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Metformin overdose causes platelet mitochondrial dysfunction in humans.

ABSTRACT: We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo.Human platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 ± 0.18 and lactate 16 ± 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 ± 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments).In vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls.Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.NCT 00942123.

SUBMITTER: Protti A

PROVIDER: S-EPMC3682281 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Metformin overdose causes platelet mitochondrial dysfunction in humans.

Protti Alessandro A Lecchi Anna A Fortunato Francesco F Artoni Andrea A Greppi Noemi N Vecchio Sarah S Fagiolari Gigliola G Moggio Maurizio M Comi Giacomo Pietro GP Mistraletti Giovanni G Lanticina Barbara B Faraldi Loredana L Gattinoni Luciano L

Critical care (London, England) 20121003 5

<h4>Introduction</h4>We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo.<h4>Methods</h4>Human platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain ...[more]

PMID: 23034133

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Project description:ImportanceA recent increase in patients presenting with nonfatal opioid overdoses has focused clinical attention on characterizing their risks of premature mortality.ObjectiveTo describe all-cause mortality rates, selected cause-specific mortality rates, and standardized mortality rate ratios (SMRs) of adults during their first year after nonfatal opioid overdose.Design, setting, and participantsThis US national longitudinal study assesses a cohort of patients aged 18 to 64 years who were Medicaid beneficiaries and experienced nonfatal opioid overdoses. The Medicaid data set included the years 2001 through 2007. Death record information was obtained from the National Death Index. Data analysis occurred from October 2017 to January 2018.Main outcomes and measuresCrude mortality rates per 100 000 person-years were determined in the first year after nonfatal opioid overdose. Standardized mortality rate ratios (SMR) were estimated for all-cause and selected cause-specific mortality standardized to the general population with respect to age, sex, and race/ethnicity.ResultsThe primary cohort included 76 325 adults and 66 736 person-years of follow-up. During the first year after nonfatal opioid overdose, there were 5194 deaths, the crude death rate was 778.3 per 10 000 person-years, and the all-cause SMR was 24.2 (95% CI, 23.6-24.9). The most common immediate causes of death were substance use-associated diseases (26.2%), diseases of the circulatory system (13.2%), and cancer (10.3%). For every cause examined, SMRs were significantly elevated, especially with respect to drug use-associated diseases (SMR, 132.1; 95% CI, 125.6-140.0), HIV (SMR, 45.9; 95% CI, 39.5-53.0), chronic respiratory diseases (SMR, 41.1; 95% CI, 36.0-46.8), viral hepatitis (SMR, 30.6; 95% CI, 22.9-40.2), and suicide (SMR, 25.9; 95% CI, 22.6-29.6), particularly including suicide among females (SMR, 47.9; 95% CI, 39.8-52.3).Conclusions and relevanceIn a US national cohort of adults who had experienced a nonfatal opioid overdose, a marked excess of deaths was attributable to a wide range of substance use-associated, mental health, and medical conditions, underscoring the importance of closely coordinating the substance use, mental health, and medical care of this patient population.

Dataset Information

Metformin overdose causes platelet mitochondrial dysfunction in humans.

Publications

Metformin overdose causes platelet mitochondrial dysfunction in humans.

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