Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

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   Figure 1

   Schematic model for glucose-dependent regulation of glucagon secretion in the mouse α-cell. Glucose is incorporated into the α-cell by the transporter SLC2A1. At low-glucose concentrations, the moderate activity of K_ATP channels situates the α-cell membrane potential in a range that allows the opening of voltage-dependent T- and N-type Ca²⁺ channels and voltage-dependent Na⁺ channels. Their activation triggers action potentials, Ca²⁺ influx and exocytosis of glucagon granules. The opening of A-type K⁺ channels is necessary for action potential repolarization. However, high-glucose concentrations elevate the intracellular ATP/ADP ratio, blocking K_ATP channels and depolarizing the membrane potential to a range where the inactivation of voltage-dependent channels takes place. This results in the inhibition of electrical activity, Ca²⁺ influx and glucagon secretion. The function of L-type channels predominates when cAMP levels are elevated. See text for further details.
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   Figure 2

   Opposite Ca²⁺ signalling patterns in α- and β-cells in response to glucose. At low-glucose concentrations (0.5 mM), electrical activity triggers oscillatory Ca²⁺ signals in α-cells that lead to glucagon release. Elevation of glucose levels (11 mM) inhibits all these events. By contrast, 11 mM glucose stimulate Ca²⁺ signalling and insulin secretion in β-cells. Both fluorescence records were obtained by confocal microscopy from two cells within an intact mouse islet. Inset shows a thin optical section (∼6 μm) of a mouse islet loaded with the Ca²⁺-sensitive fluorescent probe Fluo-3.
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   Figure 3

   Paracrine signalling in the α-cell. See text for details. ADCY, adenylate cyclase; AMPA-R, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GABA, γ-aminobutyric acid; GLP1, glucagon-like peptide-1; GRM, metabotrophic glutamate receptor; PKA, protein kinase A; SSTR2, somatostatin receptor-2.
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   Figure 4

   The role of glucagon and the glucagon receptor in the liver. Glucagon signalling regulates positively (+) or negatively (−) the multiple steps of the hepatic glucose metabolism. This modulation affects the expression and/or the activity of several enzymes of glucose metabolism. See text for details. ADCY, Adenylate cyclase; CREB, cAMP response element binding; F(1,6)P2, fructose-1,6-bisphosphate; F(2,6)P2, fructose-2,6-bisphosphate; F-6-P, fructose 6-phosphate; FBP1, fructose-1,6-bisphosphatase; FBP2, fructose-2,6-bisphosphatase; G-1-P, glucose 1-phosphate; G-6-P, glucose 6-phosphate; G6PC, glucose-6-phosphatase; GP, glycogen phosphorylase; GS, glycogen synthase; IP3, inositol 1,4,5-trisphosphate; OAA, oxaloacetate; PC, pyruvate carboxylase; PEP, phosphoenolpyruvate; PCK2, phosphoenolpyruvate carboxykinase; PFKM, phosphofructokinase-1; PPARGC1A, peroxisome proliferators-activated receptor-γ coactivator-1; PIP2, phosphatidylinositol 4,5-bisphosphate; PKLR, pyruvate kinase; PLC, phospholipase C; Pyr, pyruvate. Dashed lines: red, inhibition; blue, stimulation.

• © 2008 Society for Endocrinology