Objective Our previous study indicated that the efficacy of metformin in lowering glycated hemoglobin (HbA1c) levels may be influenced by the pretreatment frequency of defecation (FD) in patients with type 2 diabetes mellitus (T2DM). This study aimed to further examine how FD and the metformin dose may affect HbA1c changes (ΔHbA1c) in T2DM patients. Methods A retrospective analysis was conducted on inpatients who received antidiabetic treatment without altering dosages for six months post-discharge, except for minor insulin adjustments. For new patients, FD was assessed before (pretreatment FD) and after the initiation of antidiabetic therapy (posttreatment FD). For patients already on treatment, FD was evaluated during hospitalization (posttreatment FD). Patients were categorized based on their metformin use, and the relationship between FD and ΔHbA1c was assessed 1.5-6 months post-discharge. The impact of the metformin dose and posttreatment FD on the ΔHbA1c level was analyzed, along with other factors affecting posttreatment FD. Results The analysis included 89 patients (41 on metformin, 21 newly treated; 48 not on metformin, 17 newly treated). Both pre- and posttreatment FD were linked to ΔHbA1c levels in the metformin group. The metformin dose correlated with posttreatment FD but not with pretreatment FD. A significant relationship was observed between ΔHbA1c and the metformin dose. A multiple regression analysis identified posttreatment FD and metformin dose as significant independent factors influencing ΔHbA1c levels. Additionally, diabetic peripheral neuropathy and diabetes duration were found to diminish the effectiveness of metformin, likely due to decreased posttreatment FD. Conclusion FD may independently contribute to the dose-dependent HbA1c-lowering effects of metformin.

The human body is habitat to a wide spectrum of microbial populations known as microbiota, which play an important role in overall health. The considerable research has mostly focused on the gut microbiota due to its potential to impact numerous physiological functions and its correlation with a variety of disorders, such as cardiovascular diseases (CVDs). Imbalances in the gut microbiota, known as dysbiosis, have been linked to the development and progression of CVDs through various processes, including the generation of metabolites like trimethylamine-N-oxide and short-chain fatty acids. Studies have also looked at the idea of using therapeutic interventions, like changing your diet, taking probiotics or prebiotics, or even fecal microbiota transplantation (FMT), to change the gut microbiota's make-up and how it works in order to prevent or treat CVDs. Exploring the cause-and-effect connection between the gut microbiota and CVDs offers a hopeful path for creating innovative microbiome-centered strategies to prevent and cure CVDs. This review presents an in-depth review of the correlation between the gut microbiota and CVDs, as well as potential therapeutic approaches for manipulating the gut microbiota to enhance cardiovascular health.

Introduction: The cause-effect relationships between microbiota composition changes and type 2 diabetes (T2D) are complex, likely involving two-way interactions, and require further elucidation. Few studies have examined the interactions of antidiabetic drugs with the gut microbiota. This study's goal was to evaluate the gut microbiota of patients with type 2 diabetes at first diagnosis and again after 12 weeks of taking oral antidiabetic drugs. Methods: We performed a fecal microbiota analysis of adult patients who recently received a T2D diagnosis and healthy adults. We compared the microbiota compositions between the T2D patients and healthy controls; we also evaluated changes from baseline to 12 weeks of treatment in the total group receiving oral antidiabetics, as well as in the subgroups receiving metformin and linagliptin. Results: The alpha diversity and beta diversity indices were different at baseline between patients with type 2 diabetes and healthy controls. The LEfSe analysis showed that, at the genus level, the Lactobacillus, Rothia, Collinsella, and Eubacterium genera increased in relative abundance in the T2D group while, at the species level, the Rothia mucilaginosa, Collinsella aerofaciens, and Eubacterium bioforme strains were found to be dominant in the T2D group. Faecalibacterium at the genus level and Faecalibacterium prausnitzii at the strain level increased in relative abundance in the T2D group after 12 weeks. After 12 weeks of intervention, the alpha diversity indices were significantly lower in the T2D group compared to the control group. At the end of the 12th week, the Gemmiger and Collinsella genera were dominant in the T2D group, with Gemmiger formicilis and Collinsella aerofaciens being dominant at the species level; in the control group, Bacteroides and Alistipes were dominant at the genus level, and Prevotella stercorea and Alistipes finegoldii were dominant. There was no difference in the LEfSe analysis results between baseline and 12 weeks of linagliptin treatment. At the strain level, Gemmiger formicilis, Ruminococcus bromii, Rothia mucilaginosa, and Lactobacillus ruminis were predominant at the start of metformin treatment; however, after 12 weeks, Collinsella aerofaciens became predominant. Conclusions: We report that there is a substantial change in the composition of the gut microbiota in patients with T2D. Oral antidiabetic treatments, especially metformin, have some beneficial effects on microbiota composition. Few studies have explored the interaction of antidiabetic drugs with the gut microbiota; further research will elucidate the clinical impact of these changes in gut microbiota composition in diabetes.

Human dipeptidyl peptidase 4 (hDPP-4) has been a pharmacological target for metabolic diseases, particularly diabetes, since the early 2000s. As a ubiquitous enzyme found in both prokaryotic and eukaryotic organisms, hDPP-4 plays crucial roles in host homeostasis and disease progression. While many studies have explored hDPP-4's properties, research on gut microbially derived DPP-4 (mDPP-4) remains limited. This review discusses the significance of mDPP-4 and its health implications, analyzing crystal structures of mDPP-4 in comparison to human counterparts. We examine how hDPP-4 inhibitors could influence gut microbiome composition and mDPP-4 activity. Additionally, this review connects ongoing discussions regarding DPP-4 substrate specificity and potential access routes for mDPP-4, emphasizing the urgent need for further research on mDPP-4's role in health and improve the precision of DPP-4 inhibitor therapies.

Diabetic complications are among the most pressing health issues currently. Cardiovascular problems, particularly diabetic cardiomyopathy (DCM), are responsible for almost 80% of diabetic deaths. Because of the increasing prevalence of diabetes and the increased threat of death from its consequences, researchers are searching for new pharmaceutical targets to delay or cure it. Currently, there are a few medicines available for the treatment of DCM, some of which have serious side effects. To address this issue, researchers are focusing on natural products. Thus, in this review, we discuss the prevalence, incidence, risk factors, histological spectrum, diagnosis, pathogenic pathways of DCM, genetic and epigenetic mechanisms involved in DCM, the current treatments, and the beneficial effects of natural product-based therapeutics. Natural treatments range from single doses to continuous regimens lasting weeks or months. Flavonoids are the largest class of natural compounds reported for the treatment of DCM. Natural regimens may cover the way for new treatment strategies for DCM for being multi-target agents in the treatment of DCM, with the ability to play a variety of functions via distinct signaling pathways.

This study examines the effects of metformin on brain functions focusing on the variability of the results reported in the literature. While some studies suggest that metformin may have neuroprotective effects in diabetic patients, others report an insignificant impact of metformin on cognitive function, or even a negative effect. We propose that this inconsistency may be due to intrinsic cellular-level variability among individuals, which we term "biovariance". Biovariance persists even in demographically homogeneous samples due to complex and stochastic biological processes. Additionally, the complex metabolic actions of metformin, including its influence on neuroenergetics and neuronal survival, may produce different effects depending on individual metabolic characteristics.

High consumption of Ultra-processed foods (UPF) have been identified as a potential risk factor for Non-alcoholic fatty liver disease (NAFLD). Nevertheless, there is limited empirical evidence regarding the impact of UPF, which are typical combination of processed foods, on liver health through alterations in gut microbiota and metabolic processes. We aim to examine the potential impact of UPF on liver health and to explore the role of gut microbiota and metabolites.

This study used Sprague-Dawley rats to mimic modern UPF diets for 90 days. Some serum biochemical indices, inflammatory factors, oxidative stress markers, hematoxylin-eosin (HE) staining of the liver, 16S ribosomal RNA (rRNA) and Liquid chromatography-mass spectrometry (LC-MS) of rat feces were detected.

The UPF diet-induced simple steatosis of the liver in rats without affecting the levels of IL-6, GSH, MDA, and SOD. Additionally, it modified the gut microbiota, increasing potentially harmful bacteria, such as norank_f__Desulfovibrionaceae and Staphylococcus, while also elevating the relative abundance of potentially beneficial bacteria, including Dubosiella and Allobaculum. Furthermore, the consumption of UPF led to a metabolomic disorder characterized by disruptions in the sphingolipid signaling pathway, sulfur relay system, and arachidonic acid metabolism.

In conclusion, the findings of this study indicate that the consumption of UPF influences the development of simple hepatic steatosis, potentially through alterations in gut microbiota and metabolomics.

Diabetes mellitus represents a significant global health problem. The number of people suffering from this metabolic disease is constantly rising and although the incidence is heterogeneous depending on region, country, economic situation, lifestyle, diet and level of medical care, it is increasing worldwide, especially among youths and children, mainly due to lifestyle and environmental changes. The pathogenesis of the two most common subtypes of diabetes mellitus, type 1 (T1DM) and type 2 (T2DM), is substantially different, so each form is characterized by a different causation, etiology, pathophysiology, presentation, and treatment. Research in recent decades increasingly indicates the potential role of the gut microbiome in the initiation, development, and progression of this disease. Intestinal microbes and their fermentation products have an important impact on host metabolism, immune system, nutrient digestion and absorption, gut barrier integrity and protection against pathogens. This review summarizes the current evidence on the changes in gut microbial populations in both types of diabetes mellitus. Attention is focused on changes in the abundance of specific bacterial groups at different taxonomic levels in humans, and microbiome shift is also assessed in relation to geographic location, age, diet and antidiabetic drug. The causal relationship between gut bacteria and diabetes is still unclear, and future studies applying new methodological approaches to a broader range of microorganisms inhabiting the digestive tract are urgently needed. This would not only provide a better understanding of the role of the gut microbiome in this metabolic disease, but also the use of beneficial bacterial species in the form of probiotics for the treatment of diabetes.

It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still the first-line drug for treatment of T2DM unless there are contra-indications. The drug primarily inhibits hepatic gluconeogenesis and increases the sensitivity of target cells (hepatocytes, adipocytes and myocytes) to insulin; however, increasing evidence suggests that it may also influence the gut. As T2DM patients exhibit gut dysbiosis, the intestinal microbiome has gained interest as a key target for metabolic diseases. Interestingly, changes in the gut microbiome were also observed in T2DM patients treated with metformin compared to those who were not. Therefore, the aim of this review is to present the current state of knowledge regarding the association of the gut microbiome with the antihyperglycemic effect of metformin. Numerous studies indicate that the reduction in glucose concentration observed in T2DM patients treated with metformin is due in part to changes in the biodiversity of the gut microbiota. These changes contribute to improved intestinal barrier integrity, increased production of short-chain fatty acids (SCFAs), regulation of bile acid metabolism, and enhanced glucose absorption. Therefore, in addition to the well-recognized reduction of gluconeogenesis, metformin also appears to exert its glucose-lowering effect by influencing gut microbiome biodiversity. However, we are only beginning to understand how metformin acts on specific microorganisms in the intestine, and further research is needed to understand its role in regulating glucose metabolism, including the impact of this remarkable drug on specific microorganisms in the gut.

Akkermansia muciniphila, a Gram-negative anaerobic bacterium colonizing the intestinal mucus layer, is regarded as a promising "next-generation probiotic". There is mounting evidence that diabetes and its complications are associated with disorders of A. muciniphila abundance. Thus, A. muciniphil and its components, including the outer membrane protein Amuc_1100, A. muciniphila-derived extracellular vesicles (AmEVs), and the secreted proteins P9 and Amuc_1409, are systematically summarized with respect to mechanisms of action in diabetes mellitus. Diabetes treatments that rely on altering changes in A. muciniphila abundance are also reviewed, including the identification of A. muciniphila active ingredients, and dietary and pharmacological interventions for A. mucinihila abundance. The potential and challenges of using A. muciniphila are also highlighted, and it is anticipated that this work will serve as a reference for more in-depth studies on A. muciniphila and diabetes development, as well as the creation of new therapeutic targets by colleagues domestically and internationally.

It has been reported that High-Fructose (HF) consumption, considered one of the etiological factors of Metabolic Syndrome (MetS), causes changes in the gut microbiota and metabolic disorders. There is limited knowledge on the effects of metformin in HF-induced intestinal irregularities in male and female rats with MetS.

In this study, we investigated the sex-dependent effects of metformin treatment on the gut microbiota, intestinal Tight Junction (TJ) proteins, and inflammation parameters in HF-induced MetS.

Fructose was given to the male and female rats as a 20% solution in drinking water for 15 weeks. Metformin (200 mg/kg) was administered by gastric tube once a day during the final seven weeks. Biochemical, histopathological, immunohistochemical, and bioinformatics analyses were performed. Differences were considered statistically significant at p < 0.05.

The metformin treatment in fructose-fed rats promoted glucose, insulin, Homeostasis Model Assessment of Insulin Resistance Index (HOMA-IR), and Triglyceride (TG) values in both sexes. The inflammation score was significantly decreased with metformin treatment in fructose-fed male and female rats (p < 0.05). Moreover, metformin treatment significantly decreased Interleukin-1 Beta (IL-1β) and Tumor Necrosis Factor-Alpha (TNF-α) in ileum tissue from fructose-fed males (p < 0.05). Intestinal immunoreactivity of Occludin and Claudin-1 was increased with metformin treatment in fructose-fed female rats. HF and metformin treatment changed the gut microbial composition. Firmicutes/Bacteroidetes (F/B) ratio increased with HF in females. In the disease group, Bifidobacterium pseudolongum; in the treatment group, Lactobacillus helveticus and Lactobacillus reuteri are the prominent species in both sexes. When the male and female groups were compared, Akkermansia muciniphila was prominent in the male treatment group.

In conclusion, metformin treatment promoted biochemical parameters in both sexes of fructose-fed rats. Metformin showed a sex-dependent effect on inflammation parameters, permeability factors, and gut microbiota. Metformin has partly modulatory effects on fructose-induced intestinal changes.

Diabetes is a major global health concern. This study aimed to investigate the correlation between differentially expressed lncRNAs in mice with type 2 diabetes mellitus (T2DM) and alterations in the intestinal flora and intestinal pathology. A T2DM mouse model was constructed by feeding mice a high-fat diet. Serum fat metabolism-related indices and insulin levels were biochemically detected. Serum inflammatory factors (IL-1β, IL-6, TNF-α, IL-10) and endotoxin (LPS) were measured by ELISA. Histopathological changes in the small intestines of mice were observed by HE. The short-chain fatty acid (SCFA) content was analyzed using GC-MS. Analysis of altered intestinal flora in T2DM mice was performed using a 16sRNA sequencing assay. Differences in lncRNA expression profiles in small intestinal tissues were analyzed using RNA-seq assays. Spearman's correlation analysis was used to correlate the expression of candidate lncRNAs with changes in differential gut flora. Spearman's correlation analysis was used to analyze the correlation between the expression of candidate differentially expressed lncRNAs, small intestinal permeability, and glucose absorption. We found that serum levels of LPS, BUN, Scr, TC, TG, LDL-C, IL-1β, IL-6, and TNF-α were elevated and levels of HDL-C, insulin, and IL-10 were decreased in T2DM mice. The ileal enterochromes of T2DM mice were disorganized and broken, the number of enterochromes was reduced, the local epithelial cells were necrotic, and the plasma membrane layer was locally absent. In addition, the protein expression of ZO-1 and occludin was decreased, and the protein expression of SGLT-1 and GLUT-2 was elevated in the model group compared to the control group. The levels of Acetic acid, Propionic acid and Butyric acid were decreased and the levels of Isobutyric acid and Isovaleric acid were increased, the abundance of beneficial bacteria was decreased and the abundance of harmful bacteria was increased in the feces of T2DM mice. RNA-seq identified nine differentially expressed lncRNAs (LINC00675, Gm33838, Gm11655, LOC6613926, LOC6613788, LOC6613791, LOC6613795, Arhgap27os3, and A330023F24Rik). In addition, we found significant correlations between differentially expressed lncRNAs and a variety of intestinal flora, as well as between small intestinal permeability and glucose absorption. A significant correlation was observed between differentially expressed lncRNAs in the intestinal tissues of T2DM mice and intestinal flora imbalance, small intestinal permeability, and glucose absorption.

The gastrointestinal tract is an ecosystem with heterogeneous patterns, distributions, and environments, resulting in different microbial compositions in each gut segment. The relationship between diet and microbiota determines this heterogeneity. Consumption of diets high in fat and carbohydrates (HLHC) is associated with gut dysbiosis, low microbial diversity, and metabolic syndrome (MetS). Functional fiber consumption improves the profile and diversity of the gut microbiota (GM); it stimulates the production of short-chain fatty acids (SCFAs), which act as signaling molecules that maintain the gut barrier integrity and induce hormone synthesis that regulates satiety and glucose metabolism, reducing some MetS parameters. The effect of a dietary intervention with Acanthocereus tetragonus (At), a cactus rich in fiber, antioxidants, amino acids, and minerals traditionally consumed by the Mexican population, is reported here. For this purpose, Wistar rats were randomly divided into three study groups: a control (C) group, a MetS group, and an At-supplemented group. In the MetS and At groups, an HLHC was administered for 12 weeks, inducing MetS. After 18 weeks, stool samples were collected for microbiota sequencing. HLHC administration favored Firmicutes and decreased the abundance of Bacteriodetes at the phylum level in the MetS group. At the genus level, the dietary intervention with At increased the presence of Roseburia, Ruminococcus, Blautia, Bacteroides, and Christensenella, reflecting the effect of A. tetragonus consumption on GM. At diet administration reduced body weight; the plasma glucose, insulin, and lipid levels; and insulin resistance.

Metformin is the most commonly prescribed medication for treating type 2 diabetes (T2D). It is known that metformin can alter the gut microbiome, which influences the effectiveness of metformin treatment. We posited that if the gut microbiome, a reservoir of the resistome, is altered, then the resistome should change as well. To test this hypothesis, we reanalyzed microbiome data generated by Wu et al. (Nat Med 23(7):850-858, 2017), identifying antibiotic resistance genes (ARGs) and bacterial species. Through read-based analysis, we observed that the abundance of ARGs indeed changed in many samples treated with metformin. Moreover, the altered pattern was sufficiently heterogeneous across individual samples to allow subcategorization. We also found a strong correlation between the abundance of multidrug-resistant ARGs (MDR-ARGs) and the presence of E. coli. The contig-based analysis led to the same conclusion: an increase in MDR-ARGs due to metformin was associated with an increase in E. coli. In relation to this, we were able to confirm that the majority of MDR-ARGs are likely to originate from E. coli. These results suggest that metformin may have the potential side effect of increasing E. coli carrying ARGs, particularly MDR-ARGs, which could be a concern in T2D therapy that relies on metformin.

Serotonin reuptake inhibitors cause weight gain, leading to drug discontinuation, relapse, and worsening of symptoms. This study aims to investigates the effect of metformin on weight loss, anthropometric indicators and laboratory assessments in patients of Rasht city.

This clinical trial study with parallel-group design was organized based on 60 patients in treatment group (undergoing metformin) and 60 patients in control group (undergoing routine treatment) in Shafa hospital during July 2019 to January 2020. First, we determined the overweight patients. After that, a psychiatric assistant randomly divides them into two groups, intervention and control. Both groups of patients will be explained in terms of how they were studied and whether or not they received metformin. In order to statistical analysis of collected data, we applied the Mann-Whitney U test and repeated measures ANOVA. For conducting all analysis, the IBM SPSS Statistics 28 software was used.

The mean BMI and abdominal circumference decreased significantly in the intervention group. The wrist circumference in the intervention group decreased over time, but this difference was not statistically significant. There was no statistically significant difference between the average changes of the mean values of the laboratory assessment among the group.

Weight gain can cause problems related to compliance with treatment and anxiety and depression. On the other hand, in our study, metformin was not superior to lifestyle improvements and practicing preventive methods for weight control. Further research on SSRIs and monitoring of anthropometric indices is recommended.

Although good glycemic control in patients with type 2 diabetes (T2D) can prevent cardiovascular complications, many diabetic patients still have poor optimal control. A new class of antidiabetic drugs (e.g., glucagon-like peptide-1-GLP-1 receptor agonists, sodium-glucose co-transporters-SGLT2 inhibitors), in addition to the low hypoglycemic effect, exert multiple beneficial effects at a metabolic and cardiovascular level, through mechanisms other than antihyperglycemic agents. This review aims to discuss the effects of these new antidiabetic drugs, highlighting cardiovascular and metabolic benefits, through the description of their action mechanisms as well as available data by preclinical and clinical studies. Moreover, new innovative tools in the T2D field will be described which may help to advance towards a better targeted T2D personalized care in future.

This review delves into the complex interplay between obesity-induced gut microbiota dysbiosis and the progression of type 2 diabetes mellitus (T2DM), highlighting the potential of natural products in mitigating these effects. By integrating recent epidemiological data, we aim to provide a nuanced understanding of how obesity exacerbates T2DM through gut flora alterations.

Advances in research have underscored the significance of bioactive ingredients in natural foods, capable of restoring gut microbiota balance, thus offering a promising approach to manage diabetes in the context of obesity. These findings build upon the traditional use of medicinal plants in diabetes treatment, suggesting a deeper exploration of their mechanisms of action. This comprehensive manuscript underscores the critical role of targeting gut microbiota dysbiosis in obesity-related T2DM management and by bridging traditional knowledge with current scientific evidence; we highlighted the need for continued research into natural products as a complementary strategy for comprehensive diabetes care.

The gut plays a crucial role in the development and progression of metabolic disorders, particularly in relation to type 2 diabetes mellitus (T2DM). While a high intake of dietary fiber is inversely associated with the risk of T2DM, the specific effects of various dietary fibers on T2DM are not fully understood. This study investigated the anti-diabetic properties of fermented dietary fiber (FDF) derived from soy sauce residue in T2DM mice, demonstrating its ability to lower blood glucose levels and ameliorate insulin resistance. Our findings revealed that FDF could enhance hepatic glucose metabolism via the IRS-1/PI3K/AKT/mTOR pathway. Additionally, the anti-diabetic effect of FDF was correlated with alterations in gut microbiota composition in T2DM mice, promoting a healthier gut environment. Specifically, FDF increased the abundance of beneficial flora such as Dubosiella, Butyricimonas, Lachnospiraceae_NK4A136_group, Lactobacillus and Osillibacter, while reducing harmful bacteria including Bilophila, Parabacteroides and Enterorhabdus. Further analysis of microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids (BAs), provided evidence of FDF's regulatory effects on cecal contents in T2DM mice. Importantly, FDF treatment significantly restored the G-protein-coupled receptors (GPRs) expression in the colon of T2DM mice. In conclusion, our study suggests that the anti-diabetic effects of FDF are associated with the regulation of both the liver-gut axis and the gut microbiota-SCFAs-GPRs axis.

There has been increasing evidence that the gut microbiota is closely related to type 2 diabetes (T2D). Metformin (Met) is often used in combination with saxagliptin (Sax) and repaglinide (Rep) for the treatment of T2D. However, little is known about the effects of these combination agents on gut microbiota in T2D.

A T2D mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ) was employed. The T2D mice were randomly divided into six groups, including sham, Met, Sax, Rep, Met+Sax and Met+Rep, for 4 weeks. Fasting blood glucose level, serum biochemical index, H&E staining of liver, Oil red O staining of liver and microbiota analysis by 16s sequencing were used to access the microbiota in the fecal samples.

These antidiabetics effectively prevented the development of HFD/STZ-induced high blood glucose, and the combination treatment had a better effect in inhibiting lipid accumulation. All these dosing regimens restored the decreasing ratio of the phylum Bacteroidetes: Firmicutes, and increasing abundance of phylum Desulfobacterota, expect for Met. At the genus level, the antidiabetics restored the decreasing abundance of Muribaculaceae in T2D mice, but when Met was combined with Rep or Sax, the abundance of Muribaculaceae was decreased. The combined treatment could restore the reduced abundance of Prevotellaceae_UCG-001, while Met monotherapy had no such effect. In addition, the reduced Lachnospiraceae_NK4A136_group was well restored in the combination treatment groups, and the effect was much greater than that in the corresponding monotherapy group. Therefore, these dosing regimens exerted different effects on the composition of gut microbiota, which might be associated with the effect on T2D.

Supplementation with specific probiotics may further improve the hypoglycemic effects of antidiabetics and be helpful for the development of new therapeutic drugs for T2D.

Lifestyle modifications, metformin, and linagliptin reduce the incidence of type 2 diabetes (T2D) in people with prediabetes. The gut microbiota (GM) may enhance such interventions' efficacy. We determined the effect of linagliptin/metformin (LM) vs metformin (M) on GM composition and its relationship to insulin sensitivity (IS) and pancreatic β-cell function (Pβf) in patients with prediabetes. A cross-sectional study was conducted at different times: basal, six, and twelve months in 167 Mexican adults with prediabetes. These treatments increased the abundance of GM SCFA-producing bacteria M (Fusicatenibacter and Blautia) and LM (Roseburia, Bifidobacterium, and [Eubacterium] hallii group). We performed a mediation analysis with structural equation models (SEM). In conclusion, M and LM therapies improve insulin sensitivity and Pβf in prediabetics. GM is partially associated with these improvements since the SEM models suggest a weak association between specific bacterial genera and improvements in IS and Pβf.

Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D.

In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test.

At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI.

Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

Senescence is a condition of cell cycle arrest that increases inflammation and contributes to the development of chronic diseases in the aging human body. While several compounds described as senolytics and senomorphics produce health benefits by reducing the burden of senescence, less attention has been devoted to lifestyle interventions that produce similar effects. We describe here the effects of exercise, nutrition, caloric restriction, intermittent fasting, phytochemicals from natural products, prebiotics and probiotics, and adequate sleep on senescence in model organisms and humans. These interventions can be integrated within a healthy lifestyle to reduce senescence and inflammation and delay the consequences of aging.

Metformin is the initial medication recommended for the treatment of type 2 diabetes mellitus (T2DM). In addition to diabetes treatment, the function of metformin also can be anti-aging, antiviral, and anti-inflammatory. Nevertheless, further exploration is required to fully understand its mode of operation. Historically, the liver has been acknowledged as the main location where metformin reduces glucose levels, however, there is increasing evidence suggesting that the gastrointestinal tract also plays a significant role in its action. In the gastrointestinal tract, metformin effects glucose uptake and absorption, increases glucagon-like peptide-1 (GLP-1) secretion, alters the composition and structure of the gut microbiota, and modulates the immune response. However, the side effects of it cannot be ignored such as gastrointestinal distress in patients. This review outlines the impact of metformin on the digestive system and explores potential explanations for variations in metformin effectiveness and adverse effects like gastrointestinal discomfort.

Metformin is a drug with a long history of providing benefits in diabetes management and beyond. The mechanisms of action of metformin are complex, and continue to be actively debated and investigated. The aim of this study is to identify metabolic signatures associated with metformin treatment, which may explain the pleiotropic mechanisms by which metformin works, and could lead to an improved treatment and expanded use.

This is a cross-sectional study, in which clinical and metabolomic data for 146 patients with type 2 diabetes were retrieved from Qatar Biobank. Patients were categorized into: Metformin-treated, treatment naïve, and non-metformin treated. Orthogonal partial least square discriminate analysis and linear models were used to analyze differences in the level of metabolites between the metformin treated group with each of the other two groups.

Patients on metformin therapy showed, among other metabolites, a significant increase in 3-hydroxyoctanoate and 3-hydroxydecanoate, which may have substantial effects on metabolism.

This is the first study to report an association between 3-hydroxy medium chain fatty acids with metformin therapy in patients with type 2 diabetes. This opens up new directions towards repurposing metformin by comprehensively understanding the role of these metabolites.

We aimed to investigate the association between the abundance of Dysosmobacter welbionis, a commensal gut bacterium, and metabolic health in human participants with obesity and diabetes, and the influence of metformin treatment and prebiotic intervention.

Metabolic variables were assessed and faecal samples were collected from 106 participants in a randomised controlled intervention with a prebiotic stratified by metformin treatment (Food4Gut trial). The abundance of D. welbionis was measured by quantitative PCR and correlated with metabolic markers. The in vitro effect of metformin on D. welbionis growth was evaluated and an in vivo study was performed in mice to investigate the effects of metformin and D. welbionis J115T supplementation, either alone or in combination, on metabolic variables.

D. welbionis abundance was unaffected by prebiotic treatment but was significantly higher in metformin-treated participants. Responders to prebiotic treatment had higher baseline D. welbionis levels than non-responders. D. welbionis was negatively correlated with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and fasting blood glucose levels in humans with obesity and type 2 diabetes. In vitro, metformin had no direct effect on D. welbionis growth. In mice, D. welbionis J115T treatment reduced body weight gain and liver weight, and improved glucose tolerance to a better level than metformin, but did not have synergistic effects with metformin.

D. welbionis abundance is influenced by metformin treatment and associated with prebiotic response, liver health and glucose metabolism in humans with obesity and diabetes. This study suggests that D. welbionis may play a role in metabolic health and warrants further investigation.

NCT03852069.

The significantly increasing incidence of type 2 diabetes mellitus (T2DM) over the last few decades triggers the demands of T2DM animal models to explore the pathogenesis, prevention, and therapy of the disease. The altered lipid metabolism may play an important role in the pathogenesis and progression of T2DM. However, the characterization of molecular lipid species in fasting serum related to T2DM cynomolgus monkeys is still underrecognized.

Untargeted and targeted LC-mass spectrometry (MS)/MS-based lipidomics approaches were applied to characterize and compare the fasting serum lipidomic profiles of T2DM cynomolgus monkeys and the healthy controls.

Multivariate analysis revealed that 196 and 64 lipid molecules differentially expressed in serum samples using untargeted and targeted lipidomics as the comparison between the disease group and healthy group, respectively. Furthermore, the comparative analysis of differential serum lipid metabolites obtained by untargeted and targeted lipidomics approaches, four common serum lipid species (phosphatidylcholine [18:0_22:4], lysophosphatidylcholine [14:0], phosphatidylethanolamine [PE] [16:1_18:2], and PE [18:0_22:4]) were identified as potential biomarkers and all of which were found to be downregulated. By analyzing the metabolic pathway, glycerophospholipid metabolism was associated with the pathogenesis of T2DM cynomolgus monkeys.

The study found that four downregulated serum lipid species could serve as novel potential biomarkers of T2DM cynomolgus monkeys. Glycerophospholipid metabolism was filtered out as the potential therapeutic target pathway of T2DM progression. Our results showed that the identified biomarkers may offer a novel tool for tracking disease progression and response to therapeutic interventions.

The link between drug-induced dysbiosis and its influence on brain diseases through gut-residing bacteria and their metabolites, named the microbiota-gut-brain axis (MGBA), remains largely unexplored. This review investigates the effects of commonly prescribed drugs (metformin, statins, proton-pump-inhibitors, NSAIDs, and anti-depressants) on the gut microbiota, comparing the findings with altered bacterial populations in major brain diseases (depression, multiple sclerosis, Parkinson's and Alzheimer's). The report aims to explore whether drugs can influence the development and progression of brain diseases via the MGBA. Central findings indicate that all explored drugs induce dysbiosis. These dysbiosis patterns were associated with brain disorders. The influence on brain diseases varied across different bacterial taxa, possibly mediated by direct effects or through bacterial metabolites. Each drug induced both positive and negative changes in the abundance of bacteria, indicating a counterbalancing effect. Moreover, the above-mentioned drugs exhibited similar effects, suggesting that they may counteract or enhance each other's effects on brain diseases when taken together by comorbid patients. In conclusion, the interplay of bacterial species and their abundances may have a greater impact on brain diseases than individual drugs or bacterial strains. Future research is needed to better understand drug-induced dysbiosis and the implications for brain disease pathogenesis, with the potential to develop more effective therapeutic options for patients with brain-related diseases.

Metformin is a synthetic biguanide proven to have beneficial effects against various human diseases. Research has confirmed that metformin exerts its effects by regulating the composition of intestinal microbiota. The composition of intestinal microbiota influences the efficacy of anti-PD-L1 immunotherapy. We assume that the regulation of metformin on intestinal microbiota could enhance the therapeutic efficiency of anti-PD-L1 antibodies. In Lewis lung cancer-bearing C57BL/6J mice, we find that metformin enhances PD-L1 antibody efficacy mainly depending on the existence of gut microbiota, and metformin increases the anti-tumor immunity through modulation of intestinal microbiota and affects the integrity of the intestinal mucosa. Antibiotic depletion of gut microbiota abolished the combination efficacy of PD-L1 antibody and metformin, implying the significance of intestinal microbiota in metformin's antitumor action. Combining anti-PD-L1 antibody with metformin provoked tumor necrosis by causing increased CD8 T-cell infiltration and IFN-γ expression. In conclusion, metformin could be employed as a microecological controller to prompt antitumor immunity and increase the efficacy of anti-PD-L1 antibodies. Our study provided reliable evidence that metformin could be synergistically used with anti-PD-L1 antibody to enhance the anti-cancer effect.

Metformin (MET) is a first-line therapy for type-2 diabetes mellitus (T2DM). Liraglutide (LRG) is a glucagon-like peptide-1 receptor agonist used as a second-line therapy in combination with MET.

We performed a longitudinal analysis comparing the gut microbiota of overweight and/or pre-diabetic participants (NCP group) with that of each following their progression to T2DM diagnosis (UNT group) using 16S ribosomal RNA gene sequencing of fecal bacteria samples. We also examined the effects of MET (MET group) and MET plus LRG (MET+LRG group) on the gut microbiota of these participants following 60 days of anti-diabetic drug therapy in two parallel treatment arms.

In the UNT group, the relative abundances of Paraprevotella (P = 0.002) and Megamonas (P = 0.029) were greater, and that of Lachnospira (P = 0.003) was lower, compared with the NCP group. In the MET group, the relative abundance of Bacteroides (P = 0.039) was greater, and those of Paraprevotella (P = 0.018), Blautia (P = 0.001), and Faecalibacterium (P = 0.005) were lower, compared with the UNT group. In the MET+LRG group, the relative abundances of Blautia (P = 0.005) and Dialister (P = 0.045) were significantly lower than in the UNT group. The relative abundance of Megasphaera in the MET group was significantly greater than in the MET+LRG group (P = 0.041).

Treatment with MET and MET+LRG results in significant alterations in gut microbiota, compared with the profiles of patients at the time of T2DM diagnosis. These alterations differed significantly between the MET and MET+LRG groups, which suggests that LRG exerted an additive effect on the composition of gut microbiota.

Compared to Immediate-Release (IR) metformin, Extended-Release (ER) metformin reduces side effects and pill burden while improving adherence; however, there is little real-life data on patient satisfaction with this innovative formulation to guide physicians toward a more holistic approach.

Our goal is to train general practitioners on holistic patient management, with the aim of increasing patient satisfaction and treatment adherence, reducing side effects, and improving quality of life in patients with poor tolerance to metformin-IR.

We designed an educational program for physicians called SlowDiab, aimed at establishing a holistic patient approach. In this context, adult patients with T2DM who experienced gastrointestinal discomfort with metformin-IR were enrolled and switched to metformin- ER. Data on glycemic control were collected at baseline and 2 months after switching. A survey was carried out on patients to assess their level of satisfaction.

In 69 enrolled patients (mean (min-max) age, 68.2 (41-90)), side effects decreased after switching from 61.8% to 16.2% (p < 0.01), and the mean perceived burden of adverse events on a scale of 1 to 10 also decreased (6.17 vs. 3.82; p < 0.05). Among patients previously intolerant to metformin-IR, 74.3% reported no longer experiencing any side effects after the switch. The mean number of tablets taken daily (2.28 vs. 1.66; p < 0.01) and mean plasma glycated hemoglobin (HbA1c) values (7.0% vs. 6.7%; p < 0.05) decreased, while 93.8% of patients were satisfied with the treatment change. Moreover, 84.2% reported an improvement in glycemic control after the switch.

In a real-life setting, an educational program for general practitioners confirmed that metformin ER reduces side effects and improves pill burden, therapeutic adherence, and patient satisfaction compared to metformin IR.

Theaflavins are the characteristic polyphenols in black tea which can be enzymatically synthesized. In this review, the effects and molecular mechanisms of theaflavins on obesity and its comorbidities, including dyslipidemia, insulin resistance, hepatic steatosis, and atherosclerosis, were summarized. Theaflavins ameliorate obesity potentially via reducing food intake, inhibiting pancreatic lipase to reduce lipid absorption, activating the adenosine monophosphate-activated protein kinase (AMPK), and regulating the gut microbiota. As to the comorbidities, theaflavins ameliorate hypercholesterolemia by inhibiting micelle formation to reduce cholesterol absorption. Theaflavins improve insulin sensitivity by increasing the signaling of protein kinase B, eliminating glucose toxicity, and inhibiting inflammation. Theaflavins ameliorate hepatic steatosis via activating AMPK. Theaflavins reduce atherosclerosis by upregulating nuclear factor erythropoietin-2-related factor 2 signaling and inhibiting plasminogen activator inhibitor 1. In randomized controlled trails, black tea extracts containing theaflavins reduced body weight in overweight people and improved glucose tolerance in healthy adults. The amelioration on the hyperlipidemia and the prevention of coronary artery disease by black tea extracts were supported by meta-analysis.

Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population. Understanding the potential indirect or synergistic effects of metformin on gut microbiota composition and encoded functions could potentially offer new insights into predicting treatment efficacy and designing more personalized treatments in the future. We combined targeted metabolomics and metagenomic profiling of gut microbiomes in newly diagnosed T2D patients before and after metformin therapy to identify potential pre-treatment biomarkers and functional signatures for metformin efficacy and induced changes in metformin therapy responders. Our sequencing data were largely corroborated by our metabolic profiling and identified that pre-treatment enrichment of gut microbial functions encoding purine degradation and glutamate biosynthesis was associated with good therapy response. Furthermore, we identified changes in glutamine-associated amino acid (arginine, ornithine, putrescine) metabolism that characterize differences in metformin efficacy before and after the therapy. Moreover, metformin Responders' microbiota displayed a shifted balance between bacterial lipidA synthesis and degradation as well as alterations in glutamate-dependent metabolism of N-acetyl-galactosamine and its derivatives (e.g. CMP-pseudaminate) which suggest potential modulation of bacterial cell walls and human gut barrier, thus mediating changes in microbiome composition. Together, our data suggest that glutamine and associated amino acid metabolism as well as purine degradation products may potentially condition metformin activity via its multiple effects on microbiome functional composition and therefore serve as important biomarkers for predicting metformin efficacy.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases.

The study of the gut microbiome holds great promise for understanding and treating metabolic diseases, as its functions and derived metabolites can influence the metabolic status of the host. While research on the fecal microbiome has provided valuable insights, it tells us only part of the story. This limitation arises from the substantial variations in microorganism distribution throughout the gastrointestinal tract due to changes in physicochemical conditions. Thus, relying solely on the fecal microbiome may not be sufficient to draw comprehensive conclusions about metabolic diseases. The proximal part of the small intestine, particularly the jejunum, indeed, serves as the crucial site for digestion and absorption of nutrients, suggesting a potential role of its microbiome in metabolic regulation. Unfortunately, it remains relatively underexplored due to limited accessibility. This review presents current evidence regarding the relationships between the microbiome in the upper small intestine and various phenotypes, focusing on obesity and type 2 diabetes, in both humans and rodents. Research on humans is still limited with variability in the population and methods used. Accordingly, to better understand the role of the whole gut microbiome in metabolic diseases, studies exploring the human microbiome in different niches are needed.

The prevalence of overweight, obesity, type 2 diabetes, metabolic syndrome and steatotic liver disease is rapidly increasing worldwide with a huge economic burden in terms of morbidity and mortality. Several genetic and environmental factors are involved in the onset and development of metabolic disorders and related complications. A critical role also exists for the gut microbiota, a complex polymicrobial ecology at the interface of the internal and external environment. The gut microbiota contributes to food digestion and transformation, caloric intake, and immune response of the host, keeping the homeostatic control in health. Mechanisms of disease include enhanced energy extraction from the non-digestible dietary carbohydrates, increased gut permeability and translocation of bacterial metabolites which activate a chronic low-grade systemic inflammation and insulin resistance, as precursors of tangible metabolic disorders involving glucose and lipid homeostasis. The ultimate causative role of gut microbiota in this respect remains to be elucidated, as well as the therapeutic value of manipulating the gut microbiota by diet, pre- and pro- synbiotics, or fecal microbial transplantation.

Obesity is increasing in prevalence across all age groups. Long-term obesity can lead to the development of metabolic and cardiovascular diseases through its effects on adipose, skeletal muscle, and liver tissue. Pathological mechanisms associated with obesity include immune response and inflammation as well as oxidative stress and consequent endothelial and mitochondrial dysfunction. Recent evidence links obesity to diminished brain health and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Both AD and PD are associated with insulin resistance, an underlying syndrome of obesity. Despite these links, causative mechanism(s) resulting in neurodegenerative disease remain unclear. This review discusses relationships between obesity, AD, and PD, including clinical and preclinical findings. The review then briefly explores nonpharmacological directions for intervention.

Metformin is an old drug used for the treatment of type 2 diabetes mellitus and can play a variety of roles by regulating the gut microbiota. The number of research articles on metformin in the gut microbiota has increased annually; however, no bibliometric tools have been used to analyze the research status and hot trends in this field. This study presents a bibliometric analysis of publications on metformin and gut microbiota.

We searched the Web of Science core collection database on June 8, 2023, for papers related to metformin and gut microbiota from 2012 to 2022. We used Microsoft Excel 2021, VOSviewer1.6.19, CiteSpace 6.2.4, and R software package "bibliometrix" 4.0.0 to analyze the countries, institutions, authors, journals, citations, and keywords of the included publications.

We included 517 papers, and the trend in publications increased over the last 11 years. The 517 articles were from 57 countries, including 991 institutions and 3316 authors, and were published in 259 journals. China led all countries (233 papers) and the most influential institution was the Chinese Academy of Sciences (16 papers). PLOS ONE (19 papers) was the most popular journal, and Nature (1598 citations) was the most cited journal. Li and Kim were the 2 most published authors (six papers each), and Cani (272 co-citations) was the most co-cited author. "Metabolites," "aging," and "intestinal barrier" were emerging topics in this field.

This bibliometric study comprehensively summarizes the research trends and progress of metformin and gut microbiota, and provides new research topics and trends for studying the effects of metformin on gut microbiota in different diseases.