Twincritin

Tirzepatide

Type 2 diabetes is no longer seen as pure insulin deficiency (traditional view) but as a dual defect — insulin failure and glucagon excess. Tirzepatide corrects both by mimicking GLP-1 (suppressing glucagon) and GIP (enhancing insulin sensitivity) — restoring the incretin balance for superior glucose and weight control. 

Modern view: The “bihormonal hypothesis" - Dr. Roger Unger (1975) first proposed that glucagon excess is as important as insulin deficiency in causing hyperglycemia.

Glucagon: In T2DM, α-cells fail to suppress glucagon after meals. Even with high glucose (post-meal), glucagon rises → worsens postprandial hyperglycemia. 

Incretin effect = Gut hormones (GLP-1 & GIP) cause extra insulin release after oral glucose. GLP-1 & GIP are the incretin hormones that boost insulin. DPP-4 is an enzyme that destroys incretins → blocking it prolongs their effect. The incritin defect in T2DM are 1. ↓ GLP-1 secretion & 2. Impaired β-cell response to GIP

Role of Incretin in Glucagon Control

1. GLP1; Glucagon-like peptide-1

   • 1. Directly suppresses α-cell glucagon secretion.

     2. Delays gastric emptying, reducing glucose spikes that trigger glucagon.

     3. Enhances insulin only when glucose is high.

     4. ↓ Appetite/food intake via CNS

2. GIP: Glucose-Dependent Insulinotropic Polypeptide

   • 1. Normally stimulates glucagon during hypoglycemia (protective).

     2. ↑ Insulin secretion (glucose-dependent)

     3. In T2DM, α-cells are hypersensitive to GIP → excess glucagon output.

     4. But when combined with GLP-1 (as in tirzepatide), the GLP-1 dominance suppresses this pathologic glucagon surge.

3. DPP4: Dipeptidyl Peptidase-4

   • 1. Shortens incretin half-life (GLP-1 ≈ 2 min)

     2. Reduces insulinotropic effect

     3. DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, linagliptin) — prolong endogenous incretin action.

In type 2 diabetes, the incretin effect is blunted:

1. GLP-1 secretion is reduced, and

2. β-cell response to GIP is impaired.

So, less insulin is secreted after meals → postprandial hyperglycemia.

Therapeutic exploitation:

• GLP-1 receptor agonists (e.g., liraglutide, semaglutide) mimic GLP-1 to restore the incretin effect. 

• DPP-4 inhibitors (e.g., sitagliptin, linagliptin) prevent incretin breakdown, prolonging their action.

• Tirzepatide takes it further — mimicking both GLP-1 and GIP, amplifying insulin secretion and improving metabolic control.