The Dual Anaplerotic Model (DAM): Integral Roles of Pyruvate Carboxylase and the GABA Shunt in Beta Cell Insulin Secretion

We propose a Dual Anaplerotic Model (DAM) of beta cell insulin secretion, integrating two anaplerotic pathways: the classical glucose-driven route via pyruvate carboxylase (PC) and the GABA shunt–mediated pathway. PC plays a crucial role in the PEP cycle, enabling localized ATP production in microdomains near KATP channels. The GABA shunt provides fresh carbon to the TCA cycle, thereby amplifying the mitochondrial oxidative (MitoOx) phase. Replenishment of the GABA pool is linked to the cataplerosis of α-ketoglutarate during the mitochondrial cataplerotic (MitoCat) phase, a process critically supported by simultaneous PC-derived anaplerotic flux. For the first time, these pathways are recognized as integral, interdependent, and temporally coordinated routes of anaplerosis in beta cells. DAM thus synthesizes recent advances: the PC anaplerotic pathway with the PEP cycle, and the anaplerotic role of the GABA shunt, within the coordinating framework of the MitoCat–MitoOx model. This synergistic minimal model captures key experimental findings and predicts the interplay of major metabolite pools—the glycolytic, TCA, and GABA pools, together with the signaling role of Ca²⁺—highlighting the central role of the TCA–GABA–Ca²⁺ module in determining slow oscillatory periods in beta cells.