How does insulin lower blood glucose and what are its clinical indications?

How Insulin Works

Mechanism of Action

Insulin is the master regulator of glucose metabolism that lowers blood glucose by suppressing hepatic glucose production, stimulating glucose uptake into muscle and adipose tissue, inhibiting lipolysis, and promoting vasodilation in muscle. 1

Primary Glucose-Lowering Mechanisms

Following insulin secretion in response to elevated blood glucose, insulin works through four coordinated pathways 1:

• Suppression of hepatic glucose production - Insulin inhibits gluconeogenesis in the liver, which is the primary source of endogenous glucose between meals 1
• Stimulation of peripheral glucose uptake - Insulin promotes glucose transport into muscle, liver, and adipocytes 1
• Inhibition of lipolysis - By reducing plasma free fatty acid (FFA) levels, insulin indirectly enhances hepatic glucose suppression and muscle glucose uptake 1
• Vasodilation in muscle - Insulin causes blood vessel dilation in muscle tissue, which contributes to enhanced glucose disposal 1

Glucagon Suppression

Insulin also lowers blood glucose by suppressing glucagon secretion from pancreatic alpha cells 2. This is physiologically critical because excessive glucagon secretion is a major contributor to diabetic hyperglycemia 2. The mechanism involves modulation of K(ATP) channel activity and activation of the GABA-GABA(A) receptor system 2.

Clinical Indications for Insulin Therapy

Type 2 Diabetes

Insulin should be initiated when blood glucose levels are ≥300 mg/dL (≥16.7 mmol/L) or A1C >10% (>86 mmol/mol), or when patients have symptoms of hyperglycemia (polyuria, polydipsia) or evidence of catabolism (unexpected weight loss). 3

Preferred Initiation Strategy

• Start with basal insulin alone added to existing oral agents (metformin should continue; sulfonylureas should be discontinued) 3
• Basal insulin provides uniform coverage throughout the day and night, primarily suppressing hepatic glucose production between meals and during sleep 3
• Initial dosing: 0.1-0.2 units/kg/day, titrated based on fasting glucose 3

Insulin Formulation Selection

Long-acting basal insulin analogs (glargine U-100, detemir, glargine U-300, degludec) are preferred over NPH insulin because they reduce nocturnal hypoglycemia risk when titrated to the same fasting glucose target. 3, 4

However, NPH insulin (Novolin N) remains a reasonable option when cost is a barrier, as it costs approximately $25/vial compared to $165+ for analogs 4. In real-world settings with conventional treatment targets, NPH did not increase hypoglycemia-related emergency visits compared to analogs 4.

Progression to Prandial Insulin

When basal insulin alone is insufficient (fasting glucose <140 mg/dL but A1C remains >7%), add prandial insulin 5:

• Rapid-acting insulin analogs (lispro, aspart, glulisine) dosed just before meals provide better postprandial glucose control than regular insulin 3
• Start with 4 units or 10% of basal dose per meal 5
• Regular insulin (Novolin R) is a less expensive alternative but requires administration 30 minutes before meals due to slower onset 4

Hospitalized Patients

Insulin therapy should be initiated for persistent hyperglycemia starting at a threshold of 180 mg/dL (10.0 mmol/L), with a target glucose range of 140-180 mg/dL (7.8-10.0 mmol/L) for most critically ill and non-critically ill patients. 3

• Basal insulin or basal plus bolus correction insulin is the preferred regimen for non-critically ill hospitalized patients 3
• More stringent goals of 110-140 mg/dL may be appropriate for selected patients if achievable without significant hypoglycemia 3

Important Caveats

GLP-1 receptor agonists should be considered before insulin initiation in most patients without contraindications, as they allow lower glycemic targets with lower injection burden, lower hypoglycemia risk, and less weight gain than insulin alone. 3

When adding insulin or other glucose-lowering agents, reduce insulin doses by 10-20% to mitigate hypoglycemia risk 5. As glucose toxicity resolves with insulin treatment, simplifying the regimen and/or changing to non-insulin agents is often possible 3.