Human Insulin

Article Author:
Heeransh Dave
Article Editor:
Charles Preuss
Updated:
8/8/2019 5:25:36 PM
PubMed Link:
Human Insulin

Indications

The management of type 1 diabetes mellitus entails replacing the actions of the beta cells of the pancreatic islet to detect the needs of insulin and to have insulin administered according to the needs of the patient's body. Insulin is a natural hormone, and it is an essential medication for a multitude of disease states. One of the most critical uses of insulin is in type 1 diabetes mellitus and type 2 diabetes mellitus.[1][2] Insulin is one of the few medications that is indicated for use in the management of gestational diabetes.[3] Due to its effects of driving potassium into the intracellular compartment, it has use in the management of hyperkalemia.[4] Insulin is a component in the management of complications of diabetes mellitus, including diabetic ketoacidosis as well as the hyperosmolar hyperglycemic state.[5] There is proven clinical benefit of using insulin in critical illnesses to prevent or treat hyperglycemia-related toxicity.[6] Commonly, treatment of hypertriglyceridemia includes dietary modifications and medical management with the use of fibrates, fish oil, and niacin amongst others. One of the other very important uses of insulin is in the treatment of severe hypertriglyceridemia as well as hypertriglyceridemia-induced pancreatitis. Insulin lowers the triglycerides by upregulating the formation of lipoprotein lipase, which works by hydrolyzing the triglycerides. Insulin infusion can help patients with severe hypertriglyceridemia by quickly reducing the blood concentrations of triglycerides to less than 1000 mg/dl.[7]

Mechanism of Action

Insulin’s major actions focus on storing excess energy in a fed state. Insulin promotes glycogen synthesis, lipid synthesis, protein synthesis, DNA synthesis, as well as cellular growth and differentiation. Once glucose gets absorbed from a meal; it enters the blood, and then the pancreas releases insulin. Insulin synthesis occurs in the beta cells of the pancreas initially as preproinsulin. Preproinsulin then converts to proinsulin, which then transforms into a single peptide with A, B, and C peptide units. The A and B peptides are joined by disulfide bonds to make insulin and get secreted into the bloodstream. Insulin binds to its cellular receptor. The insulin receptor is composed of alpha subunits, beta subunits, and a tyrosine kinase enzyme. When Insulin binds to the alpha subunit, this triggers phosphorylation and activation of the target proteins intracellularly by the tyrosine kinase leading to many effects on cellular metabolism. Activation of the insulin receptor also leads to increased expression of GLUT ( a glucose transporter) to the membrane surface and promotes the entry of glucose to the intracellular compartment and then undergoes cellular metabolism. Insulin signals glucose conversion to glycogen for storage as well as the formation of acetyl coenzyme A and triacylglycerol which get stored in adipose tissue. Also, insulin directs amino acids for protein synthesis.[3]

In patients with diabetes, to reach the goal of normal 24-hour insulin activity like in healthy adults without diabetes, one single insulin formulation with a defined onset, peak, and duration of action is not helpful. Hence there is a need for different kinds of insulin that have different pharmacokinetics. Based on the mode of action, there are four different types of insulin analogs. The rapid-acting insulin has a rapid onset of action (about less than 30 minutes), peak action at about 1 hour and short duration of action (up to 5 hours). Insulin Lispro and Insulin Aspart are the rapid-acting insulins. These insulins help achieve glycemic control specifically in the postprandial state. The short-acting insulin analogs activity begins in about 30 to 60 minutes, peaks at 2 to 4 hours, and activity last for about 8 hours. These insulin analogs must be administered approximately 20 to 30 minutes before meals for effectiveness. The intermediate-acting insulin analogs have an onset of activity at around 1 to 2 hours, peak action at 6 to 10 hours and a duration of action up-to about 16 hours. Neutral protamine Hagedorn (NPH) and LENTE insulin are intermediate-acting insulin analogs. Some of the long-acting insulin analogs are insulin detemir and insulin glargine. Their activity begins at around 2 hours, peak effect from 6 to 20 hours and last up to about 36 hours.[8]

Administration

There are multiple routes of administration of insulin. Administration can be as a bolus as an intravenous injection or as a continuous intravenous infusion. Typically, glycemic control is achieved by using basal and prandial insulin administration or by continuous subcutaneous insulin infusion. It can be given as a subcutaneous or intramuscular injection as well. Recently, the inhalational route for administration of insulin is available for clinical use.[2][9] Transplantation of the islet cells of the pancreas or pancreatic transplantation is an investigational procedure which can mimic natural insulin synthesis and functionality.[10] Administration of insulin via oral and transdermal routes is being evaluated and may be available shortly for everyday use.[9]

Adverse Effects

Like any other medication, there are clinically significant side effects associated with the use of insulin. Insulin administration can lead to local hypersensitivity reactions such as erythema, pruritus, swelling, and pain at the site of injection. Local dermal lipo-dystrophic reactions can occur. An inappropriately excessive dose of insulin or incoordination with meals/missing meals, hypoglycemia can occur which can be life-threatening. Untreated hypoglycemia can cause seizures, coma as well as death, which makes it especially important in elderly patients who are more susceptible. Long term use of insulin can lead to the production of antibodies against it with possible development of insulin resistance. As mentioned earlier, insulin can cause the potassium to shift to the intracellular compartment and lead to hypokalemia. Hypokalemia can manifest as cardiac arrhythmias, muscle cramping, gastrointestinal upset, confusion, weakness as well as lethargy.[9]

Contraindications

There are a few contraindications to the use of insulin. A patient history of allergic reactions to insulin, its reuse is contraindicated. In patients with insulinoma, where there is excessive endogenous production of insulin, the use of exogenous insulin is contraindicated. There is a relative contraindication to using insulin in the setting of hypokalemia. The potassium concentrations must be corrected before the administration of insulin as insulin has a known effect of causing hypokalemia.

Monitoring

It is paramount to monitor the blood glucose concentrations while using insulin for optimal glycemic control without causing hypoglycemia (or hyperglycemia). This monitoring is commonly done with regular blood glucose checking with finger prick glucose testing using a glucometer. There are novel techniques now available for continuous glucose monitoring that work by a sensing device inserted subcutaneously that measure the glucose concentration in the interstitial fluid between the cells and transmitted this information to a monitoring device. The glucose concentrations can be tracked consistently during the day as well as night with this device. Also, long term glycemic control can be monitored by using glycated hemoglobin, also known as hemoglobin A1C.

Toxicity

Insulin overdose can cause toxicity by causing hypoglycemia and many additional effects, including arrhythmias, coma, seizures, hypotension, amongst other symptoms. Long term insulin use may lead to dermal toxicity by causing lipodystrophy. The patient can mitigate this adverse effect by rotating subcutaneous injection sites. Insulin can also cause hypokalemia and related complications, as mentioned earlier in this article.

Enhancing Healthcare Team Outcomes

To enhance patient health outcomes by the healthcare teams, medical education, and dissemination of information regarding diabetes mellitus, its complications, and management options are crucial for patient care. It will empower the healthcare team to be mindful of the potential complications as well as how to manage hypoglycemia, hypokalemia, and other complications of insulin pharmacotherapy. All members of the team should assist in educating the patient and family about the importance of safe insulin dosing. Demonstrations and educational workshops would go a long way toward achieving these goals. It is also crucial to educate the patient to recognize the early signs of hypoglycemia and how to manage diabetes mellitus with insulin and other glycemic control medications. This approach allows the patient to become an integral member of the healthcare team, i.e., its number one focus and to help in improving overall outcomes by close collaboration. Nursing should ensure proper administration, compliance, and verify monitoring. Pharmacists need to verify dosing, perform medication reconciliation and can instruct patients on administration as well as how to use their glucose monitor properly. If there are concerns, they should work with the clinician to improve the safe administration of the drug. Monitoring of the blood glucose concentrations, adjustment of the dose of insulin as necessary, and lifestyle modifications to prevent chronic complications of diabetes mellitus are major goals to enhance the patient health outcomes by the healthcare team. [Level V]


References

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[2] Wallia A,Molitch ME, Insulin therapy for type 2 diabetes mellitus. JAMA. 2014 Jun 11;     [PubMed PMID: 24915263]
[3] Coustan DR, Gestational diabetes mellitus. Clinical chemistry. 2013 Sep;     [PubMed PMID: 23536513]
[4] Harel Z,Kamel KS, Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review. PloS one. 2016;     [PubMed PMID: 27148740]
[5] Dhatariya KK,Vellanki P, Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA). Current diabetes reports. 2017 May;     [PubMed PMID: 28364357]
[6] Vanhorebeek I,Langouche L,Van den Berghe G, Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness? Current opinion in critical care. 2005 Aug;     [PubMed PMID: 16015107]
[7] Poonuru S,Pathak SR,Vats HS,Pathak RD, Rapid reduction of severely elevated serum triglycerides with insulin infusion, gemfibrozil and niacin. Clinical medicine     [PubMed PMID: 20852089]
[8] Ahmad K, Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan. 2014 Apr     [PubMed PMID: 24783939]
[9] Matteucci E,Giampietro O,Covolan V,Giustarini D,Fanti P,Rossi R, Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery. Drug design, development and therapy. 2015;     [PubMed PMID: 26124635]
[10] Gangemi A,Salehi P,Hatipoglu B,Martellotto J,Barbaro B,Kuechle JB,Qi M,Wang Y,Pallan P,Owens C,Bui J,West D,Kaplan B,Benedetti E,Oberholzer J, Islet transplantation for brittle type 1 diabetes: the UIC protocol. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2008 Jun;     [PubMed PMID: 18444920]