New insights concerning the glucose-dependent insulin secretagogue action of glucagon-like peptide-1 in pancreatic β-cells

The GLP-1 receptor is a Class B heptahelical G-protein-coupled receptor that stimulates cAMP production in pancreatic β-cells. GLP-1 utilizes this receptor to activate two distinct classes of cAMP-binding proteins: protein kinase A (PKA) and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). Actions of GLP-1 mediated by PKA and Epac include the recruitment and priming of secretory granules, thereby increasing the number of granules available for Ca²⁺-dependent exocytosis. Simultaneously, GLP-1 promotes Ca²⁺ influx and mobilizes an intracellular source of Ca²⁺. GLP-1 sensitizes intracellular Ca²⁺ release channels (ryanodine and IP₃ receptors) to stimulatory effects of Ca ²⁺, thereby promoting Ca²⁺-induced Ca²⁺ release (CICR). In the model presented here, CICR activates mitochondrial dehydrogenases, thereby upregulating glucose-dependent production of ATP. The resultant increase in cytosolic [ATP]/ [ADP] concentration ratio leads to closure of ATP-sensitive K⁺ channels (K-ATP), membrane depolarization, and influx of Ca²⁺ through voltage-dependent Ca ²⁺ channels (VDCCs). Ca²⁺ influx stimulates exocytosis of secretory granules by promoting their fusion with the plasma membrane. Under conditions where Ca²⁺ release channels are sensitized by GLP-1, Ca²⁺ influx also stimulates CICR, generating an additional round of ATP production and K-ATP channel closure. In the absence of glucose, no "fuel" is available to support ATP production, and GLP-1 fails to stimulate insulin secretion. This new "feed-forward" hypothesis of β-cell stimulus-secretion coupling may provide a mechanistic explanation as to how GLP-1 exerts a beneficial blood glucose-lowering effect in type 2 diabetic subjects.