Continuing Education Activity

Regular insulin is a medication used in the management of diabetes mellitus and hyperglycemia of a variety of etiologies. It is in the short-acting insulin class of drugs. This activity outlines the mechanism of action, adverse event profile, labeled and off-labeled indications, contraindications, monitoring, and toxicity for regular insulin pertinent for members of the healthcare team in the management of patients with diabetes mellitus and related conditions.

Objectives:

• Describe the mechanism of action of regular insulin.
• Identify the possible adverse effects associated with regular insulin.
• Review the appropriate monitoring needed for patients using regular insulin.
• Summarize interprofessional team strategies for improving care coordination and communication to advance regular insulin and improve outcomes

Indications

Regular insulin, a short-acting human insulin, is a synthetic protein hormone, which, just as the naturally occurring endogenous insulin, exerts a wide range of physiologic effects. Clinical use of insulin is mainly to its ability to lower down serum glucose.

Labeled Indications[1]

• Insulin, regular is the mainstay therapy in the management of diabetes mellitus type 1 and type 2 (in some cases) to improve glycemic control.

Off-Label Indications[2][3][4][5][6][7][8][9]

• Use for hormonal resuscitation in cadaveric organ recovery
• For toxicity of calcium channel blockers and beta-blockers
• The mainstay treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state
• Treatment of gestational diabetes mellitus when refractory to non-pharmacologic treatment such as nutrition
• Adjunct therapy for hyperglycemia in the critically ill
• Hyperkalemia

Mechanism of Action

Insulin, a natural endogenous hormone synthesized and secreted by pancreatic beta cells, has a structure of 51 amino acids. 

Insulin is considered the most potent anabolic hormone known until today, and its effects on the body are necessary for tissue development, growth, and maintenance of glucose homeostasis. Insulin action starts by binding to two cell receptors, which are alpha and beta, that are linked by two disulfide bonds into a complex that is a heterotetrameric membrane.[10]

The conformational change of the binding between insulin and the alpha and beta receptors enables ATP to bind and activate tyrosine kinase, which causes receptor autophosphorylation.[11] Through activation of these signaling pathways, insulin has a potent regulation metabolic effect. 

Insulin can affect every tissue in the body either directly or indirectly. But in this review, we will address the metabolic effects of this hormone on the liver, skeletal muscle, and adipose tissue. The effects of insulin on glucose metabolism are the following: Stimulation of the synthesis of glycogen, increased glycolysis in fat and muscle, increased glucose transport into fat and muscle, and inhibition of glycogenolysis and gluconeogenesis.

In terms of glucose production, glycogen breakdown to synthesis in the liver is facilitated by inhibiting glycogen phosphorylase and the stimulation of glycogen synthesis through the effects of insulin directly.[12] Indirectly, insulin is involved in several pathways, such as a decrease in the flow of fatty acids to the liver and glucagon secretion inhibition to some extent, by direct inhibition of the glucagon gene in pancreatic alpha cells.[13]

Insulin coordinates glucose and free fatty acids during states of feeding, fasting, and exercise to meet the body`s demands. Several mechanisms lead to insulin's effects on fat metabolism.  

Insulin stimulates lipoprotein lipase to clear chylomicrons rich in triglycerides away from the circulation and then hydrolyzes them. The fatty acids generated from this reaction are taken up by skeletal muscle and adipose tissue to be oxidized and stored.[14] Lipolysis is inhibited by insulin through the dephosphorylation of hormone-sensitive lipase and inhibition of ATGL.[15][16] A second mechanism implicated in the inhibition of lipolysis occurs during the refeeding state, in which insulin inhibits the cAMP-dependent protein kinase that is responsible for activating hormone-sensitive lipase and phosphorylating it.[17]

The overall effect of insulin on fat metabolism is decreasing lipolysis and increasing TG storage, thereby decreasing the flow of FFA to the liver. 

In states of prolonged fasting or uncontrolled diabetes, such as DKA, in which insulin levels are low, FFA is released into circulation by lipolysis in addition to an increased hepatic FFA oxidation to ketone bodies (B-hydroxybutyrate and acetate) which results in ketonemia and metabolic acidosis.[18] 

Hyperinsulinemia decreases ketone body production by inhibiting carnitine palmitoyltransferase I by stimulating malonyl CoA, increasing ketone body peripheral clearance, and inhibiting lipolysis, as mentioned above, thereby decreasing the supply of FFA to the liver.[19] 

In general, insulin stimulates protein synthesis by increasing the number of translational efficiency ribosomes in skeletal muscle and liver and accelerating the transport of amino acids into hepatocytes, fibroblasts, and skeletal muscle, which in turn, causes a ribosome-catalyzed reaction and translation of the genetic code in specific messenger RNAs.[20]

Decreasing proteolysis is the major effect of insulin on the human body in terms of protein metabolism. These effects are dose-dependent. Essential amino acids are more sensitive to insulin´s effect; therefore, in the presence of euglycemia and hypoaminoacidemia, the effects of insulin are effective in decreasing proteolysis.[21]

Administration

Insulin, regular when administrated subcutaneously, should be injected 30 to 40 minutes before each meal. Avoid cold injections. The injection is in the buttocks, thighs, arms, or abdomen; it is necessary to rotate injection sites to avoid lipodystrophy. Do not inject if the solution is viscous or cloudy; use only if clear and colorless.

When administered intravenously, U-100 administration should be with close monitoring of serum potassium and blood glucose. Do not use if the solution is viscous or cloudy; administration should only occur if it is colorless and clear. 

For intravenous infusions, to minimize insulin adsorption to plastic IV tubing, flush the intravenous tube with a priming infusion of 20 mL from a 100 mL-polyvinyl chloride bag insulin every time a new intravenous tubing is added to the insulin infusion container.[8]

Adverse Effects

A useful and detailed way to classify the adverse effects of insulin is by separating and organizing them by organ systems:

• Cardiovascular side effects include peripheral edema
• Dermatologic side effects include pruritus and erythema at the injection site
• Hypersensitivity side effects include hypersensitivity reaction and anaphylaxis
• Local injection site adverse effects include lipoatrophy and hypertrophy
• Endocrine and metabolic side effects include hypokalemia, weight gain, and hypoglycemia

Regarding hypoglycemia, if insulin is administered not with meals or inappropriate dosage, it can be life-threatening. Untreated hypoglycemia can cause seizures, coma, and even death, especially in elderly patients. 

Insulin causes a potassium shift from the extracellular space to the intracellular space and can cause profound hypokalemia and result in muscle cramps, lethargy, cardiac arrhythmias, and even death. 

Contraindications

Regular insulin is contraindicated in patients with hypersensitivity to the drug due to the potential to cause an allergic reaction.[22]

Monitoring

In patients with DM (mainly type 1 but can also be type 2) and on an insulin regimen, blood glucose should be monitored between meals to prevent hypoglycemia. Additionally, weight measurements are necessary due to insulin-associated weight gain. Insulin's regular onset of effect is 1 hour, peaks at 2 to 4 hours, and the duration of the effect lasts 4-hours.

Patients with DKA and HHS that are on an insulin infusion regimen must have careful monitoring for the development of electrolyte abnormalities, especially hypokalemia, as well as serial blood glucose measurements.

Toxicity

Most of the symptoms of insulin toxicity are related to hypoglycemia and electrolyte abnormalities. They can categorize into neuroglycopenic and catecholaminergic symptoms. The latter appear first are characterized by tachycardia, sweating, tremors. If blood glucose continues to decrease, neuroglycopenic symptoms appear. They can be from a mild mental status alteration to seizures and coma. Patients that present with hypoglycemia can have diaphoresis, hypotension, and bradycardia. Elevated doses of insulin can lead to water and salt retention and result in dilutional hyponatremia and hypokalemia.[23]

The antidote for insulin toxicity is dextrose with a dose of 400 to 600mg/kg/hr. The antidote for severe insulin toxicity is the use of a glucagon emergency kit plus dextrose infusion.

Enhancing Healthcare Team Outcomes

Appropriately managing patients with diabetes mellitus (DM) is of absolute importance to the entire healthcare team. DM is on the rise in the U.S epidemiology statistics, so ensuring the appropriate use of insulin to control this disease is essential. The interprofessional team must recognize the importance of insulin in the treatment of DM, considering it will significantly benefit the patient in his morbidity and mortality. Clinicians, nurses, and pharmacists should know of insulin's labeled and off-label indications as well as adverse effects.

Physicians will be prescribing the medication, while the nurse will administer the drug if inpatient and will follow-up on side effects if outpatient, while the pharmacist will work in collaboration with the physician to ensure the proper dosage, indication, and duration of the medication. Finally, the nurse is the first contact with the patient and should coach the patient on administering the medication and being aware of its adverse effects. This interprofessional collaboration will optimize patient outcomes while minimizing adverse effects. [Level 5]