International Journal of Peptides / 2010 / Article / Fig 2

Review Article

Effect of Ghrelin on Glucose-Insulin Homeostasis: Therapeutic Implications

Figure 2

𝛽 -cell mechanisms of insulin release and its regulation by ghrelin. When the plasma glucose concentration rises, 𝛽 -cells oxidize it. Glucose oxidation establishes a protonmotive force (PMF) that drives ATP synthesis, increasing the ATP/ADP ratio. This causes closure of KATP-channels, depolarisation of the plasma membrane potential ( Δ 𝜓 p) and Ca2+ flux into the cell, triggering insulin release. UCP2 activity dissipates the protonmotive force, lowering ATP/ADP. Ghrelin directly acts on the 𝛽 -cell and via PTX–sensitive mechanisms attenuates glucose-induced [Ca2+]i signalling partly through enhancement of TEA-sensitive delayed outward K+ currents resulting in decrease plasma insulin levels. PTX catalyzes the ADP-ribosylation of the α subunits of the heterotrimeric G proteins Gi, Go, and Gt. This prevents the G proteins from interacting with G protein-coupled receptors on the cell membrane thus interfering with intracellular communication. Since the G 𝛼 subunits remain in their GDP-bound, inactive state, they are unable to inhibit adenylyl cyclase, thus keeping levels of adenylyl cyclase and cAMP elevated. PTX inhibited a number of insulin-stimulated cellular events, such as glucose transport and its metabolism. Antisense oligonucleotide specific for G 𝛼 i2-subunit of G proteins blocks the effects of ghrelin on [Ca2+]i and insulin release. Hence ghrelin presumably suppresses glucose-induced insulin release via G 𝛼 i2- and Kv channel–mediated attenuation of Ca2+ signalling in 𝛽 -cells.
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