(referred to the following paper: Al-Abri SA, Hayashi S, Thoren KL, Olson KR. Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs. Clin Toxicol (Phila). 2013 Apr 1. [Epub ahead of print])
To the Editor
Dear Sir,
I read with great interest the manuscript by Al-Abri and colleagues recently published in Clinical Toxicology.Citation1 It is a case of voluntary metformin intoxication complicated by severe lactic acidosis and hypoglycemia. Since co-ingestion of other hypoglycemic compounds was excluded, hypoglycemia was directly attributed to metformin overdose. In particular, the authors suggest a role for decreased hepatic glucose production, decreased glucose absorption and poor oral intake. All these mechanisms are reasonable.
Here, I would like to suggest one other mechanism for hypoglycemia during metformin intoxication. Growing experimental and clinical evidence shows that metformin can induce lactic acidosis by inhibiting mitochondrial respiratory chain (where oxygen is normally consumed to produce energy).Citation2–5 As a consequence, cellular glucose metabolism shifts from aerobic (mitochondrial) to anaerobic (extra-mitochondrial) and lactate production increases. If energy production has to remain constant, glucose consumption will have to rise, as anaerobic is far less efficient than aerobic metabolism in terms of energy produced per mole of glucose consumed.
Accordingly, in an in-vitro experiment conducted on human platelets kept in their own plasma, metformin dose-dependently inhibited mitochondrial respiratory chain and oxygen consumption while increasing cellular glucose consumption and lactate production. Final plasma glucose levels inversely linearly correlated with those of lactate (R2 0.93, p < 0.001; 8 experiments).Citation5
In the case reported by Al-Abri and colleagues, hypoglycemia occurred exactly when lactic acidosis was most severe.Citation1 Accelerated glucose consumption, together with the other mechanisms proposed by the authors, likely contributed to this finding.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Al-Abri SA, Hayashi S, Thoren KL, Olson KR. Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs. Clin Toxicol (Phila) 2013 Apr 1 [Epub ahead of print].
- El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275:223–228.
- Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348:607–614.
- Protti A, Fortunato F, Monti M, Vecchio S, Gatti S, Comi GP, et al. Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs. Crit Care 2012; 16:R75.
- Protti A, Lecchi A, Fortunato F, Artoni A, Greppi N, Vecchio S, et al. Metformin overdose causes platelet mitochondrial dysfunction in humans. Crit Care 2012; 16:R180.