Insulin

Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. There are several forms of insulin, and they differ in their time of onset, peak effect, and duration. Insulin can be classified as fast acting, short acting, intermediate acting, or long acting. A combination of classes can be used to maintain glucose control throughout the day. Common adverse effects include hypoglycemia, weight gain after initiation of an insulin regimen, and local injection site changes.

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Pharmacodynamics

Chemistry

  • Insulin is a small protein normally created and released by pancreatic beta cells. 
  • Available formulations can be:
    • Human insulin: identical to endogenously produced insulin
    • Analog insulin: altered to create pharmacokinetic advantages

Mechanism of action

  • Insulin acts on cells to ↑ glucose uptake in all tissues, including the: 
    • Liver
    • Skeletal muscle
    • Adipose tissue
  • This occurs via glucose transporters (GLUTs): 
    • GLUT4 → muscle and adipose
    • GLUT2 → liver
  • Exogenous insulin is often used to overcome hyperglycemia caused by:
    • Insulin deficiency (type 1 diabetes)
    • Insulin resistance (type 2 diabetes)

Physiologic effect

  • In the liver:
    • ↑ Glycogen synthesis
    • ↑ Glycolysis
    • ↑ Lipogenesis
    • ↑ Protein synthesis
    • ↓ Glycogenolysis and gluconeogenesis
    • ↓ Conversion of fatty and amino acids to ketones
  • In muscle:
    • ↑ Glycolysis
    • ↑ Protein synthesis
    • ↑ Lipogenesis
    • ↑ Glycogen synthesis
  • In adipose tissue:
    • ↑ Triglyceride storage
    • ↓ Lipolysis
  • On blood levels:
    • ↓ Glucose
    • ↓ Fatty acids
    • ↓ Keto acids
    • ↓ Amino acids

Pharmacokinetics

Absorption

  • Absorption and onset of action depend on:
    • Mode of administration
    • Site of administration
  • Fastest to slowest: 
    • IV > IM > SC
    • Abdomen > buttocks > thigh
  • Other factors that may have an effect:
    • Exercise
    • Temperature
    • Local blood supply

Excretion

  • Insulin is cleared through the kidneys.
  • Dosing may need to be adjusted in individuals with renal failure.

Classification

Insulin types can be classified based on their pharmacokinetics:

  • Fast acting: 
    • Absorbed quickly
    • Quick peak effect
    • Examples:
      • Lispro
      • Aspart
      • Glulisine
  • Short acting: 
    • Still absorbed rapidly
    • Slightly longer peak effect
    • Example: regular
  • Intermediate acting: 
    • Absorbed more slowly
    • Lasts longer
    • Example: neutral protamine Hagedorn (NPH)
  • Long acting:
    • Absorbed slowly
    • Minimal peak effect (provides a stable plateau effect)
    • Lasts most of the day
    • Examples: 
      • Detemir
      • Glargine
      • Degludec
A comparison of the onset, peak effect, and duration of different insulin subtypes

A comparison of the onset, peak effect, and duration of different insulin subtypes

Image: “Insulin is categorized by how fast it works it the body, how soon it peaks and then how long it lasts. Notice how rapid acting insulins have a rapid rise and fall while longer acting insulin builds more slowly to a stable baseline before declining.” by A. Peters, M. Komorniczak. License: CC BY 3.0

Indications

Diabetes

Subcutaneous insulin:

  • Type 1 diabetes mellitus:
    • Individuals with type 1 diabetes mellitus require insulin replacement at all times.
    • Multiple daily injections can be used to simulate physiologic insulin release:
      • Basal (long-acting) insulin is given once or twice daily.
      • Boluses of rapid-acting insulin are given with meals.
    • A continuous insulin infusion (via insulin pump) with meal-time boluses is also an option.
  • Type 2 diabetes mellitus:
    • Added when oral therapy has failed to provide adequate glucose control
    • Usually used in addition to other oral antidiabetic medications (e.g., metformin)
    • Indicated for initial therapy when severe hyperglycemia is noted upon diagnosis
  • Gestational diabetes: preferred therapy for uncontrolled hyperglycemia despite diet and activity modifications

IV insulin:

  • Diabetic ketoacidosis (DKA)
  • Hyperosmolar hyperglycemic state
Glycemic excursions and insulin action

Glycemic excursions and insulin action:
This graph depicts the use of basal and bolus (meal-time) insulin to cover variations in blood glucose levels throughout the day.

Image by Lecturio.

Other indications

Besides diabetes, IV insulin can be used in several other conditions (often in conjunction with dextrose to maintain euglycemia).

  • Hyperkalemia:
    • Shifts K into cells
    • Temporary treatment used to acutely ↓ K levels
  • Hypertriglyceridemia-induced acute pancreatitis:
    • ↓ Fatty acid release from adipocytes
    • ↑ Triglyceride storage
    • ↓ Triglyceride levels
  • Beta-blocker and calcium channel blocker (CCB) toxicity:
    • Indicated in hemodynamically unstable individuals refractory to other treatments
    • ↑ Inotropy in myocytes by ↑ glucose uptake needed for aerobic metabolism
    • Overcomes insulin deficiency caused by beta-blocker’s effect on the pancreas

Adverse Effects and Contraindications

Adverse effects

  • Hypoglycemia: 
    • Confusion
    • Headache
    • Palpitations
    • Tachycardia
    • Diaphoresis
  • Weight gain after initiation
  • Edema
  • Anaphylaxis
  • Injection site:
    • Erythema
    • Swelling
    • Lipoatrophy

Contraindications

  • Hypokalemia (insulin drives K+ into cells)
  • Hypersensitivity
  • Hypoglycemia

Precautions

Dosing adjustments and close monitoring may be necessary for individuals with:

  • Hepatic impairment
  • Renal impairment

Drug interactions

  • ↑ Hypoglycemic effect with:
    • Other antidiabetic agents
    • Alcohol
    • Androgens
    • Beta-blockers
    • Direct-acting antiviral agents for hepatitis C
    • Monoamine oxidase inhibitors (MAOIs)
    • Salicylates
    • Sulfa antibiotics
  • ↑ Insulin dosing may be needed with:
    • Corticosteroids
    • Estrogens/oral contraceptives
    • Thiazide diuretics
    • Antipsychotics
    • Niacin

Comparison of Insulins

Table: Different types of available insulins
Insulin effectType of InsulinClassificationOnset of actionPeak of actionDuration of action
Fast actingLisproAnalog15–30 minutes1–3 hours4–6 hours
Aspart
Glulisine
Short actingRegularHuman30 minutes1.5–3.5 hours8 hours
Intermediate actingNPHHuman1–2 hours4–6 hours> 12 hours
Long actingDetemirAnalog1–2 hours3–9 hours14–24 hours
Glargine3–4 hoursNo peakApproximately 24 hours
DegludecApproximately 1 hourNo peak> 40 hours
Note: The pharmacokinetics are based on SC administration.
NHP: neutral protamine Hagedorn

References

  1. Donner, T. (2019). Insulin: Pharmacology, therapeutic regimens, and principles of intensive insulin therapy. Endotext. NCBI Bookshelf. NCBI. Retrieved August 22, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK278938/
  2. Weinstock, R. S. (n.d.). General principles of insulin therapy in diabetes mellitus. Uptodate. Retrieved August 2, 2021, from https://www.uptodate.com/contents/general-principles-of-insulin-therapy-in-diabetes-mellitus
  3. Durnwald, C. (n.d.). Gestation diabetes mellitus: Glycemic control and maternal prognosis. Uptodate. Retrieved August 2, 2021, from https://www.uptodate.com/contents/gestational-diabetes-mellitus-glycemic-control-and-maternal-prognosis
  4. Insulin Regular Drug Information (n.d.). Uptodate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/insulin-regular-drug-information
  5. Insulin glargine (n.d.). Medscape. Retrieved July 28, 2021, from https://reference.medscape.com/drug/lantus-toujeo-insulin-glargine-999003#4
  6. Types of Insulin (n.d.). UCSF Diabetes Education Online. Retrieved August 2, 2021, from https://dtc.ucsf.edu/types-of-diabetes/type2/treatment-of-type-2-diabetes/medications-and-therapies/type-2-insulin-rx/types-of-insulin/#intacting
  7. American Diabetes Association (2020). Management of diabetes in pregnancy. Standards of Medical Care in Diabetes. 43(1): S183–S192. Retrieved August 22, 2021, from https://care.diabetesjournals.org/content/43/Supplement_1/S183
  8. Brutsaert, E. F. (2020). Drug treatment of diabetes mellitus. MSD Manual Professional Version. Retrieved August 22, 2021, from https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/drug-treatment-of-diabetes-mellitus
  9. Nolte Kennedy, M. S. (2012). Pancreatic hormones and antidiabetic drugs. In Katzung, B. G., Masters, S. B., & Trevor, A. J. (Eds.), Basic & Clinical Pharmacology (12th ed., pp. 743–765). Retrieved August 22, 2021, from https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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