Figure 1.

Effect of glucose on α‐cell Ca²⁺ and cAMP at (A) low glucose and (B) high glucose concentrations, which result in changes to glucagon secretion. (A) At low glucose, there is a low rate of glucose transport across the membrane via GLUT and SGLT proteins. Glucose is then converted to glucose‐6‐phosphate, by hexokinase 1 (HK), to generate ATP via glycolysis. A modest increase in the ATP:ADP ratio, leads to partial closure of K_ATP‐channels, maintaining the membrane potential at the point of allowing action potential (AP) generation: this enables the activation of L‐type Ca_v and Na_v channels. The resulting high‐amplitude action potentials activate P/Q‐type channels, triggering exocytosis and glucagon release. In addition, adenylyl cyclase (AC) production of cAMP primes vesicles for exocytosis and potentiates Ca²⁺‐induced Ca²⁺ release from the endoplasmic reticulum (ER). Consequently, exocytosis of glucagon‐containing vesicles is high. The firing of action potentials can also be attributable to the activation of store‐operated Ca²⁺ entry (SOCE) via ORAI and STIM1, which is triggered by ER Ca²⁺ depletion due to low SERCA activity. (B) At high glucose concentrations, there is a high rate of glucose transport into the cytosol, leading to membrane depolarisation. This occurs as a result of increased ATP production via glycolysis, due to substrate abundance: high K_m glucokinase (GCK) phosphorylates glucose to produce glucose‐6‐phosphate. High intracellular ATP results in complete closure of K_ATP‐channels and, consequently, membrane depolarisation. Membrane depolarisation can also be induced by the process of glucose transport through sodium/glucose co‐transporters (SGLTs): Na⁺ is co‐transported with glucose and thus provides a depolarising membrane conductance. Na_v channels, at this membrane potential, become inactivated, whereas L‐type Ca_v channels remain activatable and contribute to action potential generation. However, action potential amplitude is reduced at high glucose concentrations (despite firing at a higher frequency) and are no longer able to activate P/Q‐type Ca_v channels, the exocytosis‐related Ca_v channel in α‐cells. The effect of membrane depolarisation and higher action potential firing frequency may also lead to increased cytosolic Ca²⁺ within domains adjacent to Ca²⁺‐sensitive adenylyl cyclase, inhibiting cAMP production and vesicle priming. However, higher ATP may also result in α‐cell membrane repolarisation. High ATP‐activated SERCA uptake of Ca²⁺ replenish ER Ca²⁺, deactivating ORAI‐mediated Ca²⁺ entry, resulting in suppression of α‐cell excitability and glucagon secretion. Red arrows indicate action potential propagation. Figure created using BioRender.com