Insulin Therapy

Insulin is the most effective glucose-lowering therapy available.

It replaces or supplements endogenous insulin when pancreatic beta-cell function is inadequate or absent.

Used in:

Type 1 Diabetes (required)
Advanced Type 2 Diabetes
DKA / HHS
Severe hyperglycemia
Hospital settings

→ Diabetes Pharmacology

Mechanism of Action

Insulin binds to the insulin receptor (a tyrosine kinase receptor).

This activates:

IRS signaling pathways
PI3K/Akt cascade
GLUT4 translocation (muscle & adipose)

Effects:

Liver:

↓ Gluconeogenesis
↑ Glycogen synthesis
↑ Lipogenesis

Muscle:

↑ Glucose uptake
↑ Glycogen storage

Adipose:

↑ Glucose uptake
↓ Lipolysis

Insulin is anabolic.

Insulin Comparison Table

Type	Agent	Onset	Peak	Duration	Dosing Role	Key Features
Rapid-Acting	Lispro	10–15 min	~1 hr	3–5 hr	Mealtime	Rapid absorption, less stacking
Rapid-Acting	Aspart	10–20 min	1–3 hr	3–5 hr	Mealtime	Structurally modified, rapid profile
Rapid-Acting	Glulisine	10–20 min	~1 hr	3–5 hr	Mealtime	Rapid analog, comparable to lispro/aspart
Short-Acting	Regular	30–60 min	2–4 hr	6–8 hr	Mealtime / IV use	Only insulin used IV (DKA, HHS)
Intermediate	NPH	1–2 hr	4–8 hr	12–18 hr	Basal (older regimens)	Protamine-bound, clear peak
Long-Acting	Glargine	1–2 hr	Minimal	~24 hr	Basal	pH-dependent precipitation
Long-Acting	Detemir	1–2 hr	Minimal	12–24 hr	Basal	Albumin binding, may require BID
Ultra-Long	Degludec	~1 hr	None	>42 hr	Basal	Multi-hexamer depot, very stable

Types of Insulin

Insulins are categorized by onset and duration.

Rapid-Acting (Mealtime)

Onset: 10–30 minutes Duration: 3–5 hours

Used for:

Mealtime glucose control
Correction dosing

Short-Acting

Regular Insulin

Onset: 30–60 minutes Duration: 6–8 hours

Used in:

IV infusion (DKA)
Some prandial regimens

Intermediate-Acting

Duration: ~12–18 hours

Older basal insulin option.

Long-Acting (Basal)

Provide steady background insulin.

Ultra-Long Acting

Degludec

Very flat, prolonged profile (>24 hours).

Basal-Bolus Concept

Physiologic insulin secretion includes:

Basal insulin (background suppression of hepatic glucose production)
Bolus insulin (mealtime glucose control)

Modern therapy mimics this:

Basal insulin:

Once daily (glargine, degludec)

Bolus insulin:

Rapid-acting insulin before meals

This is the most physiologic regimen.

Initiating Insulin (Type 2)

Step 1:

Start basal insulin
Titrate based on fasting glucose

Step 2:

Add prandial insulin if needed

Continue:

Metformin when possible
Consider combination with:
- GLP-1 Receptor Agonists
- SGLT2 Inhibitors

Adverse Effects

Common:

Hypoglycemia
Weight gain

Serious:

Severe hypoglycemia
Hypokalemia (high-dose therapy)

Hypoglycemia symptoms:

Sweating
Tremor
Confusion
Seizures (severe)

DKA & HHS

Insulin deficiency leads to:

Unchecked lipolysis
Ketone production
Metabolic acidosis (DKA)

Treatment requires:

IV Regular Insulin
Fluid resuscitation
Electrolyte management

Insulin vs Other Therapies

Compared to:

Sulfonylureas → direct replacement vs stimulation
Metformin → more potent glucose lowering
GLP-1 Receptor Agonists → more hypoglycemia, more weight gain
SGLT2 Inhibitors → no intrinsic CV benefit

Insulin is unmatched in glucose-lowering potency.

Clinical Pearls

Most potent antihyperglycemic therapy
Required in Type 1 Diabetes
Basal suppresses hepatic glucose output
Bolus controls meals
Causes weight gain
Hypoglycemia is primary risk
Continue metformin when possible