title: New insights into the anti-diabetic actions of metformin: from the liver to the gut.
abstract: Metformin is established as the first-line therapy for type 2 diabetes (T2DM), but its mode of action remains elusive. Elucidation of the mechanisms underlying the anti-diabetic action of metformin may have the potential to optimise its glucose-lowering efficacy and lead to the development of agents acting on novel targets for the management of type 2 diabetes. Areas covered: This review highlights key pharmacokinetic features of metformin, summarises recent insights into its hepatic and gastrointestinal actions relevant to blood glucose homeostasis, and discusses the common gastrointestinal side effects of metformin. Literature concerning these areas was reviewed on PubMed. Expert commentary: The mechanisms by which metformin improves glycaemic control in type 2 diabetes are complex. Although novel hepatic pathways continue to be reported in preclinical studies, there is a lack of human evidence for most of these. Considering the fundamental role of the gastrointestinal tract in the regulation of blood glucose homeostasis and pleiotropic actions of metformin on several gastrointestinal targets relevant to glycaemic control, the gut is likely to represent at least as important a site of metformin action as the liver in the management of type 2 diabetes.
authors.affiliation: a Discipline of Medicine and Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia.
authors.forename: Tongzhi
authors.initials: T
authors.lastname: Wu
authors.affiliation: a Discipline of Medicine and Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Horowitz
authors.affiliation: a Discipline of Medicine and Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Rayner
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Metformin; bile salt; glucose absorption; gut microbiota; hepatic glucose production; incretin hormones