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Unveiling Metformins Molecular Mechanism of Action

Unveiling Metformin’s Molecular Mechanism of Action: Part 1

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Introduction to Metformin

Metformin, derived from the plant Galega officinalis, commonly known as goat’s rue, is a cornerstone in the treatment of type 2 diabetes. First approved in the UK in 1958 and later in the US in 1995, metformin is not just limited to managing diabetes. Emerging discussions suggest its potential in extending life expectancy, especially if started decades earlier.

Understanding Metformin’s Mechanism

Metformin’s mechanism is intricate and not yet fully understood. This article aims to simplify the complex biochemical processes, focusing on therapeutic ranges and potential toxicity. Key concepts include gluconeogenesis, enzymes, upstream and downstream reactions, cytosol, ATP, and oxidative phosphorylation.

Gluconeogenesis: The production of glucose from non-sugar sources.  

Enzyme: A protein that accelerates biochemical reactions.  

Upstream and Downstream Reactions: Reactions occurring before or after a certain point in a biochemical pathway.  

Cytosol: The liquid inside a cell.  

ATP (Adenosine Triphosphate): The primary energy molecule for cellular functions.  

Oxidative Phosphorylation: A process in the mitochondria that produces ATP using oxygen.

Metformin’s Primary Mechanism

Metformin tricks the body into using fats more efficiently by decreasing gluconeogenesis, thus forcing mitochondria to enhance fat metabolism. This is crucial for diabetic patients where gluconeogenesis operates at higher rates than normal. The goal is to reduce gluconeogenesis to homeostatic levels without entirely shutting it down, as it is essential for red blood cells during fasting.

Detailed Biochemical Pathway

Metformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), increasing the cytosolic NADH/NAD+ ratio. This higher ratio hampers the conversion of lactate to pyruvate by lactate dehydrogenase, leading to reduced glucose production. Additionally, the accumulation of FBP1 signals the upregulation of AMPK, further decreasing gluconeogenesis at the genetic level. This mechanism ensures lactate, which is acidic and potentially harmful in high concentrations, is minimized by boosting mitochondrial efficiency to replace the energy deficit from reduced gluconeogenesis.

Metformin Toxicity

At high concentrations, metformin can inhibit mitochondrial complex I, halting oxidative phosphorylation. At high metformin concentrations, the NADH/NAD+ ratio increases inside the mitochondria, which while is a desired outcome in the cytosol, is a devastating result if it occurs in the mitochondria. This leads to a rapid buildup of lactate in the cytosol, as the mitochondria can no longer process it, causing lactic acidosis—a medical emergency.

Metformin follows the principle of hormesis, where small doses are beneficial but large doses are harmful. The biphasic hormetic dose response of metformin involves activating AMPK, signaling significant metabolic stress and promoting energy efficiency. However, excessive doses can disable mitochondria, leading to death from lack of energy necessary to sustain life

Key Takeaways

  • Metformin is beneficial at the correct doses.
  • Metformin works best when the cytosol NADH/NAD+ ratio is elevated as it forces several biochemical pathways to make fat oxidation more efficient
  • Metformin is toxic when the dosage is high enough to inhibit mitochondrial complex I as the body will accumulate toxic levels of lactate and energy production will come to a halt.
  • At high enough lactate levels, the heart will no longer be able to function causing cardiac arrest and death in minutes, therefore lactic acidosis is a medical emergency.

Conclusion

Metformin, when used correctly, offers significant benefits beyond diabetes management, potentially enhancing metabolic efficiency and extending life. Understanding its molecular mechanism and maintaining appropriate dosages are crucial to harnessing its full potential while avoiding toxicity.

Medically Verified

Profile image of Dr Pawel Zawadzki

Medically Verified By Dr Pawel ZawadzkiDr. Pawel Zawadzki, a U.S.-licensed MD from McMaster University and Poznan Medical School, specializes in family medicine, advocates for healthy living, and enjoys outdoor activities, reflecting his holistic approach to health.

Profile image of Dr Pawel Zawadzki

Written by Dr Pawel ZawadzkiDr. Pawel Zawadzki, a U.S.-licensed MD from McMaster University and Poznan Medical School, specializes in family medicine, advocates for healthy living, and enjoys outdoor activities, reflecting his holistic approach to health. on August 21, 2024

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