Insulin

Insulin is a peptide hormone that is produced by the beta cells of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. 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 Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, weight gain after initiation of an insulin regimen, and local injection site changes.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Skeletal muscle
    • Adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. 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 Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. 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 Thigh The thigh is the region of the lower limb found between the hip and the knee joint. There is a single bone in the thigh called the femur, which is surrounded by large muscles grouped into 3 fascial compartments. Thigh
  • Other factors that may have an effect:
    • Exercise
    • Temperature
    • Local blood supply

Excretion

  • Insulin is cleared through the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. 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 NPH Normal pressure hydrocephalus (NPH) is a neurodegenerative disorder characterized by the triad of gait abnormalities, dementia, and urinary urgency or incontinence. Normal pressure hydrocephalus can be either idiopathic or secondary to intraventricular or subarachnoid hemorrhage. Normal Pressure Hydrocephalus)
  • 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 Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:
    • Individuals with type 1 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. 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 Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. 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 Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises)
  • Hyperosmolar hyperglycemic state Hyperosmolar hyperglycemic state Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises
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 Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia:
    • Shifts K into cells
    • Temporary treatment used to acutely ↓ K levels
  • Hypertriglyceridemia-induced acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. 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 Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas

Adverse Effects and Contraindications

Adverse effects

  • Hypoglycemia: 
    • Confusion
    • Headache
    • Palpitations
    • Tachycardia
    • Diaphoresis
  • Weight gain after initiation
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Anaphylaxis
  • Injection site:
    • Erythema
    • Swelling
    • Lipoatrophy

Contraindications

  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. 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 Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
    • Beta-blockers
    • Direct-acting antiviral agents for hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus
    • Monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors (MAOIs)
    • Salicylates
    • Sulfa antibiotics
  • ↑ Insulin dosing may be needed with:
    • Corticosteroids
    • Estrogens/oral contraceptives
    • Thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics
    • Antipsychotics
    • Niacin

Comparison of Insulins

Table: Different types of available insulins
Insulin effect Type of Insulin Classification Onset of action Peak of action Duration of action
Fast acting Lispro Analog 15–30 minutes 1–3 hours 4–6 hours
Aspart
Glulisine
Short acting Regular Human 30 minutes 1.5–3.5 hours 8 hours
Intermediate acting NPH NPH Normal pressure hydrocephalus (NPH) is a neurodegenerative disorder characterized by the triad of gait abnormalities, dementia, and urinary urgency or incontinence. Normal pressure hydrocephalus can be either idiopathic or secondary to intraventricular or subarachnoid hemorrhage. Normal Pressure Hydrocephalus Human 1–2 hours 4–6 hours > 12 hours
Long acting Detemir Analog 1–2 hours 3–9 hours 14–24 hours
Glargine 3–4 hours No peak Approximately 24 hours
Degludec Approximately 1 hour No 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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