1/31/2024 0 Comments Fatal side effect of metforminĪnother consequence of inhibition of complex 1 in the mitochondrial respiratory chain is the reduced ability of mitochondria to recycle and intracellularly buffer hydrogen ions produced by ATP hydrolysis. Both reduced gluconeogenesis and glycogenolysis, in addition to reliance on glycolysis and increased glucose utilization, all contribute to hypoglycemia, which can occasionally be seen in some MALA cases. Additionally, metformin inhibits glucose-6-phosphatase, which impairs glycogenolysis. Impaired gluconeogenesis leads to reduced hepatic clearance of lactate. This leads to increased AMP levels, which inhibit fructose-1-6-bisphosphatase, a rate-limiting enzyme in gluconeogenesis. With impaired oxidative phosphorylation and pyruvate utilization, ATP generation is decreased. Metformin also causes inhibition of pyruvate carboxylase leading to reduced metabolism of pyruvate and increased conversion to lactate. Supratherapeutic metformin levels cause inhibition of complex 1 in the mitochondrial respiratory chain leading to impaired oxidative phosphorylation. Hyperlactatemia results from several processes. Metformin overdose induces two distinct metabolic derangements – hyperlactatemia and metabolic acidosis – primarily through inhibition of aerobic respiration. Depending on the setting, it carries a mortality rate of up to 50%, which is correlated with worsening of acidosis and hyperlactatemia. Metformin-associated lactic acidosis (MALA) is a rare complication of altered lactate and hydrogen metabolism defined as pH 5.0 mmol/L in the setting of metformin use or overdose. It has several notable side effects, including gastrointestinal symptoms (nausea, vomiting, and diarrhea), increased lactate production, reduced lactate clearance, and the potential to induce acidosis. Metformin exerts several physiologic actions directed at overall blood glucose reduction through insulin sensitization, antagonization of gluconeogenesis, and increasing intracellular glucose uptake. Phenformin, metformin’s predecessor, was the first oral biguanide that was withdrawn from the market for a high incidence of fatal lactic acidosis. It was used as an herbal remedy in Medieval Europe and found in the 1920s to contain guanidine, an anti-hyperglycemic compound. It is a derivative of Galega officinalis, also known as French lilac or goat’s rue. It is also used to treat several other conditions, including polycystic ovary syndrome (PCOS), hyper-insular obesity, and weight gain from antipsychotic therapy. Metformin is a biguanide compound used as first-line therapy for the treatment of diabetes mellitus and prevention of diabetic-related microvascular and macrovascular complications.
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