Figure 6.

Diagram of K_ATPHI β-cell glucose and amino acid metabolism. In K_ATPHI, inactivating mutations of the β-cell K_ATP channels result in chronic β-cell depolarization and elevation of [Ca²⁺]_i, which leads to alterations in fuel sensing and dramatic changes in fuel metabolism. Glycolysis is markedly increased, and the serine/glycine biosynthesis pathway is activated. The activation of a serine/glycine biosynthesis pathway may lead to increased nucleotide biosynthesis, β-cell nucleomegaly, and increased β-cell proliferation. K_ATPHI islets also have impaired GABA shunt and increased glutamine biosynthesis. Increased mitochondrial mass, oxygen consumption, and ATP synthase expression lead to high production of ATP. High rate of insulin release and increased expression of ATPases result in high ATP consumption. 3-PG, 3-phospoglycerate; α-KG, α-ketoglutarate; ALT, alanine transaminase; GDH, glutamate dehydrogenase; Glu, glutamate; GS, glutamine synthetase; OAA, oxaloacetate; PAST1, phosphoserine aminotransferase 1; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; TAs, transaminases; TCA cycle, tricarboxylic acid cycle.