Insulin

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.”

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

Insulin function and metabolic effects

• Insulin binds to insulin receptors (a type of tyrosine kinase receptor) located in various tissues in the body (e.g., liver, skeletal muscle, adipose tissue, cell membranes). ^[4]
• In target tissues, insulin acts as an anabolic hormone.

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

• Glucose may enter cells throughout the body via a variety of transporters.
• Different tissue types have unique glucose transporters (e.g., GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5), some of which are insulin-dependent and some of which are insulin-independent.
• See “Important glucose transporters” in "Carbohydrates.”

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

• Type 1 diabetes mellitus ^[2]
• Type 2 diabetes mellitus ^[18][19]
  • Indicated if weight normalization, physical activity, and oral antidiabetic drugs do not keep blood glucose levels in the target range.
  • Patients with end-stage renal failure should have doses of insulin titrated according to the glomerular filtration rate. ^[20]
• Exocrine pancreatic insufficiency with secondary diabetes
• Gestational diabetes mellitus
• Acute hyperkalemia: A drip containing regular insulin and a solution of glucose reduces blood potassium levels.
• See “Insulin therapy” in “Diabetes mellitus” and “Inpatient management of hyperglycemia.”

• Hypoglycemia ^[21]
• Weight gain ^[22]
• Lipodystrophy at the injection site ^[23]
• Hypokalemia
• Allergic or hypersensitivity reactions
• Edema ^[24]
• Pain and erythema at the injection site

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

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

Increased insulin demand

• Thiazide diuretics and loop diuretics

• Heparin
• Glucocorticoids
• Immunosuppressive drugs (e.g., calcineurin inhibitors)
• Tricyclic antidepressants
• Antipsychotic drugs ^[26]
• Lithium ^[27]
• HIV-protease inhibitors
• Thyroid hormones
• Estrogen (contraceptives)
• Sympathomimetic drugs that interact with the β₁-adrenergic receptor (e.g., dobutamine)
• Derivatives of nicotinic acid

Decreased insulin demand

• Analgesics (e.g., NSAIDs, tramadol)

• Antibiotics (e.g., cotrimoxazole and other sulfonamides , fluoroquinolones)
• Antimalarial drugs (e.g., mefloquine, quinine)
• MAO inhibitors
• Fibrates
• Haloperidol

Either increased or decreased insulin demand

• Ethanol

• Beta blockers

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)
    • Long-acting insulin (e.g., glargine) OR bedtime NPH insulin
    • Starting dose: 10 units/day OR 0.1–0.2 units/kg/day
  • 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
  • Short-acting insulin or rapid-acting insulin is injected before major meals in patients already on a basal insulin regimen.
  • Prandial insulin can be added before one meal (the largest meal of the day) or several meals.
• 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
  • Twice-daily injections of a fixed combination of NPH mixed with either short-acting insulin or rapid-acting insulin; can be self-mixed or premixed
  • Simple regimens that require minimal patient education and time
• Indication: Consider for patients with T2DM who are not meeting glycemic targets with a basal insulin regimen.
• Starting dose
  • Self-mixed insulin
    • Calculate 80% of the current NPH dose.
    • Add 4 units of short-acting or rapid-acting insulin per injection.
  • Premixed insulin: Use the same previous total insulin dose (i.e., the same as for the twice-daily NPH regimen).
• 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
  • T1DM
  • T2DM that cannot be sufficiently managed otherwise
  • Gestational diabetes mellitus
• 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

• Preprandial glucose
  • Mainly affected by the basal insulin dose
  • Daily capillary early morning measurements and measurements before applying an insulin dose are advised.
• Postprandial glucose is mainly affected by meal intake and prandial insulin dose.
• Certain conditions require temporary insulin adjustments.
  • Increased insulin demand
    • Illness
    • Stress
  • Decreased insulin demand
    • Physical exercise: Increase carbohydrate intake and/or reduce prandial and/or basal insulin either before or after exercise. ^[21][34]
      • Moderate intensity exercise: Reduce 50% of meal insulin.
      • High intensity exercise: Reduce 75% of meal insulin.
      • Patients on multiple daily insulin injections: reduce daily basal insulin by 20% on the day of exercise ^[34]
      • Encourage glucose self-monitoring to reach appropriate insulin reduction and/or need for snacks.
    • Vomiting and diarrhea: can lead to decreased glucose uptake, increasing the risk of hypoglycemia
• Fasting, e.g., for surgery (see “Preoperative medication management” and “Fasting guidelines for elective surgery.”)

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.

• If the patient is eating all or most of each meal: Administer as short-acting insulin (or rapid-acting insulin) before each meal and at bedtime.
• If the patient is not eating: Administer as short-acting insulin every 6 hours.

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

Insulin regimens for glucocorticoid-induced hyperglycemia

• Basal-bolus insulin regimen (preferred)
  • Consider splitting the total daily dose of insulin 30/70 (i.e., 30% long-acting insulin and 70% prandial short-acting insulin).
  • Patients usually require about 0.4 units/kg/day but in patients receiving dexamethasone, insulin doses as high as 1.0–1.2 units/kg/day may be necessary. ^[35]
  • The total required insulin dosage depends on individual patient factors (e.g., prior insulin sensitivity) and the potency of the steroid.
• Sliding-scale insulin regimen: may be adequate for short-term management
• Weight-based NPH insulin regimen ^[36]
  • Convert glucocorticoid to equivalent prednisone dose (see “Glucocorticoids”).
  • Calculate daily NPH dose based on prednisone dose equivalent and patient weight.
  • Administer glucocorticoid with NPH as a single dose in the morning.

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 ^[37][38]

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.
   • For patients on continuous tube feedings: Administer rapid-acting insulin (e.g., lispro) every 4 hours or regular insulin every 6 hours.
   • For patients receiving bolus feedings: Administer rapid-acting insulin before every meal.
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) ^[37][39]

• Add short-acting insulin to IV parenteral nutrition solution.
  • Diabetic patient: 1 unit per 10–15 g dextrose
  • Nondiabetic patient: 0.5 units per 10 g dextrose
• Add sliding scale insulin as supplemental insulin: Administer as short-acting insulin (e.g., regular insulin) every 6 hours or rapid-acting insulin (e.g., lispro) every 4 hours.
• Adapt protocol to glycemic targets, changes in medication, and changes in nutrition.

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