Fig. 9: Schematic representation of the molecular regulation of Nrf1/Sglt2 and glucose reabsorption in the proximal tubule by Bmal1 and Rev-erbα during fasting and refeeding.

a During fasting, blood glucose is lower, and less glucose is filtered, requiring less glucose transport capacity to prevent urinary glucose loss. Increases in glucagon during fasting induce p-Mapk signaling and Bmal1, thus increasing Rev-erbα levels and the binding of Rev-erbα to the Nrf1 promoter, and decreasing expression of Nrf1. Decreased nuclear Nrf1 reduces Sglt2 levels and glucose reabsorption capacity. b Refeeding increases blood glucose levels and filtered glucose. During refeeding, glucagon signaling is attenuated resulting in decreased Bmal1 and Rev-erbα expression. Subsequently, binding of Rev-erbα to Nrf1 decreases and is associated with increased expression of Nrf1. Increased nuclear Nrf1 is associated with increased Sglt2 levels, and the glucose reabsorption capacity is adjusted to the enhanced filtered glucose load. In addition, feeding-induced insulin might enhance the consequences of falling glucagon levels by independently upregulating Nrf1 and Sglt2 through an yet-unidentified mechanism.