MCAT Practice Test 10

Stimulus–secretion coupling in pancreatic β cells

¹Pancreatic β cells release insulin in proportion to the plasma glucose concentration. Glucose enters β cells through GLUT2, a transporter with a high $K_m$ for glucose, so the rate of entry rises over the physiological range of blood glucose. Inside the cell, glucose is phosphorylated by glucokinase and metabolized by glycolysis and oxidative phosphorylation, and the cytosolic ATP/ADP ratio rises as glucose increases.

²ATP binds ATP-sensitive potassium (${\text{K}}_{\text{ATP}}$) channels in the plasma membrane and closes them. At low glucose, open ${\text{K}}_{\text{ATP}}$ channels hold the membrane potential near –70 mV. When the channels close, ${\text{K}}^{+}$ efflux falls and the membrane depolarizes until voltage-gated ${\text{Ca}}^{2+}$ channels open at about –50 mV. β-Cell action potentials have a ${\text{Ca}}^{2+}$-dependent upstroke and are repolarized by voltage-gated ${\text{K}}^{+}$ channels. The rise in cytosolic ${\text{Ca}}^{2+}$ during these action potentials triggers fusion of insulin-containing granules with the plasma membrane.

³This triggering pathway is amplified by hormones released from the intestine after a meal. Glucagon-like peptide-1 (GLP-1) binds a G protein–coupled receptor on β cells that activates the stimulatory G protein ${\text{G}}_s$, which stimulates adenylyl cyclase. The resulting cAMP activates protein kinase A and a cAMP-binding exchange factor, which together increase the number of granules ready for release and their sensitivity to ${\text{Ca}}^{2+}$. Because GLP-1 acts on a pathway that is triggered only when glucose closes ${\text{K}}_{\text{ATP}}$ channels, GLP-1 has been reported to have little effect on secretion when glucose is low, a property called glucose dependence.

⁴Neighboring islet cells also restrain insulin release. Somatostatin from δ cells acts on receptors coupled to the inhibitory G protein ${\text{G}}_i$, which lowers adenylyl cyclase activity in β cells. Insulin released into the islet interstitium, in turn, suppresses glucagon secretion from adjacent α cells, so the two hormones rarely rise together.