Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

• Published in: Nature reviews. Drug discovery Vol. 15; no. 11; pp. 786 - 804
• Main Authors: Rines, Amy K., Sharabi, Kfir, Tavares, Clint D. J., Puigserver, Pere
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2016; Nature Publishing Group
• Subjects: 631/154; 631/443/319/1642; 631/443/319/1642/137; Animals; Biomedicine; Biotechnology; Cancer Research; Care and treatment; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Drug Delivery Systems - methods; Drug Delivery Systems - trends; Genetic aspects; Glucose - antagonists & inhibitors; Glucose - metabolism; Health aspects; Humans; Hypoglycemic Agents - administration & dosage; Liver - drug effects; Liver - metabolism; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; review-article; Signal Transduction - drug effects; Signal Transduction - physiology; Type 2 diabetes
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd.2016.151

Key Points 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. Although the liver has a key role in maintaining blood glucose homeostasis, few existing type 2 diabetes therapies directly target this organ. Here, Puigserver et al . provide an overview of the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, focusing on emerging strategies to target hepatic glucose metabolism for the treatment of diabetes. Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycaemia. Although current diabetes treatments have exhibited some success in lowering blood glucose levels, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycaemia. Novel antidiabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver 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.