Pathophysiology of Diabetic Ketoacidosis
Diabetic ketoacidosis is one of the potentially life-threatening acute complications of diabetes mellitus. In the past, diabetic ketoacidosis was considered as the hallmark of Type I diabetes, but current data show that it can be also diagnosed in patients with type II diabetes mellitus. It is often seen among patients who are poorly compliant to insulin administration during an acute illness. It is commonly precipitated by an acute stressful event such as the development of infection leading to overt sepsis, organ infarction such as stroke and heart attack, burns, pregnancy or intake of drugs that affect carbohydrate metabolism such as corticosteroids, anti-hypertensives, loop diuretics, alcohol, cocaine, and ecstasy. The presence of these stressful conditions incite the release of counter-regulatory hormones such as glucagon, catecholamines and growth hormone. These hormones induce the mobilization of energy stores of fat, glycogen and protein. The net effect of which is the production of glucose.
As a result of absent or deficient insulin release, diabetic ketoacidosis present with the following metabolic derangements: profound hyperglycemia, hyperketonemiaand metabolic acidosis. The production of ketones outweighs its excretion by the kidneys. This results in further reduction of systemic insulin, elevated concentrations of glucagon, cortisol, growth hormone and catecholamine. In peripheral tissues, such as the liver, lipolysis occurs to free fatty acids, resulting in further production of excess ketones. Thereby, causing ketosis and metabolic acidosis.
Symptoms of diabetic ketoacidosis usually develop within 24 hours. Gastrointestinal symptoms such as nausea and vomiting are very prominent. If these symptoms are present in diabetics, investigation for diabetic ketoacidosis becomes imperative. When the renal threshold is reached, profound hyperglycemia leads to glucosuria. This is accompanied by dehydration causing volume depletion and reactive tachycardia. As a result of volume depletion, hypotension may occur. Classically, these patients present with Kussmaul’s respiration and fruity odor due to metabolic acidosis and ketosis respectively. Patients should be investigated for the presence of an underlying infection. Finally,neurological symptoms such as decreasing sensorium when present warrant emergent care.
Insulin deficiency is the main underlying cause of diabetic complications. Under stressful situations, insulin deficiency combined with increased insulin counter-regulatory hormones as previously mentioned, and peripheral insulin resistance lead to profound hyperglycemia, dehydration, ketosis, and electrolyte imbalance. Both insulin deficiency and excess glucagon are required for diabetic ketoacidosis to develop. These promote gluconeogenesis, glycogenolysis and ketone body formation in the liver, as well as increased mobilization of substrates from fat and muscle.
The biochemical sequalae of insulin deficiency combined with hyperglycemia is reduced hepatic level of fructose 2,6 phosphate which alters the activity of phosphofructokinase and fructose 1,6 bisophosphatase. These are key regulatory enzymes for the metabolic processes of glycolysis and gluconeogenesis. The excess in glucagon concentration decreases the activity of pyruvate kinase, whereas the presence of insulin deficiency increases the activity of phosphoenolpyruvatecarboxykinase. These combined enzymatic activities causes a metabolic shift away from glycolysis, leading to the synthesis of glucose. In the face of stressful conditions, the presence of excessive glucagon and catecholamine release, when combined with insulin deficiency promote glycogenolysis. In addition, another effect of insulin deficiency is reduced GLUT-4 transporter levels, which causes impaired glucose uptake into skeletal muscle and fat. Impaired glucose uptake leads to a further reduction in intracellular glucose metabolism contributing to overt hyperglycemia.
This results from excessive fatty acid release from fat stores with a resulting ketone body synthesis in the liver. Under normal physiologic conditions, these fatty acids are converted to triglycerides and very low density lipoproteins in the liver. However, in patients with diabetic ketoacidosis, excess glucagon alters hepatic metabolism. An enzyme called, carnitinepalmitoyltransferase I is activated. This is the key enzyme for fatty acid transport to the mitochondria, wherein beta-oxidation and ketone body formation occurs. The activation of this enzyme causes a favor towards ketone body synthesis.Hence, ketosis ensues.
The formation of ketone bodies and their utilization as an energy source is initially a protective mechanism against cellular starvation. However, as the overproduction of ketone bodies continues and their metabolism decreases due to limited cellular uptake mechanisms, ketone bodies accumulate. Overproduction of ketones rather than decreased utilization, however, appears to be the primary mechanism of ketone body accumulation in diabetic ketoacidosis.
Under normal physiologic conditions, normal acid-base balance is maintained through the presence of buffers, which function to neutralize acids. Ketone bodies, such as beta hydroxybutic acid and acetoacetic acid are strong acids. They dissociate freely and produce a large amount of hydrogen ions. This overproduction of hydrogen ions overwhelms the buffering capacity of the body. Buffers, such as bicarbonate become depleted due to the overt blood concentration of ketoacid seen in ketosis. As a result, ketoacids are not neutralized, eventually leading to metabolic acidosis. Lactic acid, a biochemical end product of metabolism accumulates, further contributing to the acidosis. Also, increased fatty acid release causes excessive production of triglycerides and very low density lipoproteins causing hypertriglyceridemia. All of these metabolic derangements act in concert to the ongoing state of hyperglycemia, glucosuria, osmotic diuresis, electrolyte changes, ketosis, and acidosis which are pathophysiologic mechanisms seen in diabetic ketoacidosis.
- Alourfi, Z., &Homsi, H. (2015). Precipitating factors, outcomes, and recurrence of diabetic ketoacidosis at a university hospital in Damascus. Avicenna Journal of Medicine, 5(1), 11–15. http://doi.org/10.4103/2231-0770.148503
- Fowler, M. (2009). Hyperglycemic Crisis in Adults: Pathophysiology, Presentation, Pitfalls, and Prevention. Clinical Diabetes,27(1), 19-23.doi:10.2337/diaclin.27.1.19
- Gosmanov, A. R., Gosmanova, E. O., & Dillard-Cannon, E. (2014).Management of adult diabetic ketoacidosis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 7, 255–264. http://doi.org/10.2147/DMSO.S50516
- Kitabchi, A. E., Umpierrez, G. E., Fisher, J. N., Murphy, M. B., &Stentz, F. B. (2008). Thirty Years of Personal Experience in Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. The Journal of Clinical Endocrinology and Metabolism, 93(5), 1541–1552. http://doi.org/10.1210/jc.2007-2577
- Mumme, Laura E. (2015) “Diabetic Ketoacidosis: Pathophysiology and Treatment” The Kabod 2( 1 (2015)), Article 3. Retrieved from http://digitalcommons.liberty.edu/kabod/vol2/iss1/3
- Nyenwe, E. A., Razavi, L. N., Kitabchi, A. E., Khan, A. N., & Wan, J. Y. (2010). Acidosis: The Prime Determinant of Depressed Sensorium in Diabetic Ketoacidosis. Diabetes Care, 33(8), 1837–1839. http://doi.org/10.2337/dc10-0102
- Rosenbloom, A. L. (2010). The management of diabetic ketoacidosis in children.Diabetes Therapy DiabTher,1(2), 103-120. doi:10.1007/s13300-010-0008-2