Human Insulin


Article Author:
Heeransh Dave


Article Editor:
Charles Preuss


Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/8/2019 5:25:36 PM

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]


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Human Insulin - Questions

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A 61-year-old woman presents to the emergency department in a confused state. The patient's daughter called 911 when her mother became unresponsive to conversations with her. The daughter also notes that the patient was recently diagnosed with community-acquired pneumonia. Lab values are the following: plasma glucose = 625 mg/dL, arterial pH = 7.35, sodium bicarbonate = 19 mEq/L, serum ketone = small, and serum osmolality = 325 mOsm/kg. Which of the following would provide the best management for this patient?



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A 62-year-old male with type two diabetes mellitus presents to the hospital for alcohol intoxication. He denies any other medical history or surgical history. He reports to drinking 2 glasses of vodka every night. His temperature is 98.6 degrees Fahrenheit, pulse 90 beats per minute, blood pressure is 150/100 mm Hg, respiratory rate is 18 times a minute and is blood oxygen saturation is 98%. On physical examination, he is lethargic and does not respond appropriately to commands. He has normal S1 and S2, no murmurs, no wheezes or crackles. His abdomen is soft, non-tender and non-distended. There is no edema or cyanosis on his extremities. On laboratory evaluation, the hemoglobin is 15 gm/dL and his white blood cell count is 7000/mcL. His blood glucose level is 110 mg/dl and his blood potassium level is 2.9 mmol/L. On the EKG, ST-segment depression and U waves are present. He is started on treatment for alcohol intoxication. He will be started on insulin soon. What medication must be administered to the patient before starting insulin in this clinical scenario?



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A 20-year-old male presents to the emergency department for altered mental status. Per the patient’s mother, the patient suddenly started sweating and became unresponsive. She reports that he does not have any medical history, surgical history or any significant family history. He does not take any medications. The patient has a temperature of 98.9 degrees Fahrenheit, the pulse is 110 beats per minute, his blood pressure is 110/60 mm hg, blood oxygen saturation is 100% and he is breathing 14 times a minute. On physical examination, he appears lethargic. His heart, lung, and abdominal examination is normal. His skin is moist. His blood glucose level is found to be 20 mg/dL. He is given a dextrose injection intravenously. Within a few minutes, he regains his consciousness with no residual deficits. He denies any complaints. His EKG and troponins are within normal limits. His urine sulphonyl-urea level is zero. The c-peptide levels are 4 ng/ml. The CT scan of his brain was done and was negative for any abnormalities. What is the most likely cause of the patient’s symptoms?



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A 22-year-old male with newly diagnosed diabetes mellitus type 1 presents to the emergency room with complaints of nausea, vomiting, and epigastric abdominal pains. In the emergency room, his blood glucose was measured and found to be 500. ABGs revealed high anion gap metabolic acidosis. He was immediately transferred to the ICU and was started on treatment. Fluids and electrolytes were being replaced. What type of insulin should be administered in this setting?



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A 46-year-old gentleman with a history of type 2 diabetes mellitus for 1 year presents with night sweats and morning headaches for about the last 3 months. He reports that he has started a new diet plan after he learned about it on the television. His diet plan includes a big breakfast and a small lunch. He skips his dinner. He has been compliant with his insulin regimen as prescribed by his primary care provider about 6 months ago. He has a history of travel to India 6 years ago. His most recent Hba1C is 7.1%. His PPD test is negative and his weight is stable. You notice morning hyperglycemia on his blood glucose log. What is the cause of his symptoms?



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A 33-year-old female with recently diagnosed type 1 diabetes presents to the office for a follow-up visit. She has brought with her the blood glucose log for the past month. You notice that her pre-breakfast blood glucose has been ranging between 250-350s. She also reports that in spite of taking the insulin as directed and being careful of what she eats; it is very difficult to control her blood glucose in the mornings. The pre-lunch and pre-dinner blood glucose readings have been well controlled. She denies any nocturnal hypoglycemia. How can we control her blood glucose better?



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A 16-year-old male was brought to the emergency department by his mother after she found him passed out in his room. She states that he recently broke up with his girlfriend and has been very sad about it for the past 1 month. She found his father's insulin injections in his room, and she suspects that he may have injected himself in an attempt to commit suicide. A lab test reveals an elevated insulin level in the patient's blood. Which of the following can differentiate between an elevated insulin level due to exogenous insulin intake or an insulinoma?



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A student is studying the synthesis and function of insulin in his biology class. He learns that insulin binds to insulin receptors on the cells, which will induce glucose uptake by this cell through glucose transporters. He also learns that there are 5 different types of glucose transports (GLUT1-5). If there is a mutation in GLUT-4, glucose uptake into which of the following will be affected?



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A 17-year-old healthy male with a 10-year history of diabetes mellitus type I presents to his healthcare provider with complaints of abdominal pain, nausea, and vomiting. He ran out of his insulin about 2 weeks ago. His vital signs are stable. There is some abdominal tenderness on physical examination. His blood glucose was found to be 289 mg/dL. Liver enzymes are normal. The right upper quadrant ultrasound and the CT scan of the abdomen were normal. What is the most likely cause of the patient’s symptoms?



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A 17-year-old girl presents to her healthcare provider for a regular follow up visit. She reports increased urination and thirst over the last few days and 5 lb weight loss in the last 2 months. Her fasting blood glucose value is 130 mg/dL. She is diagnosed with type 1 diabetes mellitus and she is started on insulin therapy. Which of the following is a major physiologic effect of insulin?



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A 65-year-old woman presents to her healthcare provider for follow up of her diabetes mellitus. She reports that her hemoglobin A1c is 5.7% and her random blood glucose concentration is 100 mg/dL. She reports adherence with her medications which include atorvastatin and glipizide. Which of the following can be measured in the body which correlates the most with the amount of endogenous insulin release?



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An 88-year-old woman is brought to the emergency department due to seizures and she is unresponsive. She was in her usual state of health till a few hours ago when her daughter saw her having seizures and called 911. She has a history of type 2 diabetes mellitus, hypercholesterolemia, bilateral cataracts, dementia, multiple falls, end-stage renal disease on hemodialysis, and a hip fracture. Fingerstick blood glucose performed reveals glucose levels of 44 mg/dL. Upon administration of glucose and intravenous fluids, the patient wakes up and she is back to her normal self. CT scan of her head is within normal limits. Which of the following is the most likely cause of her seizures?



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An 87-year-old man presents with episodes of muscle cramps and palpitations for the last 2 weeks. He also reports increased weakness and fatigue. He has a history of type 2 diabetes mellitus, hypertension, stroke, and right eye blindness. He takes insulin, amlodipine, and over the counter vitamins regularly. He is adherent with his medications. He is active, and he manages his medications independently. At the previous visit a month ago, the dose of his insulin was increased, and atorvastatin was discontinued due to elevated liver enzymes. ECG shows nonspecific changes and U waves. Which of the following is the most likely cause of his symptoms?



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Human Insulin - References

References

Mathieu C,Gillard P,Benhalima K, Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nature reviews. Endocrinology. 2017 Jul;     [PubMed]
Wallia A,Molitch ME, Insulin therapy for type 2 diabetes mellitus. JAMA. 2014 Jun 11;     [PubMed]
Coustan DR, Gestational diabetes mellitus. Clinical chemistry. 2013 Sep;     [PubMed]
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]
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]
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]
Poonuru S,Pathak SR,Vats HS,Pathak RD, Rapid reduction of severely elevated serum triglycerides with insulin infusion, gemfibrozil and niacin. Clinical medicine     [PubMed]
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]
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]
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]

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