Dose‐dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by <sup>18</sup>F‐labelled fluorodeoxyglucose positron emission tomography‐<scp>MRI</scp>

Ito, Jun; Nogami, Munenobu; Morita, Yasuko; Sakaguchi, Kazuhiko; Komada, Hisako; Hirota, Yushi; Sugawara, Kenji; Tamori, Yoshikazu; Zeng, Feibi; Murakami, Takamichi; Ogawa, Wataru

doi:10.1111/dom.14262

Cited by 18 publications

(42 citation statements)

References 36 publications

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“…In addition, it was very recently reported that metformin altered glucose absorption from the intestine [ 74 , 75 ]. Indeed, positron emission tomography (PET)-computed tomography has shown that metformin facilitates the intestinal accumulation of [ 18 F] fluorodeoxyglucose (FDG), a non-metabolizable glucose derivative.…”

Section: Metformin Alters the Gut Microbiome And Glucose Absorptiomentioning

confidence: 99%

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

Kaneto

Kimura

Obata

et al. 2021

IJMS

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While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.

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Section: Metformin Alters the Gut Microbiome And Glucose Absorptiomentioning

confidence: 99%

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

Kaneto

Kimura

Obata

et al. 2021

IJMS

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“…There is consistent evidence that, after oral administration, the accumulation of metformin within enterocytes contributes significantly to its plasma glucose-lowering activity [ 41 , 95 , 96 ]. Indeed, delayed-release formulations of metformin have been associated to a decrease in plasma glucose levels without any increase in circulating metformin levels, suggesting a local action in the gut [ 97 ].…”

Section: Molecular Mechanisms Underlying Metformin Actionsmentioning

confidence: 99%

“…Hence, it can mediate the effects of metformin on energy balance and body weight, whereas it is not required for the plasma glucose-lowering effect [ 34 , 109 , 110 , 111 ]. In summary, gut hormones and peripheral metabolites both contribute to the regulation of plasma glucose- and body weight homeostasis by metformin [ 40 , 96 , 112 ].…”

Section: Molecular Mechanisms Underlying Metformin Actionsmentioning

confidence: 99%

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Tulipano

2021

IJMS

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Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.

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“…Positron emission tomography with 18 F-fluorodeoxyglucose ( 18 FDG-PET) has proven to be an important tool to describe organ-specific glucose metabolism in vivo, allowing to detect and monitor abnormalities underlying metabolic and cardiovascular diseases in insulin-sensitive tissues [1][2][3][4][5][6][7]. Tissue metabolism has been most commonly studied under standardized euglycemic hyperinsulinemic conditions, in which controlled glucose and insulin infusions are delivered via the intravenous route to maintain equal plasma levels in all study subjects [2][3][4][5]7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Tissue metabolism has been most commonly studied under standardized euglycemic hyperinsulinemic conditions, in which controlled glucose and insulin infusions are delivered via the intravenous route to maintain equal plasma levels in all study subjects [2][3][4][5]7,8]. Likewise, 18 FDG is administered intravenously to quantify organ-specific glucose metabolism during the procedure [2][3][4][5][6][7][8]. Notably, this paradigm does not account for the physiological entry of glucose in the body, occurring via oral ingestion and gastrointestinal (GI) absorption.…”

Section: Introductionmentioning

confidence: 99%

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice

Guzzardi

Rosa

Campani

et al. 2022

IJMS

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Interventions affecting gastrointestinal (GI) physiology suggest that the GI tract plays an important role in modulating the uptake of ingested glucose by body tissues. We aimed at validating the use of positron emission tomography (PET) with oral 18FDG administration in mice, and to examine GI effects on glucose metabolism in adipose tissues, brain, heart, muscle, and liver, and interfering actions of oral lipid co-administration. We performed sequential whole-body PET studies in 3 groups of 10 mice, receiving i.p. glucose and 18FDG or oral glucose and 18FDG ± lipids, to measure tissue glucose uptake (GU) and GI transit, and compute the absorption lumped constant (LCa) as ratio of oral 18FDG-to-glucose incremental blood levels. GI and liver histology and circulating hormones were tested to generate explanatory hypothesis. Median LCa was 1.18, constant over time and not significantly affected by lipid co-ingestion. Compared to the i.p. route, the oral route (GI effect) resulted in lower GU rates in adipose tissues and brain, and a greater steatohepatitis score (+17%, p = 0.03). Lipid co-administration accelerated GI transit, in relation to the suppression in GIP, GLP1, glucagon, PP, and PYY (GI motility regulators), abolishing GI effects on subcutaneous fat GU. Duodenal crypt size, gastric wall 18FDG uptake, and macro-vesicular steatosis were inversely related to adipose tissue GU, and positively associated with liver GU. We conclude that 18FDG-PET is a suitable tool to examine the role of the GI tract on glucose transit, absorption, and bio-distribution. The GI effect consists in the suppression of glucose metabolism selectively in organs responsible for energy intake and storage, and is blunted by lipid ingestion. Modulation of gut and liver inflammation, as reflected by high GU, may be involved in the acute signalling of the energy status.

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Dose‐dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by ¹⁸F‐labelled fluorodeoxyglucose positron emission tomography‐MRI

Cited by 18 publications

References 36 publications

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice

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Dose‐dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by 18F‐labelled fluorodeoxyglucose positron emission tomography‐MRI

Cited by 18 publications

References 36 publications

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice

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Dose‐dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by ¹⁸F‐labelled fluorodeoxyglucose positron emission tomography‐MRI