What are the different types and modes of action of insulin?

Insulin Classification and Mode of Action

Primary Mechanism of Action

Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake (especially by skeletal muscle and fat) and by inhibiting hepatic glucose production, while also inhibiting lipolysis and proteolysis and enhancing protein synthesis. 1

Classification by Duration of Action

Insulins are classified into four main categories based on their pharmacokinetic profiles 2:

Rapid-Acting Insulin Analogs

• Onset: 5 minutes after subcutaneous injection 2
• Peak effect: 1-2 hours 2
• Duration: 3-4 hours 2
• Examples: Insulin aspart, insulin lispro, insulin glulisine 3, 4
• Clinical use: Primarily control postprandial glucose levels and can be injected just before meals 2, 5
• Pharmacodynamics: Maximum glucose-lowering effect occurs between 1-3 hours after injection, with median time to maximum concentration of 40-50 minutes 1

Short-Acting (Regular) Insulin

• Onset: 15 minutes after subcutaneous injection 2, 6
• Peak effect: 3-4 hours 2, 6
• Duration: 6-8 hours 2, 6
• Clinical consideration: The extended duration creates higher risk of late postprandial hypoglycemia, particularly if meals are delayed or physical activity increases 6

Intermediate-Acting Insulin

• Example: NPH (Neutral Protamine Hagedorn) insulin 7
• Clinical profile: Less flat activity profile compared to long-acting analogs, with more pronounced peaks 7
• Special formulation: U-500 insulin has delayed onset and longer duration similar to intermediate-acting insulin, indicated for patients requiring more than 200 units daily 2

Long-Acting (Basal) Insulin Analogs

• Examples: Insulin glargine (U-100, U-300), insulin detemir, insulin degludec 7, 3
• Characteristics: Longer duration of action with flatter, more constant plasma concentrations and activity profiles than NPH insulin 7
• Clinical advantages: Associated with less hypoglycemia and weight gain compared to NPH insulin 7, 3
• Insulin degludec: Mean half-life of 25.4 hours with duration of action >42 hours and low variability 3

Comparative Clinical Outcomes

Rapid-Acting Analogs vs Regular Human Insulin

• Better postprandial glucose control with rapid-acting analogs due to faster onset and shorter duration 3, 8
• Less hypoglycemia overall, with decreased frequency of both severe and nocturnal hypoglycemia 8
• Greater convenience as they can be injected immediately before meals rather than 30 minutes prior 5

Long-Acting Analogs vs NPH Insulin

• Lower absolute risk of hypoglycemia with long-acting analogs, though they are more expensive 2
• Better fasting glucose control and reduced nocturnal hypoglycemia risk 4
• Newer formulations (U-300 glargine, degludec) may confer even lower hypoglycemia risk compared to U-100 glargine in type 1 diabetes 7

Dosing Principles for Type 1 Diabetes

• Total daily insulin requirement: Typically 0.4-1.0 units/kg/day, with 0.5 units/kg/day as a typical starting dose in metabolically stable patients 7
• Basal-bolus distribution: Approximately 50% of daily insulin as basal and 50% as prandial 7
• Basal insulin: Titrated to regulate overnight and fasting glucose 7
• Prandial insulin: Timing varies based on formulation pharmacokinetics, premeal blood glucose level, and carbohydrate consumption 7

Absorption Variability

• Injection site affects absorption rate: Abdomen has fastest absorption, followed by arms, thighs, and buttocks 2, 9
• Exercise increases absorption at injection sites due to increased blood flow 2
• Site rotation within same area is recommended to reduce day-to-day variability in absorption 2, 9

Common Pitfalls

• Insulin detemir has lower intraindividual variability than both NPH and glargine, which may contribute to lower hypoglycemia rates 4
• Time course of action may vary considerably between individuals or within the same individual, so designated parameters should be considered general guidelines only 1
• Proper storage and handling is essential for maintaining insulin effectiveness 9