Figure 7

A working model for GCGR disruption resulting in hyperglucagonemia. Disruption of GCGR increases glucagon demand due to feedback signals from the liver and other tissues. The metabolic remodeling following GCGR disruption in the liver induces circulating factor/factors and these are transmitted to the islet. The α cells in the islet respond to these factors in two ways, one of which is to upregulate glucagon expression and the other is to induce α-cell hyperplasia. Both induce more glucagon secretion to meet the increased glucagon demand, which results in hyperglucagonemia in the circulation. However, administering high-level glucose or knockdown of pnoca in the GCGR KO animals suppresses both glucagon expression and α-cell hyperplasia. The dashed lines and circles indicate that there is uncertainty as to whether these effects are direct or indirect. GCGR, glucagon receptor.