Medicine and surgery
Which of the following insulin preparations is preferred for acute management of diabetic ketoacidosis?
Content Reviewers:Yifan Xiao, MD
Contributors:Robyn Hughes, MScBMC, Alaina Mueller, Sam Gillespie, BSc, Jake Ryan, Royce Rajan, MD, MBA
Insulin is a type of peptide hormone that reduces the amount of glucose in the blood. It is produced in the pancreas by beta cells. These cells are found within clusters of endocrine cells called the Islets of Langerhans, which are distributed across the pancreas. If the body is unable to produce enough insulin, then insulin therapy is used to keep the blood glucose low.
Insulin’s main function is to facilitate the transport of glucose from the blood into the various insulin-responsive tissues like muscle cells and adipose tissue. This hormone binds to insulin receptors on the surface of the cell membrane. Now, these receptors have two alpha and two beta subunits. Alpha subunits are located outside of the cell and they bind insulin; while two beta subunits are located within the cell and they have tyrosine kinase activity which carries signals into the cell. Once stimulated, insulin receptors cause intracellular storage vesicles, which contain glucose transport proteins called GLUT4, to fuse with the cell membrane. Next, the GLUT4 proteins embed themselves into the membrane and allow glucose to move into the cell.
As a result, insulin promotes glucose uptake and glycogenesis, which is the conversion of glucose to glycogen. Glycogenesis is the process that takes place in the liver and skeletal muscles. When glycogen storage capacity is reached, insulin promotes glycolysis, which is the breakdown of glucose to pyruvate. It also stimulates lipogenesis, the synthesis of fatty acids and triglycerides in the liver and adipose tissue; and amino acid uptake and protein synthesis in skeletal muscles.
Finally, insulin activates Na+/K+- ATPase pumps and shifts potassium into intracellular space, thereby decreasing potassium levels in the blood. On the flip side, insulin inhibits glycogenolysis, which stands for the breakdown of glycogen; and gluconeogenesis, which is glucose production from lactic acids and noncarbohydrate molecules. Finally, insulin inhibits lipolysis, the breakdown of lipids; and proteolysis, the breakdown of proteins.
Type 1 diabetes mellitus, which most commonly affects children and adolescents, arises when a person’s own T cells attack the pancreas. Normally, maturing T cells in our body go through a process called “self-tolerance” where the T cells that would attack our own body are eliminated. In type 1 diabetes, there is a genetic abnormality which causes the loss of self-tolerance among T cells that target the beta cells. The result is the destruction of the beta cells which leads to decreased insulin production and hyperglycemia, or increased blood glucose.
Type 2 diabetes is caused by insulin resistance in the cells of the body. When blood glucose rises after a meal, the pancreas produces insulin as a response. Since the peripheral cells are resistant to insulin, they do not take in the glucose, so the pancreas has to produce even more insulin. Eventually, the poor pancreas gets so overworked that the beta cell starts to atrophy, which leads to decreased insulin production and high blood glucose levels.
In order to correct the insulin deficiency found in Type 1 diabetes and later stages of type 2 diabetes, exogenous insulins can be used. Insulin is administered subcutaneously because they can be broken down in the GI tract. Insulin is typically administered through syringes or insulin pens. When injected into the abdominal region, the absorption is the quickest, followed by arms, thighs, and buttocks. Some diabetics prefer the insulin pump since insulin dosages are programmed into the device and will be delivered subcutaneously throughout the day, thus preventing the need for multiple daily insulin injections.
Now, there are multiple categories of insulin therapies, more commonly referred to as insulin preparations. These preparations are categorized according to their onset of action and duration of effect; and they include rapid-acting, short-acting, intermediate-acting, long-acting, and ultra long-acting insulins.
Rapid-acting and short-acting insulins are used for bolus insulin regimen, where they are taken before each meal to counteract the post-meal increase in blood glucose. Intermediate-acting, long-acting, and ultra long-lasting insulins are used for basal insulin regimen to maintain a steady background level of insulin throughout the day. They are given once or twice daily to regulate the basal, or fasting blood glucose, level.
Next, there's a basal-bolus regimen where a basal insulin is used to maintain fasting blood glucose levels, and a bolus insulin is taken before meals. Lastly, is the sliding-scale regimen. This regimen is typically reserved for hospital settings where a person’s blood glucose level could fluctuate rapidly due to metabolic stressors like infections or other illnesses. In this regimen, every 4-6 hours, the person’s glucose level is measured and an appropriate dosage of short acting insulin is given. Finally, it’s important to note that insulins are the preferred medications in managing diabetes in pregnancy and breastfeeding.
Now let’s look at each class of insulin, starting with rapid-acting insulins, which include insulin aspart, lispro, and glulisine. These medications are given subcutaneously and they are actually modified versions of regular insulin with different sequences of amino acids. This makes them less stable, and they break down into single monomers soon after injection. Rapid-acting insulins begin working within 5 to 15 minutes of administration, with a peak effect at 1 hour. Their effects last for 3 to 4 hours. These insulins are injected right before a meal or they can be used in insulin pumps. They are also the preferred insulin for treating diabetic ketoacidosis.
Next are the short-acting insulins, or regular insulin, which is the only type of insulin that could be given subcutaneously and intravenously. Regular insulin in the body is generally produced and stored as a hexamer, which is simply a term used to describe a single unit of 6 insulin molecules. This structure allows insulin to remain stable within the body, and break down into individual monomers in order to become active. Thus, regular insulin only begins working 30 minutes after administration and its effect peaks at 2-3 hours. Its duration of action lasts between 5-8 hours and, besides diabetes melitus, it can be used to treat hyperkalemia.
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