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    Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion. Panaro Brandon L,Yusta Bernardo,Matthews Dianne,Koehler Jacqueline A,Song Youngmi,Sandoval Darleen A,Drucker Daniel J Molecular metabolism OBJECTIVE:Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues. METHODS:Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (Gcg) and (2) selective reduction of Gcg expression in the distal gut (Gcg). RESULTS:The acute GLP-1 response to olive oil or arginine administration was markedly diminished in Gcg but preserved in Gcg mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the Gcg mice. The GLP-1 response to LPS was also markedly attenuated in the Gcg mice and remained submaximal in the Gcg mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the Gcg mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the Gcg mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the Gcg mice. CONCLUSION:These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues. 10.1016/j.molmet.2020.100990
    Comparative effects of proximal and distal small intestinal administration of metformin on plasma glucose and glucagon-like peptide-1, and gastric emptying after oral glucose, in type 2 diabetes. Borg Malcolm J,Bound Michelle,Grivell Jacqueline,Sun Zilin,Jones Karen L,Horowitz Michael,Rayner Christopher K,Wu Tongzhi Diabetes, obesity & metabolism AIMS:The gastrointestinal tract, particularly the lower gut, may be key to the anti-diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon-like pepetide-1 (GLP-1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM). MATERIALS AND METHODS:Ten diet-controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg C-acetate. "Arterialized" venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP-1, insulin and glucagon, and GE, respectively. RESULTS:Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP-1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin. CONCLUSIONS:In diet-controlled T2DM patients, glucose-lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP-1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose-lowering capacity of metformin. 10.1111/dom.13567
    Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Wu Hao,Esteve Eduardo,Tremaroli Valentina,Khan Muhammad Tanweer,Caesar Robert,Mannerås-Holm Louise,Ståhlman Marcus,Olsson Lisa M,Serino Matteo,Planas-Fèlix Mercè,Xifra Gemma,Mercader Josep M,Torrents David,Burcelin Rémy,Ricart Wifredo,Perkins Rosie,Fernàndez-Real José Manuel,Bäckhed Fredrik Nature medicine Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects. 10.1038/nm.4345
    Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Foretz Marc,Guigas Bruno,Viollet Benoit Nature reviews. Endocrinology 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. 10.1038/s41574-019-0242-2
    Metformin in 2019. Flory James,Lipska Kasia JAMA 10.1001/jama.2019.3805
    Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Sun Lulu,Xie Cen,Wang Guang,Wu Yue,Wu Qing,Wang Xuemei,Liu Jia,Deng Yangyang,Xia Jialin,Chen Bo,Zhang Songyang,Yun Chuyu,Lian Guan,Zhang Xiujuan,Zhang Heng,Bisson William H,Shi Jingmin,Gao Xiaoxia,Ge Pupu,Liu Cuihua,Krausz Kristopher W,Nichols Robert G,Cai Jingwei,Rimal Bipin,Patterson Andrew D,Wang Xian,Gonzalez Frank J,Jiang Changtao Nature medicine The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia. 10.1038/s41591-018-0222-4
    Effect of Serotonin Transporter 5-HTTLPR Polymorphism on Gastrointestinal Intolerance to Metformin: A GoDARTS Study. Dujic Tanja,Zhou Kaixin,Tavendale Roger,Palmer Colin N A,Pearson Ewan R Diabetes care OBJECTIVE:The mechanism causing gastrointestinal intolerance to metformin treatment is unknown. We have previously shown that reduced-function alleles of organic cation transporter 1 (OCT1) are associated with increased intolerance to metformin. Considering recent findings that serotonin reuptake transporter (SERT) might also be involved in metformin intestinal absorption, and the role of serotonin in gastrointestinal physiology, in this study we investigated the association between a common polymorphism in the SERT gene and metformin gastrointestinal intolerance. RESEARCH DESIGN AND METHODS:We explored the effect of composite SERT 5-HTTLPR/rs25531 genotypes, L*L* (LL), L*S* (LL, LS), and S*S* (SS, SL, LL), in 1,356 fully tolerant and 164 extreme metformin-intolerant patients by using a logistic regression model, adjusted for age, sex, weight, OCT1 genotype, and concomitant use of medications known to inhibit OCT1 activity. RESULTS:The number of low-expressing SERT S* alleles increased the odds of metformin intolerance (odds ratio [OR] 1.31 [95% CI 1.02-1.67], P = 0.031). Moreover, a multiplicative interaction between the OCT1 and SERT genotypes was observed (P = 0.003). In the analyses stratified by SERT genotype, the presence of two deficient OCT1 alleles was associated with more than a ninefold higher odds of metformin intolerance in patients carrying the L*L* genotype (OR 9.25 [95% CI 3.18-27.0], P < 10); however, it showed a much smaller effect in L*S* carriers and no effect in S*S* carriers. CONCLUSIONS:Our results indicate that the interaction between OCT1 and SERT genes might play an important role in metformin intolerance. Further studies are needed to replicate these findings and to substantiate the hypothesis that metformin gastrointestinal side effects could be related to the reduced intestinal serotonin uptake. 10.2337/dc16-0706
    Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by ) and Organic Cation Transporter 1 (OCT1) (Encoded by ) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study. Dawed Adem Y,Zhou Kaixin,van Leeuwen Nienke,Mahajan Anubha,Robertson Neil,Koivula Robert,Elders Petra J M,Rauh Simone P,Jones Angus G,Holl Reinhard W,Stingl Julia C,Franks Paul W,McCarthy Mark I,'t Hart Leen M,Pearson Ewan R, Diabetes care OBJECTIVE:Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS:The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the and genes on odds of intolerance. RESULTS:Women ( < 0.001) and older people ( < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 () was associated with gastrointestinal intolerance (OR 1.34, = 0.005). rs3889348 is the top -expression quantitative trait locus for in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, < 0.001). Use of a genetic risk score derived from rs3889348 and variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, = 0.01). CONCLUSIONS:These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin. 10.2337/dc18-2182
    Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes. Dujic T,Causevic A,Bego T,Malenica M,Velija-Asimi Z,Pearson E R,Semiz S Diabetic medicine : a journal of the British Diabetic Association AIMS:Metformin is the most widely used oral anti-diabetes agent and has considerable benefits over other therapies, yet 20-30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter-individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced-function polymorphisms with common metformin-induced gastrointestinal side effects in Type 2 diabetes. METHODS:This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss-of-function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced-function alleles with gastrointestinal side effects was analysed using logistic regression. RESULTS:Forty-three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced-function alleles was significantly associated with over two-fold higher odds of the common metformin-induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07-5.01, P = 0.034). CONCLUSIONS:In conclusion, we showed for the first time the association between OCT1 variants and common metformin-induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment. 10.1111/dme.13040
    Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Bauer Paige V,Duca Frank A,Waise T M Zaved,Rasmussen Brittany A,Abraham Mona A,Dranse Helen J,Puri Akshita,O'Brien Catherine A,Lam Tony K T Cell metabolism The gut microbiota alters energy homeostasis. In parallel, metformin regulates upper small intestinal sodium glucose cotransporter-1 (SGLT1), but whether changes of the microbiota or SGLT1-dependent pathways in the upper small intestine mediate metformin action is unknown. Here we report that upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower glucose production in rodents. High-fat diet (HFD) feeding reduces glucose sensing and SGLT1 expression in the upper small intestine. Upper small intestinal metformin treatment restores SGLT1 expression and glucose sensing while shifting the upper small intestinal microbiota partly by increasing the abundance of Lactobacillus. Transplantation of upper small intestinal microbiota from metformin-treated HFD rats to the upper small intestine of untreated HFD rats also increases the upper small intestinal abundance of Lactobacillus and glucose sensing via an upregulation of SGLT1 expression. Thus, we demonstrate that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway. 10.1016/j.cmet.2017.09.019
    Enhanced Release of Glucose Into the Intraluminal Space of the Intestine Associated With Metformin Treatment as Revealed by [F]Fluorodeoxyglucose PET-MRI. Morita Yasuko,Nogami Munenobu,Sakaguchi Kazuhiko,Okada Yuko,Hirota Yushi,Sugawara Kenji,Tamori Yoshikazu,Zeng Feibi,Murakami Takamichi,Ogawa Wataru Diabetes care OBJECTIVE:Positron emission tomography (PET)-computed tomography has revealed that metformin promotes the intestinal accumulation of [F]fluorodeoxyglucose (FDG), a nonmetabolizable glucose derivative. It has remained unknown, however, whether this accumulation occurs in the wall or intraluminal space of the intestine. We here addressed this question with the use of [F]FDG PET-MRI, a recently developed imaging method with increased accuracy of registration and high soft-tissue contrast. RESEARCH DESIGN AND METHODS:Among 244 individuals with type 2 diabetes who underwent PET-MRI, we extracted 24 pairs of subjects matched for age, BMI, and HbA level who were receiving treatment with metformin (metformin group) or were not (control group). We evaluated accumulation of [F]FDG in different portions of the intestine with both a visual scale and measurement of maximum standardized uptake value (SUV), and such accumulation within the intestinal wall or lumen was discriminated on the basis of SUV. RESULTS:SUV of the jejunum, ileum, and right or left hemicolon was greater in the metformin group than in the control group. [F]FDG accumulation in the ileum and right or left hemicolon, as assessed with the visual scale, was also greater in the metformin group. SUV for the intraluminal space of the ileum and right or left hemicolon, but not that for the intestinal wall, was greater in the metformin group than in the control group. CONCLUSIONS:Metformin treatment was associated with increased accumulation of [F]FDG in the intraluminal space of the intestine, suggesting that this drug promotes the transport of glucose from the circulation into stool. 10.2337/dc20-0093
    Effects of berberine and metformin on intestinal inflammation and gut microbiome composition in db/db mice. Zhang Wang,Xu Ji-Hao,Yu Tao,Chen Qi-Kui Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Berberine and metformin, both established pharmaceutical agents with herbal origins, have incidental beneficial effects on multiple diseases, including diabetes. These effects have been speculated to occur via the gut microbiome. In this study, we administered either berberine or metformin to db/db mice and investigated changes in body weight, food intake, and blood glucose levels. Fresh stool samples were analyzed using 16 s rDNA high-throughput sequencing to evaluate the gut microbiome. Short-chain fatty acids (SCFA) in the stool were quantified using gas chromatography. The expression of NF-κB signaling pathway and tight junction (ZO1 and occludin) proteins in the intestinal epithelium was determined using qPCR and western blotting. The intestinal barrier structure was examined using transmission electron microscopy and serum lipopolysaccharide (LPS) was measured using a commercial kit. Both berberine and metformin reduced food intake, body weight, and blood glucose and HbA1c levels. Both treatments effectively restored the intestinal SCFA content, reduced the level of serum LPS, relieved intestinal inflammation, and repaired intestinal barrier structure. Intervention with metformin or berberine modified the gut microbiome in db/db mice, increasing the number of SCFA-producing bacteria (e.g., Butyricimonas, Coprococcus, Ruminococcus) and reducing opportunistic pathogens (e.g., Prevotella, Proteus). An increased abundance of other probiotics including Lactobacillus and Akkermansia was also observed. Berberine and metformin can modulate the composition of the gut microbiome and reduce body weight, blood glucose levels, and intestinal inflammation in db/db mice, which demonstrates their effectiveness in the reduction of diabetic complications in this model. 10.1016/j.biopha.2019.109131
    Metformin and the gastrointestinal tract. McCreight Laura J,Bailey Clifford J,Pearson Ewan R Diabetologia Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance. 10.1007/s00125-015-3844-9