The Hormetic Effect of Metformin: “Less Is More”?

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.

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Statins Stimulate Hepatic Glucose Production via the miR-183/96/182 Cluster

10.1101/726695 ◽

2019 ◽

Author(s):

Tyler J. Marquart ◽

Ryan M. Allen ◽

Mary R. Chen ◽

Gerald W. Dorn ◽

Scot J. Matkovich ◽

...

Keyword(s):

Molecular Mechanisms ◽

Association Studies ◽

Hepatic Glucose Production ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Hepatic Clearance ◽

Glucose Production ◽

Genome Wide Association Studies ◽

Medical Advance

Statins are the most common pharmacologic intervention in hypercholesterolemic patients, and their use is recognized as a key medical advance leading to a 50% decrease in deaths from heart attack or stroke over the past 30 years. The atheroprotective outcomes of statins are largely attributable to the accelerated hepatic clearance of low-density lipoprotein (LDL)-cholesterol from circulation, following the induction of the LDL receptor. However, multiple studies suggest that these drugs exert additional LDL–independent effects. The molecular mechanisms behind these so-called pleiotropic effects of statins, either beneficial or undesired, remain largely unknown. Here we determined the coding transcriptome, miRNome, and RISCome of livers from mice dosed with saline or atorvastatin to define a novel in vivo epitranscriptional regulatory pathway that links statins to hepatic gluconeogenesis, via the SREBP2–miR-183/96/182–TCF7L2 axis. Notably, multiple genome-wide association studies identified TCF7L2 (transcription factor 7 like 2) as a candidate gene for type 2 diabetes, independent of ethnicity. Conclusion: our data reveal an unexpected link between cholesterol and glucose metabolism, provides a mechanistic explanation to the elevated risk of diabetes recently observed in patients taking statins, and identifies the miR-183/96/182 cluster as an attractive pharmacological candidate to modulate non-canonical effects of statins.

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Metformin Targets Foxo1 to Control Glucose Homeostasis

Biomolecules ◽

10.3390/biom11060873 ◽

2021 ◽

Vol 11 (6) ◽

pp. 873

Author(s):

Xiaoqin Guo ◽

Xiaopeng Li ◽

Wanbao Yang ◽

Wang Liao ◽

James Zheng Shen ◽

...

Keyword(s):

Transcription Factor ◽

Blood Glucose ◽

Signaling Pathway ◽

Glucose Homeostasis ◽

Molecular Mechanisms ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Suppressive Effect ◽

Dependent Manner ◽

Glucose Lowering Effect

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.

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Cellular and molecular mechanisms of metformin: an overview

Clinical Science ◽

10.1042/cs20110386 ◽

2011 ◽

Vol 122 (6) ◽

pp. 253-270 ◽

Cited By ~ 852

Author(s):

Benoit Viollet ◽

Bruno Guigas ◽

Nieves Sanz Garcia ◽

Jocelyne Leclerc ◽

Marc Foretz ◽

...

Keyword(s):

Respiratory Chain ◽

Complex I ◽

Molecular Mechanisms ◽

Ovarian Function ◽

Polycystic Ovary ◽

Hepatic Glucose Production ◽

Chain Complex ◽

Respiratory Chain Complex ◽

Energy Status ◽

Mitochondrial Respiratory Chain Complex

Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.

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Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

Pharmaceuticals ◽

10.3390/ph14030238 ◽

2021 ◽

Vol 14 (3) ◽

pp. 238

Author(s):

Marco Carli ◽

Shivakumar Kolachalam ◽

Biancamaria Longoni ◽

Anna Pintaudi ◽

Marco Baldini ◽

...

Keyword(s):

Metabolic Syndrome ◽

Weight Gain ◽

Atypical Antipsychotics ◽

Molecular Mechanisms ◽

Psychotic Disorders ◽

Partial Agonist ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Therapeutic Drug ◽

Metabolic Disturbances

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.

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The metabolic impact of small intestinal nutrient sensing

Nature Communications ◽

10.1038/s41467-021-21235-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Frank A. Duca ◽

T. M. Zaved Waise ◽

Willem T. Peppler ◽

Tony K. T. Lam

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Potential ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Nutrient Sensing ◽

Metabolic Homeostasis ◽

Obesity And Diabetes ◽

Hepatic Glucose ◽

Regulate Food Intake ◽

Small Intestinal

AbstractThe gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes.

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Considerations for Maximizing the Exercise “Drug” to Combat Insulin Resistance: Role of Nutrition, Sleep, and Alcohol

Nutrients ◽

10.3390/nu13051708 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1708

Author(s):

Mary-Margaret E. Remchak ◽

Kelsey L. Piersol ◽

Sabha Bhatti ◽

Andrea M. Spaeth ◽

Jennifer F. Buckman ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Nutrient Timing ◽

First Line Therapy ◽

Hepatic Glucose ◽

Skeletal Muscle Glucose Uptake

Insulin resistance is a key etiological factor in promoting not only type 2 diabetes mellitus but also cardiovascular disease (CVD). Exercise is a first-line therapy for combating chronic disease by improving insulin action through, in part, reducing hepatic glucose production and lipolysis as well as increasing skeletal muscle glucose uptake and vasodilation. Just like a pharmaceutical agent, exercise can be viewed as a “drug” such that identifying an optimal prescription requires a determination of mode, intensity, and timing as well as consideration of how much exercise is done relative to sitting for prolonged periods (e.g., desk job at work). Furthermore, proximal nutrition (nutrient timing, carbohydrate intake, etc.), sleep (or lack thereof), as well as alcohol consumption are likely important considerations for enhancing adaptations to exercise. Thus, identifying the maximal exercise “drug” for reducing insulin resistance will require a multi-health behavior approach to optimize type 2 diabetes and CVD care.

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