Insulin

Last updated: March 4, 2022

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Insulin is an anabolic peptide hormone that is produced and secreted from β cells located in the islets of Langerhans of the pancreas. By modulating glucose absorption from the blood, insulin lowers blood glucose levels. Further important metabolic functions of insulin include the promotion of carbohydrate, amino acid, and fat storage in the liver, skeletal muscle, and adipose tissues. There are several insulin analogs (e.g., insulin glargine) with a different molecular structure but similar properties to human insulin, with differences mainly in the onset, peak, and duration of action. Insulin therapy is an important part of treatment for individuals with no or insufficient insulin production (e.g., diabetes mellitus, gestational diabetes). It is crucial that patients receiving insulin therapy undergo in-depth training to prevent potentially life-threatening conditions such as hypoglycemia as a result of an insulin overdose or drug interactions.

See also “Antihyperglycemic treatment of diabetes mellitus” and “Inpatient management of hyperglycemia.”

For synthesis and regulation of insulin see “Endocrine pancreas.”

Overview of the different types of insulin
Types of insulin Pharmacokinetics [1] Application [2][3] Additional considerations [1]
Rapid-acting insulin
Insulin lispro
  • Onset: 5–15 minutes
  • Peak: ∼ 1 hour
  • Duration: 3–4 hours
  • Insulin analogs
  • Rapid absorption due to immediate dissociation into individual insulin molecules
  • No time interval between injection and meal necessary
  • Usually combined with long-acting insulin
Insulin aspart
Insulin glulisine
Short-acting insulin
Regular insulin
  • Onset: ∼ 30 minutes
  • Peak: 2–3 hours
  • Duration: 4–6 hours
  • Recommended interval between injections and meals: 15–30 minutes
  • Often used in combination with long-acting insulin
  • The only insulin available for intravenous use
Intermediate-acting insulin
NPH insulin
  • Onset: 1–2 hours
  • Peak: 6–10 hours
  • Duration: 10–16 hours
  • Crystalline suspension consisting of regular insulin (with a high level of solubility) and protamine (with a low level of solubility)
  • Recommended interval between injections and meal, if it is the only antidiabetic drug used: 30–60 minutes
  • Often used in combination with rapid-acting or short-acting insulin
  • Usually administered twice daily
Long-acting insulin
Insulin glargine
  • Onset: 1–4 hours
  • Peak: flat; not defined
  • Duration: ∼ 24 hours
  • Insulin analogs
  • More consistent effect and longer duration of action compared to NPH insulin
  • Often used in combination with rapid or short-acting insulin
  • Administered once or twice daily
Insulin detemir
Insulin degludec
Mixed insulin
Mixed insulin
  • Typically a mixture of NPH insulin and either rapid-acting insulin or regular insulin, in a predefined ratio
  • Administered 2–3 times daily
  • Only requires one injection per application without the need to mix fast- and intermediate-acting insulin

Rapid-acting insulins are your favorite GAL pals (Glulisine, Aspart, Lispro).

Insulin function and metabolic effects

Metabolic actions of insulin
Increases Decreases
Carbohydrate metabolism
Lipid metabolism
Protein metabolism
  • Proteolysis
  • Other physiologic actions of insulin
    • Cellular uptake of potassium [10]
    • Sodium retention by the kidney [11]
    • Ovarian androgen hypersecretion [12]
    • Decreased fibrinolytic activity [13]
    • Secretion of gastric acid [14]
    • Cell growth and differentiation [15][16]

Cellular and insulin-mediated uptake of glucose

The absorption time determines the onset, peak, and duration of effect. [17]

  • Prolonged insulin absorption time
    • Cold injection site
    • Obesity
    • Peripheral injection site
    • Superficial subcutaneous injection
  • Shorter insulin absorption time
    • Manipulative therapy (e.g., massages)
    • Deep subcutaneous injection
    • Injection into the abdominal skin around the navel

We list the most important adverse effects. The selection is not exhaustive.

Certain drugs can either increase or decrease insulin demand. [25]

Insulin regimens should be tailored individually to each patient. There are a variety of options for patients with T2DM. Treatment of T1DM requires intensive insulin therapy with a multi injection regimen or insulin pump.

Basal insulin regimens [28]

  • Description: Basal insulin is added to an oral antidiabetic drug regimen.
  • Indication: T2DM with persistently elevated A1C levels despite adequate treatment with noninsulin antidiabetics
  • Treatment options
    • Once-daily injection (recommended starting regimen)
    • Twice-daily NPH insulin: Consider for patients not meeting their glycemic target with bedtime NPH.
      • Starting dose: 80% of the previously prescribed bedtime NPH insulin dose, with two-thirds given in the morning and one-third at bedtime
  • Titration
    • Adjust according to glycemic monitoring.
      • Levels above target: Increase insulin dose by 2 units every 3 days until preprandial fasting glucose target is met.
      • If hypoglycemia due to insulin therapy occurs, reduce insulin dose by 10–20%.
    • If treatment remains insufficient despite appropriate adjustments , intensify treatment by either adding prandial insulin or considering a mixed regimen.

Not all noninsulin antidiabetics can be combined with insulin. Combination therapy with insulin and sulfonylureas should be avoided because of the risk of hypoglycemia and increased mortality! Once insulin is started, consider tapering and eventual discontinuation of sulfonylureas. Insulin combined with pioglitazone increases the risk of edema, weight gain, and congestive heart failure. Metformin is usually continued.

Addition of prandial insulin [28]

  • Description
  • Indication: T2DM that is not adequately controlled with basal insulin alone
  • Starting dose
    • Basal insulin injections are continued at the previous dose.
    • 4 units of short-acting or rapid-acting insulin before chosen meals
  • Titration: Adjust according to glycemic monitoring.
    • Increase prandial insulin dose by 1–2 units twice weekly until preprandial fasting glucose target is met.
    • If hypoglycemia occurs, reduce the corresponding prandial insulin dose by 10–20%.

Mixed insulin regimens [28]

  • Description
  • Indication: Consider for patients with T2DM who are not meeting glycemic targets with a basal insulin regimen.
  • Starting dose
  • Titration
    • Adjust according to glycemic target.
    • If treatment results remain inadequate, consider a full basal-bolus regimen.

Mixed insulin regimens are simpler to use and reduce the number of injections required, as both types of insulin are combined into one injection.

Intensive insulin therapy [28][29]

This regimen provides optimal glycemic control as well as more flexibility in the daily diet and exercise plan, and it reduces the risk of complications in patients with good adherence.

  • Indications
  • Full basal-bolus regimen: basal regimen with additional short-acting or rapid-acting insulin bolus before every major meal
  • Insulin pump [30]
    • Insulin (usually a rapid-acting insulin analog) is subcutaneously infused through a small device attached to the skin.
    • Basal rates and bolus insulin can be separately tailored to the patient's needs.
    • May be beneficial in patients with dawn phenomenon

The goal of intensive insulin therapy is to simulate physiological glucose metabolism (e.g., by keeping fasting blood glucose levels < 100 mg/dL (5.6 mmol/L) and postprandial blood glucose levels < 140 mg/dL (< 7.8 mmol/L).

Patients on a full basal-bolus regimen require intensive education, high motivation, and commitment, as this is the most complex and time-consuming treatment for diabetes and has an increased risk for hypoglycemia.

Full Basal-bolus insulin regimen [2][3][31]

Basal-bolus regimens may vary. Institutional standards should be followed and intensive insulin therapy tailored individually to each patient.

  1. Calculate the total daily dose of insulin (TDD) needed.
    • If the patient is already on a correction scale: Increase or decrease TDD by 10–20% as needed.
    • If the patient is aged ≥ 70 years, and/or has GFR < 60 mL/min: 0.2–0.3 units/kg
    • If none of the above criteria apply, use the blood glucose level:
      • BG 140–200 mg/dL: 0.4 units/kg
      • BG > 200 mg/dL: 0.5 units/kg
  2. Divide the TDD of insulin into basal insulin (50%) and nutritional insulin (50%).
    • Basal insulin: administer as long-acting insulin (e.g., glargine) at bedtime
    • Prandial insulin: administer as rapid-acting insulin (e.g., lispro) in equally divided doses before meals
  3. Consider adding a correction bolus before each meal estimated with one of the following methods:
    • Insulin correction factor [31][32]
      • Divide 1500 (for short-acting insulin) or 1800 (for rapid-acting insulin) by the total daily dose of insulin
      • The result is the blood glucose level (in mg/dL) that 1 additional unit of insulin is expected to lower for a specific individual.
      • 1–2 units of insulin typically lower the blood glucose level by ∼ 30–50 mg/dL
    • Insulin-to-carbohydrate ratio (ICR) [31][32]
      • Divide 500 by the total daily dose of insulin.
      • The result is the carbohydrates (g) that 1 unit of insulin is expected to lower for a specific patient.
      • An adult typically requires 1 unit of insulin for 10 g of carbohydrates, although this varies greatly from patient to patient. [33]
  4. Adjust as needed.
    • In cases of hypoglycemia < 70 mg/dL: Reduce basal insulin by 20% and/or reduce correction bolus.
    • If fasting glucose is persistently > 140 mg/dL and no episodes of hypoglycemia occur: Increase basal insulin by 20% and/or increase correction bolus.

Decrease or hold nutritional insulin if the patient is NPO.

Principles of insulin adjustment

Sliding-scale insulin regimen [3]

Sliding-scale insulin regimens vary and institutional standards should be followed. Sliding-scale regimens alone should not be used for the long-term management of diabetes.

Administration of sliding scale insulin (example)
Blood glucose (mg/dL) Insulin units
Insulin sensitive Usual insulin Insulin resistant
71–140 0 0 0
141–180 2 4 6
181–220 4 6 8
221–260 6 8 10
261–300 8 10 12
301-350 10 12 14
351-400 12 14 16

If blood glucose is < 70 mg/dL, hold all insulin and administer measures to control hypoglycemia.

Insulin regimens for glucocorticoid-induced hyperglycemia

Prednisone dose equivalent (mg/day) NPH (units/kg/day)
10 0.1
20 0.2
30 0.3
≥ 40 0.4

NPH doses should be administered in addition to usual basal insulin in patients who are already receiving insulin.

Consider using glargine or detemir in patients receiving dexamethasone. Dexamethasone has a longer hyperglycemic effect than prednisone and most other commonly used systemic glucocorticoids.

Insulin regimens for enteral and parenteral nutrition

Enteral nutrition [36][37]

  1. Determine basal insulin needs.
    • For patients already on insulin: Continue prior dose or administer 30–50% of the total daily dose as long-acting insulin (e.g., glargine) daily.
    • For patients not already on insulin, consider:
      • 5 units of NPH every 12 hours
      • or 10 units of glargine (or equivalent) daily
  2. Add nutritional insulin.
    • For patients receiving continuous tube feedings
      1. Calculate the total daily nutritional insulin dose:
        • 1 unit of insulin per 10–15 g of carbohydrates per day
        • or 50–70% of the total daily dose
      2. Administer as rapid-acting insulin (e.g., lispro) in divided doses every 4–6 hours.
    • For patients receiving bolus feeding
      1. Calculate the nutritional insulin dose to cover each meal: 1 unit of insulin per 10–15 g of carbohydrates per meal
      2. Administer as rapid-acting insulin (e.g., lispro) before each feeding.
  3. Add sliding scale insulin as supplemental insulin.
  4. Adjust as needed to glycemic targets, changes in medication, and changes in nutrition.

Patients with type 1 diabetes mellitus require basal insulin even if (enteral) feeding is discontinued.

Total parenteral nutrition (TPN) [36][38]

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