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 noninsulin 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

General principles

• Insulin regimens should be tailored individually to each patient.
• Treatment of T1DM requires intensive insulin therapy with a multi injection regimen or insulin pump.
• There are a variety of options for patients with T2DM.
• Certain diabetes medications (e.g., sulfonylureas) should be stopped when insulin therapy is started.
• Hospital standards vary; specialists should be involved early.

Not all noninsulin diabetes medications 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.

Basal insulin regimens ^[28]

• Description: Basal insulin is added to an oral diabetes medication regimen.
• Indication: : initiated if there are indications for insulin therapy in T2DM (e.g., 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 is insufficient despite adjustments, intensify therapy by either:
    • Adding prandial insulin
    • Switching to mixed insulin regimen

Prandial insulin ^[28]

• Description
  • Short-acting, rapid-acting, ultra-rapid-acting, or inhaled human insulin administered 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
  • Part of full basal-bolus insulin regimen (e.g., in T1DM)
• Starting dose
  • Basal insulin injections are continued at the previous dose.
  • Prandial insulin dosed at 4 units (or 10% of daily basal insulin dose) before chosen meals.
• Titration: Adjust according to glycemic monitoring.
  • Increase prandial insulin dose by 1–2 units (or 10–15%) 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
  • Administered as two-thirds of the total daily dose 30 minutes before breakfast and one-third 30 minutes before dinner.
  • 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 split insulin
    • Calculate 80% of the current NPH dose.
    • Add 4 units (or 10% of the NPH dose) 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 of diabetes 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).

Full basal-bolus insulin regimen ^[3][31]

• 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 lean, has T1DM, is aged ≥ 70 years, and/or has a GFR < 60 mL/minute: 0.2–0.3 units/kg
  • If none of the above criteria apply, use the blood glucose level:
    • Blood glucose 140–200 mg/dL: 0.4 units/kg
    • Blood glucose > 200 mg/dL: 0.5 units/kg
• Divide the TDD of insulin into basal insulin (50%) and prandial 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.
• Add correction insulin therapy.
  1. Take 5% of the TDD (e.g., 5% of a 60 unit TDD is 3 units); round down to the nearest whole number dose if necessary.
  2. Increase the prandial insulin dose by this increment for every 40 mg/dL (2.2 mmol/L) above the glycemic target of 140 mg/dL.
• Adjust as needed.
  • If fasting or mean glucose persistently > 140 mg/dL and no episodes of hypoglycemia: Increase basal insulin by 20%.
  • If fasting or premeal glucose persistently > 140 mg/dL and no episodes of hypoglycemia: Increase prandial insulin by 2 units.
  • In case of hypoglycemia < 70 mg/dL: Reduce basal insulin by 20% and/or prandial insulin by 2 units.

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.

Decrease or hold prandial 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][32]
      • 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. ^[32]
      • 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.”)

Correction insulin therapy ^[2][3]

• Rapid-acting or regular insulin that is administered before meals (based on the premeal blood glucose level) or every 4–6 hours (in patients who are not eating).
• Used alone or in combination with scheduled insulin therapy.

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

Sliding-scale insulin regimen ^[3]

• Description: rapid-acting or short-acting insulin used to treat a given level of hyperglycemia and often given independent of food intake, prior insulin administration, or insulin sensitivity
• Correction insulin therapy is typically preferred; institutional standards should be followed.
• Sliding-scale regimens alone should not be used for the long-term management of diabetes.

Use of sliding scale insulin therapy alone without basal insulin is discouraged in the inpatient setting. ^[33]

Insulin regimens for glucocorticoid-induced hyperglycemia

• Basal-bolus insulin regimen (preferred)
  • Consider splitting the total daily dose 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. ^[34]
  • The total required insulin dosage depends on individual patient factors (e.g., prior insulin sensitivity) and the potency of the steroid.
• Correction insulin therapy: may be adequate for short-term management
• Weight-based NPH insulin regimen
  • Convert glucocorticoid to equivalent prednisone dose.
  • Calculate daily NPH dose based on weight and prednisone dose equivalent.
  • Administer glucocorticoid with NPH as a single dose in the morning.
  • Consider adding basal insulin if the patient is on long-acting glucocorticoids.
  • Adjust insulin doses (e.g., correction insulin) if the patient is on high-dose glucocorticoids.

In patients with glucocorticoid-induced hyperglycemia who are already receiving insulin, administer NPH insulin in addition to the patient's usual basal insulin regimen.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

Basal-bolus insulin therapy for patients receiving enteral nutrition ^[33]

• For patients already on insulin: Continue prior basal dose.
• Patients receiving continuous enteral feedings
  • Prandial insulin
    • 1 unit of insulin per 10–15 g of carbohydrates per day
    • Administer as NPH every 8–12 hours or regular insulin every 6 hours.
  • Correction insulin: Administer rapid-acting insulin (e.g., lispro) every 4 hours or regular insulin every 6 hours.
• Patients receiving bolus feedings
  • Prandial insulin
    • 1 unit of insulin per 10–15 g of carbohydrates per meal
    • Administer as rapid-acting insulin (e.g., lispro) or regular insulin before each feeding.
  • Correction insulin: Administer rapid-acting insulin before every meal.
• Start a dextrose infusion to prevent hypoglycemia if enteral nutrition is interrupted.
• Adjust as needed to glycemic targets, changes in medication, and changes in nutrition.

Abrupt discontinuation of enteral feeding in patients receiving insulin can result in hypoglycemia.

Patients with T1DM require basal insulin even if feeding is discontinued.

Insulin therapy for patients receiving total parenteral nutrition (TPN) ^[33][35]

• Add regular insulin to IV parenteral nutrition solution.
  • Patients with diabetes: 1 unit per 10 g dextrose
  • Patients without diabetes: 0.5 units per 10 g dextrose
• Add correction 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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