Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Abstract

Type 2 diabetes is characterized by elevated blood glucose levels and insulin resistance. Current diabetes drugs can lower blood glucose but often have side effects, and the most widely used drug — metformin — does not have a clear mechanism of action. Targeting glucose and glycogen metabolism in the liver is a strategy for type 2 diabetes treatment, as it can decrease hepatic glucose output, but this approach has not been fully explored. Gluconeogenic and glycogenolytic enzymes or their regulators present numerous drug targets that are currently being investigated or have the potential to be developed. Transcriptional co-activators and transcription factors are emerging diabetes drug targets with the ability to control entire gene programmes involved in glucose and glycogen metabolism. It may be possible to specifically target these transcriptional regulators by modulating their protein–protein interactions or post-translational modifications. Novel diabetes drugs would most probably be used in combination with existing therapies to enable sustained blood glucose suppression, and so that each drug could be used at a lower concentration to limit side effects. Drugs decreasing hepatic glucose output may be most effectively used with drugs that work by other mechanisms, such as thiazolidinediones or sodium-glucose co-transporter 2 (SGLT2) inhibitors. Challenges of inhibiting hepatic glucose output include preventing hypoglycaemia, enabling tissue-specific targeting, analysing the possible effects of redirecting carbons to triglyceride or cholesterol synthesis, and avoiding lactic acidosis.