Question

Illustrate and explain how an elevation in plasma glucose levels leads to glucose-stimulated insulin secretion by pancreatic β-cells. Your illustration and explanation should include GLUT2, Glycolysis, TCA Cycle, Oxidative Phosphorylation, ATP, ATP:ADP, Kir6.2, calcium channel, synaptotagmin, secretory granules, proinsulin, insulin, and C-peptide.

Answer 1

Metabolic hypothesis of glucose-stimulated insulin release from β-cells. In mammalian β-cells, the rate of glucose phosphorylation, catalyzed via glucokinase, is the bottleneck for further metabolic flux. Because of the kinetic properties of GK, this rate is proportional to the extracellular glucose concentration. It is unknown if other hexokinases and G6P dephosphorylation can influence this rate-limiting step. Mitochondrial uptake and metabolism of pyruvate—both carboxylation and decarboxylation—allows production of various messengers for exocytosis, such as the ATP/ADP ratio and the efflux of mitochondrial metabolic intermediates. Glucose signaling pathways are amplified via production of cAMP, which is stimulated by activated GLP-1Rs, GIP, and glucagon (not shown). This effect is further modulated by the phospholipase C pathway (not shown) and the signaling induced by insulin receptors (not shown) and leptin-receptors (Ob-R). Recent data indicate that part of the effect of cAMP on exocytosis in β-cells is mediated via a protein kinase A—independent pathway involving the GDP/GTP-exchanging protein cAMP-GEFII (117). ▵V, membrane depolarization.