FIG. 7.

Postulated mechanisms regarding pancreatic β-cell dysfunction caused by Nrf1 deficiency. Upper panel: Proper GSIS requires coordinating glucose uptake, glycolysis, mitochondrial metabolism, cell membrane depolarization, calcium influx, and insulin exocytosis. Levels of HK1, 2, and 3 that have high affinities for glucose are low in normal islet β-cells. The absence of high-affinity HKs allows low-affinity GCK to serve as the primary enzyme regulating the rate-limiting step of glycolysis, thereby making β-cells more responsive to changes in glucose levels. Lower panel: Nrf1 deficiency in the β-cell results in induction of multiple glucose-metabolizing enzymes, including Glut2, Hk1, Gapdh, and Ldh1, leading to elevated glycolysis and lactate production. The aberrant expression of glucose metabolic enzymes, in particular HK1 overexpression, in the β-cell alters its responsiveness to changes in glucose levels, leading to elevated basal insulin release but reduced GSIS. GCK, glucokinase.