No abstract

Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon–cAMP–protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α–mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions.

No abstract

There is a growing body of evidence that the formation and accumulation of advanced glycation end products (AGE) have been known to progress under diabetic conditions, thereby being involved in diabetic vascular complications. Further, we, along with others, have recently found AGE could disturb insulin actions in cultured adipocytes and skeletal muscles. However, the pathological role of AGE in insulin resistance in vivo is not fully understood. Therefore, in this study, we examined whether pyridoxamine, an inhibitor of AGE formation could ameliorate insulin resistance in KK-A(y) mice, a model animal of obese, type 2 diabetes. Fasting blood glucose, serum levels of insulin and AGE in KK-A(y) mice were elevated as the mice got older (from 5 weeks old to 15 weeks old). Serum levels of AGE were positively correlated with insulin (R(2)=0.3956, P=0.002) in KK-A(y) mice. Administration of pyridoxamine dose-dependently decreased fasting insulin levels and improved insulin sensitivity in KK-A(y) mice of 10 weeks old, although it did not affect fasting blood glucose levels. Our present study suggests the involvement of AGE in insulin resistance in KK-A(y) mice. Inhibition of AGE formation may be a novel therapeutic target for improving insulin resistance in diabetes with obesity.