Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

McCreight, Laura; Mari, Andrea; Coppin, Lucy; Jackson, Nicola; Umpleby, A. Margot; Pearson, Ewan R.

doi:10.1007/s00125-019-05042-1

Cited by 23 publications

(30 citation statements)

References 12 publications

(15 reference statements)

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“…The outcomes may be the opposite of improvement, but a further deterioration in reproductive functions. This possibility is supported by the data from clinical trials on metabolic changes, including an increase in fasting glucose clearance and endogenous glucose production [ 117 , 118 ], as well as changes in the microbiota in non-diabetic individuals [ 119 ], as well as data on metabolic and hormonal dysfunctions in normal rodents, for a long time receiving MF [ 120 ].…”

Section: Metformin and Polycystic Ovary Syndromementioning

confidence: 98%

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

2021

Pharmaceuticals

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Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus (GDM) and T2DM. MF treatment is demonstrated to improve the efficiency of in vitro fertilization and is considered a supplementary drug in assisted reproductive technologies. MF administration shows positive effect on steroidogenesis and spermatogenesis in men with metabolic disorders, thus MF treatment indicates prospective use for improvement of male reproductive functions and fertility. MF lacks teratogenic effects and has positive health effect in newborns. The review is focused on use of MF therapy for restoration of female and male reproductive functions and improvement of pregnancy outcomes in metabolic and endocrine disorders. The mechanisms of MF action are discussed, including normalization of metabolic and hormonal status in PCOS, GDM, T2DM and metabolic syndrome and restoration of functional activity and hormonal regulation of the gonadal axis.

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Section: Metformin and Polycystic Ovary Syndromementioning

confidence: 98%

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

2021

Pharmaceuticals

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“…As a first-line therapy for the treatment of T2D, metformin is very effective at improving glycemic control in patients with T2D. However, metformin has also been shown to have paradoxical effects on hepatic glucose metabolism in nondiabetic patients ( 34 , 35 ). Thus, early clinical studies in T2D patients investigating metformin’s mechanism of action have provided important insights into our current understanding of its glucose-lowering effects ( 3 , 18 , 36 , 37 ).…”

Section: Insights From Metformin’s Effects On Glucose Metabolism In Pmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Metformin Action

2020

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Metformin is a first-line therapy for the treatment for type 2 diabetes due to its robust glucose-lowering effects, well-established safety profile and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (> 1mM) metformin concentrations which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox dependent mechanism of metformin action. Here, we review the current literature regarding metformin’s cellular and molecular mechanisms of action

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“…Type 2 diabetes is commonly associated with nutrient excess which predicts compromised intracellular homeostasis. Recent studies have reported lack of efficacy of metformin in healthy non-diabetic people as well as in newly diagnosed well-controlled type 2 diabetes [116,117]. Although several factors may interact with the efficacy of metformin on endogenous glucose production, further work on the metformin mechanism should focus on cell and animal models with compromised intracellular metabolite homeostasis that more closely simulate the dysregulation in poorly controlled type 2 diabetes, to determine whether AMPK-independent repression of G6pc by metformin predominates in the compromised metabolic state.…”

Section: Perspectivesmentioning

confidence: 99%

The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective

Agius

Ford

Chachra

2020

IJMS

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Metformin therapy lowers blood glucose in type 2 diabetes by targeting various pathways including hepatic gluconeogenesis. Despite widespread clinical use of metformin the molecular mechanisms by which it inhibits gluconeogenesis either acutely through allosteric and covalent mechanisms or chronically through changes in gene expression remain debated. Proposed mechanisms include: inhibition of Complex 1; activation of AMPK; and mechanisms independent of both Complex 1 inhibition and AMPK. The activation of AMPK by metformin could be consequent to Complex 1 inhibition and raised AMP through the canonical adenine nucleotide pathway or alternatively by activation of the lysosomal AMPK pool by other mechanisms involving the aldolase substrate fructose 1,6-bisphosphate or perturbations in the lysosomal membrane. Here we review current interpretations of the effects of metformin on hepatic intermediates of the gluconeogenic and glycolytic pathway and the candidate mechanistic links to regulation of gluconeogenesis. In conditions of either glucose excess or gluconeogenic substrate excess, metformin lowers hexose monophosphates by mechanisms that are independent of AMPK-activation and most likely mediated by allosteric activation of phosphofructokinase-1 and/or inhibition of fructose bisphosphatase-1. The metabolite changes caused by metformin may also have a prominent role in counteracting G6pc gene regulation in conditions of compromised intracellular homeostasis.

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Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

Cited by 23 publications

References 12 publications

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

Cellular and Molecular Mechanisms of Metformin Action

The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective

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