Understanding the action mechanisms of metformin in the gastrointestinal tract

Cheng, Meihui; Ren, Lili; Jia, Xianxian; Wang, Jianwei; Cong, Bin

doi:10.3389/fphar.2024.1347047

Front. Pharmacol.

2024

DOI: 10.3389/fphar.2024.1347047

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Understanding the action mechanisms of metformin in the gastrointestinal tract

Meihui Cheng,

Lili Ren,

Xianxian Jia

et al.

Abstract: 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 sign… Show more

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Cited by 3 publications

References 141 publications

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Advances in metformin‐delivery systems for diabetes and obesity management

Abbasi,

Heath,

McGinness

2024

Diabetes Obesity Metabolism

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Metformin is a medication that is commonly prescribed to manage type 2 diabetes. It has been used for more than 60 years and is highly effective in lowering blood glucose levels. Recent studies indicate that metformin may have additional medical benefits beyond treating diabetes, revealing its potential therapeutic uses. Oral medication is commonly used to administer metformin because of its convenience and cost‐effectiveness. However, there are challenges in optimizing its effectiveness. Gastrointestinal side effects and limitations in bioavailability have led to the underutilization of metformin. Innovative drug‐delivery systems such as fast‐dissolving tablets, micro/nanoparticle formulations, hydrogel and microneedles have been explored to optimize metformin therapy. These strategies enhance metformin dosage, targeting, bioavailability and stability, and provide personalized treatment options for improved glucose homeostasis, antiobesity and metabolic health benefits. Developing new delivery systems for metformin shows potential for improving therapeutic outcomes, broadening its applications beyond diabetes management and addressing unmet medical needs in various clinical settings. However, it is important to improve drug‐delivery systems, addressing issues such as complexity, cost, biocompatibility, stability during storage and transportation, loading capacity, required technologies and biomaterials, targeting precision and regulatory approval. Addressing these limitations is crucial for effective, safe and accessible drug delivery in clinical practice. In this review, recent advances in the development and application of metformin‐delivery systems for diabetes and obesity are discussed.

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Advances in metformin‐delivery systems for diabetes and obesity management

Abbasi,

Heath,

McGinness

2024

Diabetes Obesity Metabolism

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show abstract

Region-Specific Effects of Metformin on Gut Microbiome and Metabolome in High-Fat Diet-Induced Type 2 Diabetes Mouse Model

Cheng,

Jia,

Ren

et al. 2024

IJMS

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The glucose-lowering drug metformin alters the composition of the gut microbiome in patients with type 2 diabetes mellitus (T2DM) and other diseases. Nevertheless, most studies on the effects of this drug have relied on fecal samples, which provide limited insights into its local effects on different regions of the gut. Using a high-fat diet (HFD)-induced mouse model of T2DM, we characterize the spatial variability of the gut microbiome and associated metabolome in response to metformin treatment. Four parts of the gut as well as the feces were analyzed using full-length sequencing of 16S rRNA genes and targeted metabolomic analyses, thus providing insights into the composition of the microbiome and associated metabolome. We found significant differences in the gut microbiome and metabolome in each gut region, with the most pronounced effects on the microbiomes of the cecum, colon, and feces, with a significant increase in a variety of species belonging to Akkermansiaceae, Lactobacillaceae, Tannerellaceae, and Erysipelotrichaceae. Metabolomics analysis showed that metformin had the most pronounced effect on microbiome-derived metabolites in the cecum and colon, with several metabolites, such as carbohydrates, fatty acids, and benzenoids, having elevated levels in the colon; however, most of the metabolites were reduced in the cecum. Thus, a wide range of beneficial metabolites derived from the microbiome after metformin treatment were produced mainly in the colon. Our study highlights the importance of considering gut regions when understanding the effects of metformin on the gut microbiome and metabolome.

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Oligomalt, a New Slowly Digestible Carbohydrate, Reduces Post-Prandial Glucose and Insulin Trajectories Compared to Maltodextrin across Different Population Characteristics: Double-Blind Randomized Controlled Trials in Healthy Individuals, People with Obesity, and People with Type 2 Diabetes

Johansen,

Neutel,

Gupta

et al. 2024

Metabolites

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We assessed the glucometabolic effects of oligomalt, a novel fully slowly digestible carbohydrate, compared with maltodextrin, in cross-over randomized controlled trials (NCT05058144; NCT05963594) involving healthy volunteers (HV), people with overweight or obesity (PwO), and people with type 2 diabetes (T2D). We tested 33 g and/or 50 g of oligomalt/maltodextrin, which were dissolved in 300 mL of water and consumed after fasting in the morning. The primary exploratory endpoint was the incremental area under the curve (iAUC) for postprandial glucose, assessed by frequent blood sampling over 3 h. Insulin levels were also assessed. In the HV cohort, a 4 h hydrogen breath test was performed with 15 g of inulin as a positive control. Analysis was performed by a mixed model. Oligomalt elicited a lower post-prandial glucose response compared to maltodextrin in HV (50 g, n = 15 [7 women], mean age/BMI 31 years/22.6 kg/m2), in PwO (33 g and 50 g, n = 26 [10 women], age/BMI 44 years/29.9 kg/m2, mean HbA1c 5.3%), and in people with T2D (50 g, n = 22 [13 women], age/BMI 61 years/31.8 kg/m2, HbA1c 7.4%), with significant reductions observed in PwO and T2D for the 0–1 h window (HV: −19% [p = 0.149]/PwO33g-38% [p = 0.0002]/PwO50g-28% [p = 0.0027]/T2D-38% [p < 0.0001]; the 0–2 h window (HV: −17% [p = 0.311]/PwO33g-34% [p = 0.0057]/PwO50g-21% [p = 0.0415]/T2D-37% [p < 0.0001]), and the 0–3 h window (HV: −15% [p = 0.386]/PwO33g-30% [p = 0.0213]/PwO50g0−19% [p = 0.0686]/T2D−37% [p = 0.0001]). The post-prandial insulin response was significantly lower, by 38–60%, across all populations, dose, and time points, with oligomalt. In HV, the breath-hydrogen pattern was comparable between oligomalt and maltodextrin, but increased significantly with inulin. These data support the glucometabolic advantages of oligomalt over maltodextrin, hence confirming it as a healthier carbohydrate, and underscoring its full digestibility. This therefore opens up the possibility for the incorporation of oligomalt in relevant food products/matrices.

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Understanding the action mechanisms of metformin in the gastrointestinal tract

Cited by 3 publications

References 141 publications

Advances in metformin‐delivery systems for diabetes and obesity management

Advances in metformin‐delivery systems for diabetes and obesity management

Region-Specific Effects of Metformin on Gut Microbiome and Metabolome in High-Fat Diet-Induced Type 2 Diabetes Mouse Model

Oligomalt, a New Slowly Digestible Carbohydrate, Reduces Post-Prandial Glucose and Insulin Trajectories Compared to Maltodextrin across Different Population Characteristics: Double-Blind Randomized Controlled Trials in Healthy Individuals, People with Obesity, and People with Type 2 Diabetes

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