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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #32: Beta-Cell biology of insulin secretion Part 2 of 5

Metabolism-secretion coupling

Triggering pathway

Glucose metabolism increases the cytosolic ATP concentration in pancreatic β cells, this rise in ATP causing closure of the KATP channels and depolarization of the β-cell membrane. Thus, KATP channels couple the cell’s metabolic state to electrical activity. The β-cell KATP channel is composed of two subunits: Kir6.2 as a pore-forming subunit and the sulfonylurea receptor SUR1 as a regulatory subunit. Activity of the KATP channel is critical for GIIS. Membrane depolarization opens VDCCs, which allows Ca2+ influx into β cells, the resultant rise in intracellular Ca2+ triggering exocytosis of insulin granules. Thus, KATP channels and VDCCs are major ion channels required for metabolism-secretion coupling in insulin release.

The intracellular Ca2+ concentration ([Ca2+]i) in pancreatic β cells is tightly regulated. Micromolar increases in [Ca2+]i are required to trigger insulin secretion [15]. Opening of the VDCCs is a common step in insulin secretion induced by glucose, sulfonylureas, and amino acids [16]. The L-type VDCC generally gives rise to a transient Ca2+ concentration in pancreatic β cells; modulation of VDCC activity generates changes in insulin secretion [17]. Although rapid Ca2+ influx through VDCCs is indispensable in GIIS, increases in [Ca2+]i can be slowly achieved by Ca2+ release from intracellular Ca2+ stores. It has been suggested that the mobilization of intracellular Ca2+ from ryanodine-sensitive Ca2+ stores by cyclic ADP-ribose generated by glucose stimulation contributes to GIIS [18], but the notion is controversial.

Among many Ca2+-binding proteins that may function as Ca2+ sensors for vesicle fusion, the leading candidates are members of the synaptotagmin family [19]. Most of the 15 members share common regions and domains including a short intravesicular NH2-terminal region, a single membrane-spanning domain, a lysine- and arginine-rich region, as well as two C2 domains (C2A and C2B) located in the cytoplasmic tail [19]. Binding of Ca2+ to synaptotagmins via the two C2-domains transduces the Ca2+ signal into activation of the membrane fusion machinery, which is exerted by the interaction of the C2-domains with phospholipids and SNARE proteins [19]. Synaptotagmins 2-4 and 6-9 are expressed in pancreatic islets and β cells [20]. Synaptotagmin 7, which is co-localized with insulin granules, is thought to be the major Ca2+ sensor for insulin granule exocytosis [20,21].

Metabolic amplifying pathway

In addition to the KATP channel-dependent pathway that triggers insulin secretion, another pathway in GIIS augments the effect of Ca2+ on insulin secretion [22]. This pathway, which does not require an additional rise in [Ca2+]i and is distinct from the hormonal and neuronal amplifying pathway, was originally referred to as the KATP channel-independent pathway in GIIS. However, since closure of KATP channels is a prerequisite for this augmentation pathway under physiologic conditions, it is more accurately referred to as metabolic amplifying pathway.

Recent studies have focused on the mitochondrial features of this pathway. As mentioned, pyruvate readily enters the mitochondrion in pancreatic β cells and is converted to oxaloacetate by PC. In gluconeogenic tissues such as liver and kidney, the activity of PC coordinates with phosphoenolpyruvate carboxykinase (PEPCK) to initiate gluconeogenesis. Although the activity of PC is also high in pancreatic β cells, β cells lack expression of both PEPCK and fructose-1,6-bisphosphatase, indicating that PC serves in roles other than gluconeogenesis.

Several lines of evidence indicate that anaplerosis via PC is involved in GIIS [23,24]. Cataplerosis pathways, which provide mitochondrial metabolites to the cytosol, are also thought to be implicated in GIIS [25]. There are at least three pyruvate cycling pathways in pancreatic β cells: the pyruvate-malate shuttle, the pyruvate-citrate shuttle, and the pyruvate-isocitrate shuttle. These pathways may generate coupling factors associated with the metabolic amplifying pathway.

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