diabetic ketoacidosis and the euglycemic variant

  https://consultqd.clevelandclinic.org/classic-diabetic-ketoacidosis-and-the-euglycemic-variant

  Diabetic ketoacidosis (DKA), on the other hand, is defined by a triad of hyperglycemia with an ambient blood glucose level well greater than 250 mg/dL, high anion-gap acidosis, and increased plasma ketones, which are the unmeasured anions causing the gap. Euglycemic DKA (EDKA) is a variant of DKA in which the blood glucose is less than 250 mg/dL but the other features of DKA are present. […] When there is an absolute deficiency of insulin (as in type 1 diabetes) or severely augmented insulin resistance (by elevation of stress hormones and inflammatory cytokines in individuals predisposed to insulin resistance), the normal suppressive effect of insulin on glucagon is no longer operative. The unrestrained rise in glucagon disrupts the insulin-to-glucagon ratio in favor of glucagon, resulting in enhanced gluconeogenesis and release of free fatty acids.

• #2 Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-020-01930-6

  Furthermore, SGLT-2 inhibition may increase glucagon levels through multiple mechanisms. These include a direct effect on SGLT-2 proteins expressed in glucagon-secreting alpha pancreatic cells, or indirectly, i.e. acting on brain SGLT-2 receptors and promoting a cathecholamine increase, which in turn would stimulate glucagon secretion. Thus, SGLT-2 inhibitor treatment may not only decrease insulin levels but also increase glucagon, and catecholamines. […] The present case meets the criteria for the two-hit model proposed, as she was both insulinopenic due to starvation and volume depleted. There was a restriction in carbohydrate availability as the patient remained fasting for 48h postoperatively and later developed nausea and vomiting, under conditions of well-known precipitants such as surgical stress and intercurrent postoperative infection. […] Overall, euDKA associated with SGLT-2 inhibitor use in T2DM is a serious side-effect, often with a multifactorial etiology. Increased awareness and recognition of involved factors can safely restore normal acid-base balance with simple measures.

• #2 Diabetic Ketoacidosis | Veterian Key

  https://veteriankey.com/diabetic-ketoacidosis/

  The physiologic derangements that accompany DKA are a direct result of relative or absolute insulin deficiency, hyperketonemia, and hyperglycemia. […] The formation of ketones by the liver is associated with the production of an equivalent number of hydrogen ions, which titrate the plasma bicarbonate concentration. […] The excessive loss of electrolytes and water leads to further volume contraction, underperfusion of tissues, decline in the glomerular filtration rate (GFR), and worsening prerenal azotemia and dehydration. […] The rise in the blood glucose concentration raises the plasma osmolality, and the resulting osmotic diuresis further aggravates the rise in plasma osmolality by causing water losses in excess of the salt loss. […] The severe metabolic consequences of DKA, which include severe acidosis, hyperosmolality, obligatory osmotic diuresis, dehydration, and electrolyte derangements, ultimately become life-threatening.

• #3 Diabetic Ketoacidosis (DKA): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/118361-overview

  Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycemia, ketoacidosis, and ketonuria. […] DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine). This type of hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis. […] Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. […] Ketone bodies are produced from acetyl coenzyme A mainly in the mitochondria within hepatocytes when carbohydrate utilization is impaired because of relative or absolute insulin deficiency, such that energy must be obtained from fatty acid metabolism.

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