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J Nutr Hum Health 2017 Volume 1 Issue 2
Page 14
July 24-26, 2017 | Vancouver, Canada
International conference on
DIABETES, NUTRITION, METABOLISM & MEDICARE
allied
academies
M
etformin is the most frequently administered drug
for the treatment of type 2 diabetes wherein it has
vasculoprotective benefits and is also used for PCOS.
Furthermore, trials are underway to assess its anti-ageing
properties. Over the past ten years and based on evidence
from the retrospective analysis of patient data it has also
emerged that metformin may reduce the risk of various types
ofcancer.Inaddition,thedatafromanumberof
invitro
studies
indicate that high (mM) concentrations of metformin may
have anti-proliferative actions, but the relevance to clinical
use is unclear and the cellular basis for the putative anti-
cancer effect of metformin remains unknown. Our previous
work with metformin indicates that within the concentration
range that it is effective as an anti-hyperglycaemic drug
metformin also protects the endothelium against the pro-
senescence effects of hyperglycaemia (HG) and reverses
HG-induced endothelial dysfunction (1,2). In the current
study we examined the concentration-dependent effects
of metformin on markers of angiogenesis and also markers
of the pro-survival endoplasmic reticulum (ER) stress and
autophagy pathways in micro-vascular endothelial cells
(MECs) in culture.
Methods:
Mouse MECs (MMECs) were exposed for 24h to a
low concentration (50 μM), or a high concentration (2 mM)
of metformin in normal glucose (NG), high glucose (HG), or
a glucose-starved (GS) culture media. Markers of senescence
(β-galactosidase) and ageing (Sirt1), ER stress, (GRP78,
ATF4, CHOP), autophagy (LC3A & LC3B) and angiogenesis
(antiangiogenic thrombospondin 1 (TSP1) were quantified
by western blotting.
Results and Discussion:
Exposure of MMECs to 50 μM
metformin reduced HG-senescence as determined by the
β-galactosidase assay (P < 0.05) and also protected against
HG-induced reduction in Sirt1 expression (P < 0.05); however
50 μM metformin had no effect on GS-induced increases in
the protein markers of ER Stress or autophagy. In contrast,
exposure to 2 mM, but not 50 μM, metformin markedly
reversed the effect of GS on ER stress proteins as evidenced
by the significant decrease in the levels of GRP78 (~ 4 fold,
p<0.05) ATF4 (~ 2 fold, p<0.05 and CHOP (~ 3 fold, p<0.05),
similarly for autophagy (LC3A-I to LC3A-II ~ 5.5 fold, p<0.05;
LC3B-I to LC3B-II ~ 4.3 fold, p<0.05) and in contrast to 50 μM,
metformin raised TSP1 (~ 4.0 fold, p<0.05) and in both NG and
GS reduced expression of the anti-ageing deacetylase, Sirt1,
by ~ 25% (p<0.05). These data demonstrate concentration-
dependent effects of metformin on endothelial function
with pro-survival, pro-angiogenesis effects at 50 μM and
anti-angiogenic and anti-survival effects at 2 mM. Whether
anti-angiogenic effects of metformin can be achieved during
clinical use will depend on the ability of endothelial cells in
the blood vessels supplying solid tumours to accumulate
metformin – a drug that is not metabolised in humans
Biography
Chris R. Triggle, PhD, FBPhS (Fellow of the British Pharmacology Society) joined Weill
Cornell Medicine - Qatar in 2007 as Professor of Pharmacology and was the Assistant
Dean Admissions 2009-2014. He was born in Hackney, London, UK, and obtained a
B.Sc. (Honours) in Biological Sciences, University of East Anglia and Ph.D. in Pharma-
cology, University of Alberta in Edmonton with postdoctoral studies completed in the
Department of Biochemical Pharmacology, S.U.N.Y. in Buffalo. He has held academic
appointments in both Australia & Canada including the first Director of the Biotechnol-
ogy Institute and Innovation Professor at RMIT University in Melbourne; Head of the
Department of Pharmacology & Therapeutics, Chair in Cardiovascular Research - Alber-
ta Heart and Stroke Foundation, Associate Dean Research Medicine at the University
of Calgary, as well as research advisory positions with Ciba and Novartis Canada and
chaired numerous peer review grant panels.
cht2011@qatar-med.cornell.eduChris R Triggle
Weill Cornell Medicine, Qatar
Metformin: A drug for all reasons?