PMID- 33807522
OWN - NLM
STAT- MEDLINE
DCOM- 20210419
LR  - 20210419
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 5
DP  - 2021 Mar 5
TI  - Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One 
      after Another in the Long History.
LID - 10.3390/ijms22052596 [doi]
LID - 2596
AB  - While there are various kinds of drugs for type 2 diabetes mellitus at present, 
      in this review article, we focus on metformin which is an insulin sensitizer and 
      is often used as a first-choice drug worldwide. Metformin mainly activates 
      adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads 
      to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates 
      AMPK in skeletal muscle as well, which increases translocation of glucose 
      transporter 4 to the cell membrane and thereby increases glucose uptake. Further, 
      metformin suppresses glucagon signaling in the liver by suppressing adenylate 
      cyclase which leads to suppression of gluconeogenesis. In addition, metformin 
      reduces autophagy failure observed in pancreatic beta-cells under diabetic 
      conditions. Furthermore, it is known that metformin alters the gut microbiome and 
      facilitates the transport of glucose from the circulation into excrement. It is 
      also known that metformin reduces food intake and lowers body weight by 
      increasing circulating levels of the peptide hormone growth/differentiation 
      factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that 
      the frequency of various cancers is lower in subjects taking metformin. Metformin 
      suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in 
      pre-neoplastic cells, which leads to suppression of cell growth and an increase 
      in apoptosis in pre-neoplastic cells. It has been shown recently that metformin 
      consumption potentially influences the mortality in patients with type 2 diabetes 
      mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin 
      is an old drug, but multifaceted mechanisms of action of metformin have been 
      unraveled one after another in its long history.
FAU - Kaneto, Hideaki
AU  - Kaneto H
AUID- ORCID: 0000-0001-7898-1943
AD  - Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 
      577 Matsushima, Kurashiki 701-0192, Japan.
FAU - Kimura, Tomohiko
AU  - Kimura T
AUID- ORCID: 0000-0003-3986-9494
AD  - Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 
      577 Matsushima, Kurashiki 701-0192, Japan.
FAU - Obata, Atsushi
AU  - Obata A
AUID- ORCID: 0000-0003-4984-4098
AD  - Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 
      577 Matsushima, Kurashiki 701-0192, Japan.
FAU - Shimoda, Masashi
AU  - Shimoda M
AD  - Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 
      577 Matsushima, Kurashiki 701-0192, Japan.
FAU - Kaku, Kohei
AU  - Kaku K
AD  - Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 
      577 Matsushima, Kurashiki 701-0192, Japan.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20210305
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Autophagy/drug effects
MH  - COVID-19/complications/mortality
MH  - Diabetes Mellitus, Type 2/complications/*drug therapy/etiology/mortality
MH  - Gastrointestinal Microbiome/drug effects
MH  - Humans
MH  - Insulin-Secreting Cells/drug effects/metabolism
MH  - Intracellular Signaling Peptides and Proteins/drug effects/metabolism
MH  - Metformin/*pharmacology
PMC - PMC7962041
OTO - NOTNLM
OT  - AMPK
OT  - COVID-19
OT  - GDF15
OT  - autophagy
OT  - glucagon signaling
OT  - gut microbiome
OT  - mTOR
OT  - metformin
COIS- The authors declare no conflict of interest.
EDAT- 2021/04/04 06:00
MHDA- 2021/04/20 06:00
PMCR- 2021/03/05
CRDT- 2021/04/03 01:27
PHST- 2021/01/16 00:00 [received]
PHST- 2021/02/20 00:00 [revised]
PHST- 2021/03/02 00:00 [accepted]
PHST- 2021/04/03 01:27 [entrez]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/04/20 06:00 [medline]
PHST- 2021/03/05 00:00 [pmc-release]
AID - ijms22052596 [pii]
AID - ijms-22-02596 [pii]
AID - 10.3390/ijms22052596 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Mar 5;22(5):2596. doi: 10.3390/ijms22052596.