Fig. 2 ∣. Pyruvate cycling pathways implicated in the regulation of GSIS.

In the post-prandial state, increased anaplerotic metabolism of pyruvate and other fuels leads to the accumulation of tricarboxylic acid (TCA) cycle intermediates, which leave the mitochondria to engage in cytosolic reactions that create signals for the amplifying/second phase of glucose-stimulated insulin secretion (GSIS). This includes (1) the pyruvate–malate cycle (highlighted by the brown circle and involving malic enzyme (ME) and the malate carrier (MC)), (2) the pyruvate–citrate cycle (highlighted by the light blue circle and involving ATP citrate lyase (ACLY), malate dehydrogenase (MDH), the citrate/isocitrate carrier (CIC) and ME), and (3) the pyruvate–isocitrate cycle (highlighted by the green circle and involving the cytosolic NADP-linked isoform of isocitrate dehydrogenase (IDH1), the mitochondrial NADPH-linked isoform of isocitrate dehydrogenase (IDH2) and CIC). Note that the pyruvate–isocitrate pathway is a full cycle that includes reductive TCA flux, involving the carboxylation of α-ketoglutarate (αKG) to isocitrate in the mitochondria by IDH2. In β-cells, this reductive TCA cycle flux ensures that αKG generated by IDH1 is used to regenerate citrate and isocitrate to sustain IDH1 activity. NADPH produced by IDH1 in the cytosol connects to insulin granule exocytosis via glutathione reductase (GSR) to produce reduced glutathione (GSH), leading to the activation of glutaredoxin (GRX1), which mediates the reduction (S2 to SH2 isoform transition) and activation of sentrin/SUMO-specific protease 1 (SENP1). SENP1 then acts as a deSUMOylase that removes SUMO peptides from secretory granule-trafficking proteins to enhance exocytosis. The activity of the pyruvate–isocitrate cycle is maintained by the supply of glutamate, which can be converted to αKG by glutamate dehydrogenase (GDH). The supply of glutamate can be achieved either through the activity of the malate–aspartate shuttle or by the reversible activity of GDH, which is regulated by leucine and its analogue 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). Recent findings show that the effect of glutamine plus leucine/BCH co-treatment to stimulate insulin secretion is explained, in part, by the isocitrate cycle catalysed by IDH1 and IDH2. Throughout the figure, metabolic enzymes are shown in yellow ovals, whereas mitochondrial organic acid transporters are shown in red ovals. GSSG, glutathione disulfide; OGC, 2-oxoglutarate carrier; PDH, pyruvate dehydrogenase; PC, pyruvate carboxylase.