Flowchart: Mechanism of Insulin Secretion from Pancreatic β Cell

PATHWAY 1 - K-ATP Channel Pathway (SU / Meglitinide)

GLUCOSE enters β cell
        ↓
Glucose metabolism → ATP production
        ↓
ATP binds to K-ATP channel (SUR1 subunit)
        → K-ATP channel CLOSES
        ↓
K⁺ efflux stops → [K⁺] accumulates intracellularly
        ↓
Membrane DEPOLARIZATION
        ↓
Voltage-gated Ca²⁺ channels OPEN
        ↓
Ca²⁺ influx into the cell
        ↓
Intracellular Ca²⁺ rises
        ↓
Insulin granule exocytosis
        ↓
INSULIN released into circulation

SU (Sulfonylureas) e.g. Glibenclamide
Meglitinides (Megli) e.g. Repaglinide
        ↓
Bind directly to SUR1 receptor
        → CLOSE K-ATP channel independent of glucose/ATP
        → Same downstream cascade → INSULIN RELEASE

PATHWAY 2 - Incretin Pathway (GLP-1 / GIP)

Food intake (especially carbs/fat)
        ↓
Gut releases GLP-1 and GIP
(incretins from intestinal L and K cells)
        ↓
GLP-1 / GIP bind to Incretin Receptor on β cell surface
        ↓
Receptor couples to Gs protein
        ↓
Gs protein activates Adenylate Cyclase (AC)
        ↓
GDP → GTP conversion (Gαs activated)
AC converts ATP → cAMP
        ↓
↑ intracellular cAMP
        ↓
Enhances Ca²⁺-mediated insulin granule exocytosis
        ↓
INSULIN RELEASE (glucose-dependent manner)

                    ┌──────────────────────────────────┐
                    │  DPP-4 normally breaks down GLP-1│
                    │  (GLP-1 has short half-life ~2min)│
                    └──────────────────────────────────┘
                              ↓
Two strategies to boost GLP-1 effect:

1. DPP-4 Inhibitors (Gliptins)
   Sitagliptin (Sita), Vildagliptin (Vilda)
        ↓
   Block DPP-4 enzyme
        → GLP-1/GIP are NOT broken down → Inactive peptide NOT formed
        → Active GLP-1/GIP levels rise → more incretin receptor activation

2. GLP-1 Receptor Agonists
   Exenatide (Exe), Liraglutide (Lira)
        ↓
   Directly activate incretin receptor
        → Mimic GLP-1 action → ↑ cAMP → INSULIN RELEASE

SUMMARY: All Pathways Converge on Insulin Release

     SU/Meglitinides          GLP-1/GIP Incretins
           ↓                         ↓
   Close K-ATP Channel       ↑ cAMP via AC/Gs pathway
           ↓                         ↓
   Membrane Depolarization    Potentiate Ca²⁺ response
           ↓                         ↓
        Ca²⁺ INFLUX ←────────────────┘
               ↓
    Insulin Granule Exocytosis
               ↓
       INSULIN SECRETION

Key: Drugs & Their Sites of Action