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Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

Abstract

Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.

Key points

  • Metformin is the first-line drug for treatment of type 2 diabetes mellitus, with an excellent safety profile, high efficacy in glycaemic control and clear but incompletely understood cardioprotective benefits.

  • The pleiotropic properties of metformin suggest that the drug acts on multiple tissues through various underlying mechanisms rather than on a single organ via a unifying mode of action.

  • Mitochondrial respiratory chain complex 1 is targeted by metformin and its inhibition is involved in AMP-activated protein kinase-independent regulation of hepatic gluconeogenesis by triggering alterations in cellular energy charge and redox state.

  • Metformin might contribute to improvements in obesity-associated meta-inflammation and tissue-specific insulin sensitivity through direct and indirect effects on various resident immune cells in metabolic organs.

  • The gastrointestinal tract has an important role in the action of metformin, which modulates bile acid recirculation and enhances the secretion of the glucose-lowering gut incretin hormone glucagon-like peptide 1.

  • The gut microbiota is a novel target in the mechanisms of metformin action and is involved in both the therapeutic and adverse effects of the drug.

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Fig. 1: Action of metformin on mitochondrial respiratory chain complex 1.
Fig. 2: Energy-dependent mechanisms of metformin-induced inhibition of hepatic gluconeogenesis.
Fig. 3: Redox-dependent mechanisms by which metformin inhibits hepatic gluconeogenesis.
Fig. 4: Metformin and meta-inflammation.
Fig. 5: Metformin action in the gut.

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Acknowledgements

The authors acknowledge the support of grants from Inserm, CNRS, Université Paris Descartes, Agence Nationale de la Recherche (ANR), Société Francophone du Diabète (SFD), Fondation pour la Recherche Médicale (FRM), the Dutch Organization for Scientific Research (ZonMW) and DiabetesFonds.

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Glossary

Lactic acidosis

A medical condition characterized by excessively low pH in the bloodstream due to excess lactate production by glycolytic tissues, inadequate lactate utilization by gluconeogenic tissues, or varying combinations of these two processes.

Pharmacokinetics

The study of the transit of a dosed drug in body fluids and tissues over time, as defined by its rate of absorption, distribution, metabolism and excretion.

Pharmacodynamics

The study of the action of a drug in the body, and its biochemical and physiological effects.

Half-maximal inhibitory concentration

(IC50). The concentration of an inhibitor required to decrease the response of the target by 50%.

Pyruvate tolerance

A measure of glycaemic excursion in response to an intraperitoneal or intravenous injection of pyruvate, used to assess hepatic gluconeogenesis.

Cytosolic redox potential

Cytoplasmic oxidation state of the cell, which is assessed by the ratio of reduced to oxidized intracellular metabolite redox couples (for example, lactate/pyruvate ratio).

Type 2 immune cells

Cells involved in type 2 immune responses, such as type 2 innate lymphoid cells, eosinophils, T helper 2 cells, mast cells, basophils and alternatively-activated macrophages.

Reverse electron transport

(RET). The transport of electrons from ubiquinol back to respiratory complex 1, generating a substantial amount of reactive oxygen species.

Incretins

Incretins are gut hormones that are secreted after nutrient intake and stimulate glucose-stimulated insulin secretion.

Lipoapoptosis

A non-canonical form of programmed cell death, which is the result of fatty acid over-accumulation that occurs in diseases associated with over-nutrition and ageing.

Short-chain fatty acid

(SCFA). A fatty acid with fewer than six carbon atoms (for example, acetate, propionate and butyrate) that is the end-product of fermentation of dietary fibres by the anaerobic intestinal microbiota and acts as a signal molecule in the control of mammalian energy metabolism.

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Foretz, M., Guigas, B. & Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 15, 569–589 (2019). https://doi.org/10.1038/s41574-019-0242-2

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