Insulin

Mechanism of Action

Insulin acts by directly binding to its receptors on the plasma membranes of the cells. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density being on the hepatic cells and adipocytes.

The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and the beta subunits. The extracellular alpha subunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity.[16] When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit, which causes the translocation of glucose transporters from the cytoplasm to the cell's surface.[17] These glucose transporters allow the influx of glucose from the blood into the cell, thus reducing blood glucose levels.[18]

Insulin causes the following effects in the cells[19]:

• Hepatic cells: Promotes glycogenesis, inhibits gluconeogenesis
• Adipocytes: Promotes lipogenesis, inhibits lipolysis
• Muscle cells: Promotes glycogenesis and protein synthesis. Inhibits protein catabolism
• Pancreatic beta cells: Inhibits glucagon release
• Brain cells: Involved in appetite regulation

Depending on the duration of action, insulin is categorized as short-acting, intermediate-acting, and long-acting.

Rapid-acting insulins (lispro and aspart) start their action in 5 to 15 minutes and peak in 30 minutes. The duration of action is 3 to 5 hours. They are generally used before meals and are always used along with short-acting or long-acting insulins to control sugar levels throughout the day.

Short-acting (regular insulin) starts the action in 30 to 40 minutes and peaks in 90 to 120 minutes. The duration of action is 6 to 8 hours. Patients take these agents before meals, and food is necessary within 30 minutes after its administration to avoid hypoglycemia.

Intermediate-acting insulins (NPH) start the action in 1 to 4 hours and peak in 4 to 8 hours. Dosing is usually twice a day and helps maintain blood sugar levels throughout the day.

Long-acting insulins, such as glargine and detemir, start action in 1 to 2 hours. They provide a plateau effect over 12 to 24 hours. Dosing is usually during the night time after meals. Their long duration of action helps in reducing the frequency of dosing throughout the day.

Administration

Insulin administration can be via subcutaneous, intravenous, and intramuscular routes. The route of administration usually depends on the patient's condition and setting.

The subcutaneous route is the most widespread route of administration and is preferred by most patients due to its ease and convenience in administration. Patients use the subcutaneous route in the form of insulin syringes, pens, and pumps. It is an easy and convenient way for patients to self-administer.

Intravenous insulin is used in the hospital setting, especially when immediate and close monitoring of blood glucose levels is needed.[20] It is used in patients with diabetic ketoacidosis, hyperosmolar hyperglycemic state, severe hyperkalemia, beta-blocker toxicity, and calcium channel blocker toxicity. All of these cases require emergency treatment, and hence, intravenous insulin is used.

Intramuscular insulin use is rare and utilizes concentrated regular insulin. In 2014, the FDA approved an inhalable insulin formulation. It passes through the lungs and into the bloodstream and provides a rapid onset of action within 12 minutes. It can be taken by patients with diabetes type 1 and type 2 before meals. The insulin pump is a device that works like a natural pancreas. It replaces the need for long-acting insulin and continuously delivers small amounts of short-acting insulin to the body throughout the day.

Adverse Effects

Adverse effects of insulin are classified according to those caused by the drug itself and those caused by the specific route of administration. Hypoglycemia is, by far, the most common adverse effect of insulin therapy.[21] The other adverse effects of insulin therapy include weight gain and rarely electrolyte disturbances like hypokalemia, especially when used along with other drugs causing hypokalemia.

The subcutaneous route of administration also has adverse effects. Pain at the injection site and lipodystrophy at the injection site are the most common adverse effects of daily subcutaneous injections.[22] Other adverse effects like peripheral hyperinsulinemia and decreased compliance are also seen in the population using the subcutaneous route for insulin administration.

Somogyi effect: Some patients who take insulin before bed wake up with high blood sugar levels. This effect occurs when the insulin causes a hypoglycemic condition in the body, which activates hormones such as cortisol and adrenaline, resulting in rebound hyperglycemia; this can be corrected by reducing the dose of bedtime insulin or changing the time of insulin dosing.

Dawn phenomenon: It is the presence of high blood glucose levels in the body in the early hours of the day due to inadequate insulin in the body. To correct this phenomenon, the dose of bedtime insulin needs to increase to be able to keep the blood glucose levels under control throughout the night and the early hours of the morning.[23]

Contraindications

Though there are no absolute contraindications to insulin therapy, the dose of insulin needs to be adjusted and monitored in numerous settings.

• Insulin dosing requires adjustment in patients with renal impairment and liver failure, as insulin metabolism occurs in the liver, excreted in the urine.
• Insulin dose and blood glucose levels should be carefully monitored in patients with a history of hypoglycemic episodes.
• Insulin should not be given with other drugs, which also cause hypokalemia, like diuretics.
• Vomiting and diarrhea cause a hypokalemic state in the body, and clinicians and patients should exercise care when administering insulin as it also causes hypokalemia.
• Insulin is also contraindicated in patients with cresol sensitivity, as insulin preparations contain cresol.

Monitoring

Insulin has a low therapeutic index, and blood glucose levels require regular monitoring to avoid adverse effects like hypoglycemia. Patient education should be provided about symptoms of hypoglycemia so that they can take immediate action when necessary. Monitoring for glucose levels is usually performed by fingerstick blood glucose test or glucose sensor device, both of which give instantaneous readings of blood glucose levels. Other tests, such as hemoglobin-A1c, can estimate glucose control over the past three months and enable insulin adjustment accordingly.

Toxicity

Insulin taken in large doses will cause symptoms of hypoglycemia in the patient. Some of these symptoms include headache, dizziness, palpitations, sweating, abdominal pain, and blurred vision. The immediate therapy for such patients is increasing the levels of glucose. In a conscious patient, this can be done by eating a high-energy bar or drinking a glass of glucose water. If the patient is unconscious, he needs to be hospitalized, given dextrose solution intravenously, and continuously monitors glucose levels.

Enhancing Healthcare Team Outcomes

Insulin is a widely used medicine in hospital settings for the management of hyperglycemia. Insulin is regarded as a high alert medication as its misuse is associated with significant risks such as hypoglycemia, and medical errors are common when using it in hospitals.[24][25] Deal et al. found that the most commonly reported errors were related to missed doses of insulin (25%), timing errors (22.7%), and missed documentation of doses (15.5% of patients).[26] These problems reveal several system errors that merit attention. Rousseau et al. identified various problems causing errors in the hospital use of insulin, such as frequent staff turnover, the involvement of various healthcare providers, none of which are specifically responsible for overall glycemic management, lack of perception of insulin as a “high alert medication,” rapidly evolving diabetes management and lack of education of staff on insulin management.[24] To minimize these errors following measures should be undertaken,

• Availability of standardized protocols
• Continuing education of providers
• Communication between nurses on different shifts
• Adequate communication between nurses, physicians, and pharmacists
• Training professionals in insulin therapy of inpatients

Diabetes is a complex disease, and insulin is its most effective treatment. An interprofessional team approach is always essential for the management of diabetes in both outpatient as well as inpatient settings. When prescribing insulin in an outpatient setting, patient education is necessary regarding the disease, use, and side effects of insulin. A variety of healthcare professionals, such as dieticians, endocrinologists, exercise professionals, ophthalmologists, and podiatrists, should work with the patient under the coordination of the primary care providers to manage this disease. [Level 5]