FIG. 3.

NADPH facilitation of GSIS and mitochondrial redox state. Mitochondrial redox shuttles exporting reducing equivalents from the mitochondrial matrix to the cytosol are illustrated. The resulting elevated cytosolic NADPH has been reported to facilitate GSIS. The shuttles are depicted by arrows of distinct colors: dark green: pyruvate/malate shuttle; purple: pyruvate/citrate shuttle; and orange: pyruvate/isocitrate shuttle. When functional at the glucose intake, for example, the pyruvate/malate shuttle is enabled by the pyruvate carboxylase reaction; NADPH is elevated in the cytosol at the expense of unmade matrix NADH. Consequently, a lower NADH/NAD⁺ ratio is predicted to cause diminished superoxide formation within the Complex I, and hence, functional GSIS hypothetically should not increase matrix oxidative stress. At impaired GSIS and exaggerated metabolism, resulting higher NADH/NAD⁺ ratio should then increase superoxide formation and hence the matrix oxidative stress. 2-OG, 2-oxoglutarate; 2-OG C, 2-oxoglutarate carrier; 2OGDH, 2-oxoglutarate dehydrogenase; ACL, ATP citrate lyase; Cit C, citrate carrier; CS, citrate synthase; FASIS, fatty acid-stimulated insulin secretion; FASN, fatty acid synthase; FH, fumarate hydratase; GDH, glutamate dehydrogenase; MAC, malate aspartate carrier; MDH, malate dehydrogenase; ME, malic enzyme; Pyr C, pyruvate carrier; S-CoA, succinyl coenzyme A; SDH, succinate dehydrogenase.