Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Abstract

Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis resulting in hyperglycemia. Although current diabetes treatments have exhibited some success in lowering blood glucose, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycemia. Novel diabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver in order to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice

“…Our data show that expression levels of transcriptional activators FoxO1, HNF-4α, and PGC-1α were increased both in the liver and renal cortex in db/db mice. Accumulating evidences demonstrates that the expression or the promoter-binding activity of FoxO1, HNF4, PGC-1α or cAMP responsive element binding protein (CREB), which bind to the G6Pase and PEPCK1promoters, regulate gluconeogenesis in the liver [27, 31-35]. Recently, the transcriptional regulators of hepatic gluconeogenesis are also considered to be potential therapeutic targets for the treatment of T2DM [27, 35, 36].…”

“…Endogenous glucose production is mainly derived from two pathways: gluconeogenesis and glycogenolysis, both of these are enhanced in T2DM and contribute to fasting and postprandial hyperglycemia [27, 28]. In addition to the liver, the renal cortex also has the highest expression of enzymes related to gluconeogenesis and is therefore capable of generating considerable amounts of glucose (by gluconeogenesis) to be released into the circulation [29].…”

“…Accumulating evidences demonstrates that the expression or the promoter-binding activity of FoxO1, HNF4, PGC-1α or cAMP responsive element binding protein (CREB), which bind to the G6Pase and PEPCK1promoters, regulate gluconeogenesis in the liver [27, 31-35]. Recently, the transcriptional regulators of hepatic gluconeogenesis are also considered to be potential therapeutic targets for the treatment of T2DM [27, 35, 36]. However, dapagliflozin only further increased the expression of FoxO1, suggesting that FoxO1 might play an important role in dapagliflozin-induced renal and hepatic gluconeogenesis.…”

The long non-coding RNA Gm10768 activates hepatic gluconeogenesis by sequestering microRNA-214 in mice

“…Whereas during fasting, hepatic gluconeogenesis is triggered to keep normal blood glucose levels. Under pathological conditions, hepatic gluconeogenesis is abnormally over-activated, which results in hyperglycemia and contributes importantly to the pathogenesis of various metabolic disorders, such as type 2 diabetes (T2D) (2,3). Previous studies have demonstrated that hepatic gluconeogenesis, rather than glycogenolysis, is increased in patients with T2D (2).…”

“…Under pathological conditions, hepatic gluconeogenesis is abnormally over-activated, which results in hyperglycemia and contributes importantly to the pathogenesis of various metabolic disorders, such as type 2 diabetes (T2D) (2,3). Previous studies have demonstrated that hepatic gluconeogenesis, rather than glycogenolysis, is increased in patients with T2D (2). Hepatic gluconeogenesis is largely controlled through key rate-limiting enzymes in the gluconeogenic pathway, specifically phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) (4).…”