Advanced

The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin

Henriksson, Emma LU ; Huber, Anne Laure; Soto, Erin K.; Kriebs, Anna; Vaughan, Megan E.; Duglan, Drew; Chan, Alanna B.; Papp, Stephanie J.; Nguyen, Madelena and Afetian, Megan E., et al. (2017) In Journal of Biological Rhythms 32(4). p.345-358
Abstract

Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of... (More)

Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms affect the biological responses to metformin in a complex manner.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AMPK, circadian, diabetes, liver, metformin
in
Journal of Biological Rhythms
volume
32
issue
4
pages
14 pages
publisher
SAGE Publications
external identifiers
  • scopus:85027679704
  • wos:000408277100006
ISSN
0748-7304
DOI
10.1177/0748730417710348
language
English
LU publication?
yes
id
3b9deb59-87fb-4728-8159-2f61c2fb0c5b
date added to LUP
2017-09-04 09:33:25
date last changed
2017-09-18 11:44:09
@article{3b9deb59-87fb-4728-8159-2f61c2fb0c5b,
  abstract     = {<p>Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms affect the biological responses to metformin in a complex manner.</p>},
  author       = {Henriksson, Emma and Huber, Anne Laure and Soto, Erin K. and Kriebs, Anna and Vaughan, Megan E. and Duglan, Drew and Chan, Alanna B. and Papp, Stephanie J. and Nguyen, Madelena and Afetian, Megan E. and Lamia, Katja A},
  issn         = {0748-7304},
  keyword      = {AMPK,circadian,diabetes,liver,metformin},
  language     = {eng},
  number       = {4},
  pages        = {345--358},
  publisher    = {SAGE Publications},
  series       = {Journal of Biological Rhythms},
  title        = {The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin},
  url          = {http://dx.doi.org/10.1177/0748730417710348},
  volume       = {32},
  year         = {2017},
}