Summary of Key Findings on Metformin’s Impact on the Gastrointestinal Tract

Metformin, a biguanide derived from the plant Galega officinalis (French lilac), is the initial medication recommended for the treatment of type 2 diabetes mellitus (T2DM). Beyond its primary role in managing T2DM, metformin exhibits a range of therapeutic effects, including modest weight reduction, anti-aging properties, antiviral activity, and anti-inflammatory effects. Notably, recent evidence has shifted the focus from the liver to the gastrointestinal (GI) tract as a significant site of metformin’s action. This review outlines the multifaceted impact of metformin on the digestive system and explores potential explanations for variations in its effectiveness and adverse effects like gastrointestinal discomfort.

1. Effects of Metformin on Glucose Uptake and Absorption

Metformin modulates glucose metabolism in the intestine through several mechanisms:

• Inhibition of Glucose Absorption: Metformin reduces dietary glucose absorption by decreasing the expression of sodium-glucose cotransporter 1 (SGLT1) on the apical membrane of enterocytes. This leads to a lower intra- and extracellular sodium concentration gradient, thereby inhibiting glucose transport from the intestinal lumen into the bloodstream.
• Enhancement of Glucose Uptake: Positron emission tomography-computed tomography (PET-CT) imaging studies have shown that metformin increases glucose uptake from the circulation into the GI tract. In T2DM patients treated with metformin, PET-CT scans revealed increased accumulation of 18F-labeled fluorodeoxyglucose (^18F-FDG) in the intestines, indicating enhanced glucose uptake by the GI tract.
• Translocation of GLUT2: Metformin promotes the translocation of glucose transporter 2 (GLUT2) from the basolateral to the apical membrane of enterocytes. This facilitates glucose uptake from the bloodstream into enterocytes and potentially into the intestinal lumen, contributing to glucose regulation.

These actions collectively contribute to metformin’s glucose-lowering effects by reducing glucose absorption into the bloodstream and promoting glucose utilization within the intestines.

2. Increased Glucagon-Like Peptide-1 (GLP-1) Secretion

Metformin enhances the secretion of GLP-1 from L cells in the intestine, which plays a critical role in glucose homeostasis:

• Stimulation of GLP-1 Release: Metformin increases GLP-1 levels by enhancing glucose uptake in the upper small intestine, leading to increased glucose levels in the distal intestine and stimulating GLP-1 secretion.
• Inhibition of Dipeptidyl Peptidase-4 (DPP4): Metformin reduces DPP4 activity, decreasing the degradation of GLP-1 and increasing its concentration.
• Modulation of Bile Acid Reabsorption: Metformin inhibits bile acid reabsorption by downregulating bile acid transporter proteins and altering farnesoid X receptor (FXR) signaling. This increases luminal bile acid concentrations, activating the Takeda G-protein-coupled receptor 5 (TGR5) on L cells and promoting GLP-1 secretion.
• Involvement of PEN2 and Receptors: Metformin’s effect on GLP-1 secretion involves the PEN2 subunit of γ-secretase and activation of M3 cholinergic and gastrin-releasing peptide (GRP) receptors.

GLP-1 stimulates insulin secretion from pancreatic β-cells and suppresses glucagon secretion, enhancing glucose regulation.

3. Alteration of the Gut Microbiota

Metformin induces significant changes in the composition and function of the gut microbiome:

• Increase in Short-Chain Fatty Acid (SCFA)-Producing Bacteria: Metformin promotes the growth of SCFA-producing bacteria such as Akkermansia muciniphila and Lactobacillus species. This leads to increased levels of SCFAs like butyrate and propionate, which improve host metabolism by activating intestinal gluconeogenesis and increasing GLP-1 secretion.
• Decrease in Pathogenic Bacteria: Metformin reduces the abundance of bacteria like Bacteroides fragilis, which suppress bile salt hydrolase activity. This alteration increases secondary bile acids like glycoursodeoxycholic acid (GUDCA), inhibiting intestinal FXR signaling and improving glucose homeostasis.
• Enhancement of Gut Barrier Function: Metformin strengthens the intestinal mucosal barrier by increasing goblet cell numbers and thickening the mucus layer, reducing inflammation.

These microbiota changes contribute to metformin’s glucose-lowering effects and anti-inflammatory properties.

4. Metformin and Drug Transporter Proteins

Metformin’s absorption in the small intestine involves specific transporter proteins:

• Organic Cation Transporters (OCTs): OCT1, OCT2, and OCT3 facilitate metformin uptake in enterocytes and other tissues.
• Plasma Membrane Monoamine Transporter (PMAT) and Serotonin Transporter (SERT): These transporters contribute significantly to metformin’s intestinal absorption, accounting for approximately 20% each of its transport.
• Multidrug and Toxin Extrusion Proteins (MATEs): MATE1 and MATE2-K are involved in metformin’s excretion and distribution.

Genetic variations in these transporter proteins, particularly OCT1, can affect metformin’s pharmacokinetics, efficacy, and the likelihood of adverse effects. However, the impact of OCT1 polymorphisms on metformin’s glucose-lowering efficacy remains a subject of debate.

5. Modulation of Immune Response

Metformin modulates the immune system by influencing gut microbiota and reducing inflammation:

• Regulation of Cytokines: Metformin decreases pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6) in adipose tissue.
• Activation of Regulatory T Cells: By increasing A. muciniphila, metformin enhances the proliferation of regulatory T cells in visceral adipose tissue.
• Suppression of NF-κB Signaling: Metformin downregulates the nuclear factor kappa-B (NF-κB) pathway, reducing inflammatory responses.

These immune-modulating effects contribute to metformin’s therapeutic benefits in metabolic diseases and may have implications for aging and age-related conditions.

6. Other Mechanisms

Metformin exerts glucose-lowering effects through inter-organ communication:

• Gut-Liver Axis: Metformin increases glucose uptake in the intestine, leading to lactate and acetate production. These metabolites are transported to the liver via the portal vein, where they suppress hepatic glucose production.
• Gut-Liver-Brain Axis: Metformin activates duodenal GLP-1 receptors, initiating neuronal pathways that reduce hepatic glucose production through the brain.

These mechanisms emphasize the gut as the initial site of metformin’s action, highlighting its central role in glucose regulation.

Adverse Effects of Metformin

Despite its benefits, metformin is associated with certain adverse effects:

1. Gastrointestinal Side Effects

• Prevalence: Approximately 20% of patients experience gastrointestinal symptoms such as nausea, vomiting, diarrhea, and bloating.
• Impact on Treatment: About 5% of patients discontinue metformin due to these side effects.
• Mechanisms: The side effects may be related to:
  • Alterations in Gut Microbiota: Metformin-induced changes can increase gas production and affect gut motility, leading to discomfort.
  • High Local Concentrations: Accumulation of metformin in the intestines due to transporter protein saturation can cause irritation.
• Genetic Factors: Variants in genes encoding transporter proteins like OCT1, PMAT, and SERT may increase the risk of gastrointestinal side effects.

2. Lactic Acidosis

• Incidence: Metformin-associated lactic acidosis (MALA) is rare but severe, with a mortality rate of up to 50%.
• Risk Factors: Renal impairment, hepatic dysfunction, and conditions causing hypoxia increase the risk.
• Mechanism: Metformin inhibits mitochondrial respiratory chain complex I, increasing anaerobic glucose metabolism and lactate production.
• Management: Differentiating MALA from other types of lactic acidosis is crucial for appropriate treatment.

3. Vitamin B12 Deficiency

• Prevalence: Long-term metformin use can lead to vitamin B12 deficiency in up to 30% of patients.
• Mechanism: Metformin may interfere with the calcium-dependent absorption of the vitamin B12–intrinsic factor complex in the terminal ileum.
• Clinical Implications: Vitamin B12 deficiency can cause peripheral neuropathy, which may be mistaken for diabetic neuropathy.
• Recommendations: Regular monitoring of vitamin B12 levels is advised for patients on long-term metformin therapy.

Significance and Contribution to the Body of Knowledge

The recognition of the gastrointestinal tract as a primary target of metformin’s action significantly enhances our understanding of its therapeutic mechanisms:

• Shift in Understanding: Previously, the liver was considered the main site of metformin’s glucose-lowering effects. The new focus on the GI tract provides a more comprehensive view of its action.
• Therapeutic Implications: Understanding metformin’s effects on glucose uptake, GLP-1 secretion, gut microbiota, and immune modulation opens avenues for optimizing therapy and minimizing adverse effects.
• Personalized Medicine: Identifying genetic variations in transporter proteins and gut microbiota composition can inform individualized treatment plans, improving efficacy and tolerability.
• Side Effect Management: Insights into the mechanisms underlying gastrointestinal side effects can lead to strategies that mitigate these reactions, enhancing patient adherence.
• Broadening Applications: Metformin’s impact on gut microbiota and immune modulation may have implications beyond T2DM, including potential benefits in obesity, cancer, cardiovascular diseases, aging, and even COVID-19.

Key Statistical Numbers Quantifying the Effects

• Gastrointestinal Side Effects: Affect approximately 20% of patients, with 5% discontinuing therapy due to intolerance.
• Lactic Acidosis Mortality Rate: MALA has a mortality rate of up to 50%, however this condition is extremely rare
• Vitamin B12 Deficiency: In a study of 256 participants, 19 patients on metformin had vitamin B12 deficiency (<150 pmol/L) compared to 5 in the placebo group; 35 in the metformin group had low vitamin B12 levels (150–220 pmol/L) versus 13 in the placebo group.
• Transporter Protein Contribution to Metformin Uptake: OCT1, PMAT, and SERT contribute approximately 25%, 20%, and 20% respectively to metformin’s intestinal uptake.

Conclusion

Metformin remains a cornerstone in the management of T2DM due to its efficacy, safety profile, and affordability. The emerging understanding of the gastrointestinal tract’s central role in metformin’s action provides valuable insights into its multifaceted mechanisms. By affecting glucose uptake and absorption, enhancing GLP-1 secretion, altering the gut microbiota, and modulating immune responses, metformin exerts comprehensive effects that extend beyond glycemic control.

Understanding these mechanisms not only contributes to the body of knowledge but also has practical implications for improving metformin therapy. It enables healthcare professionals to tailor treatments based on individual patient factors, potentially improving outcomes and reducing adverse effects. Further research into metformin’s actions within the GI tract may reveal additional therapeutic targets and enhance the management of T2DM and related conditions.

Disclaimer: This article is for informational purposes only and does not substitute professional medical advice. Always consult a qualified healthcare provider for guidance tailored to your health situation.

At CanadianInsulin, we’re dedicated to providing up-to-date information and quality medications to support your health needs. Explore our range of GLP-1 receptor agonists and consult with our pharmacists for more information.