Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial.
OBJECTIVE
Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1).


METHODS
In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-(3)H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP).


RESULTS
Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogen-depleting fast without hypoglycaemia.


CONCLUSIONS
Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogen-depleted state. This may trigger a rise in glucose counter-regulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia.


BACKGROUND
ClinicalTrials.gov NCT01400191 FUNDING: Danish Research Council for Health and Disease (0602-02695B) and Odense University Hospital Free Research Fund, 2012.
Department of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winsloews Vej 19, 5000, Odense, Denmark. mmchristensen@health.sdu.dk.
Mette Marie H
MM
Christensen
Department of Endocrinology, Odense University Hospital, Odense, Denmark.|Section of Molecular Diabetes & Metabolism, Institute of Molecular Medicine & Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Kurt
K
Højlund
Department of Endocrinology, Odense University Hospital, Odense, Denmark.
Ole
O
Hother-Nielsen
Department of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winsloews Vej 19, 5000, Odense, Denmark.
Tore B
TB
Stage
Department of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winsloews Vej 19, 5000, Odense, Denmark.|Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
Per
P
Damkier
Department of Endocrinology, Odense University Hospital, Odense, Denmark.
Henning
H
Beck-Nielsen
Department of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winsloews Vej 19, 5000, Odense, Denmark.
Kim
K
Brøsen
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D018592:Cross-Over Studies; D005215:Fasting / Q000097:blood; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D055815:Young Adult
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D005934:Glucagon; D008687:Metformin; D005947:Glucose
EGP; Fast; Metformin; OCT1