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Role of AMP-activated protein
kinase in mechanism of metformin action
Zhou G, Myers R, Li Y, et al. J Clin Invest.
2001:108:1167–1174.
Metformin is a widely used drug for treatment of type 2 diabetes
with no defined cellular mechanism of action. Its glucose-lowering
effect results from decreased hepatic glucose production and increased
glucose utilization. Metformin’s beneficial effects on circulating
lipids have been linked to reduced fatty liver. AMP-activated
protein kinase (AMPK) is a major cellular regulator of lipid and
glucose metabolism. Here we report that metformin activates AMPK
in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity
is reduced, fatty acid oxidation is induced, and expression of
lipogenic enzymes is suppressed. Activation of AMPK by metformin
or an adenosine analog suppresses expression of SREBP-1, a key
lipogenic transcription factor. In metformin-treated rats, hepatic
expression of SREBP-1 (and other lipogenic) mRNAs and protein
is reduced; activity of the AMPK target, ACC, is also reduced.
Using a novel AMPK inhibitor, we found that AMPK activation is
required for metformin’s inhibitory effect on glucose production
by hepatocytes. In isolated rat skeletal muscles, metformin stimulates
glucose uptake coincident with AMPK activation. Activation of
AMPK provides a unified explanation for the pleiotropic beneficial
effects of this drug; these results also suggest that alternative
means of modulating AMPK should be useful for the treatment of
metabolic disorders.
Commentary
AMPK is an important regulator of energy metabolism in muscle.
Activation of AMPK stimulates fatty acid oxidation and glucose
uptake in both heart and skeletal muscle. This article demonstrates
that metformin, a drug used to treat type 2 diabetes mellitus,
stimulates AMPK in muscle. This article also provides evidence
that metformin activation of AMPK increases glucose uptake in
skeletal muscle. Indirect evidence is provided to show that metformin
may also activate fatty acid oxidation in muscle. Of interest
is that this group uses a novel inhibitor of AMPK to overcome
the effects of metformin on AMPK.
This paper provides important insights into the mechanism of action
of metformin. Since AMPK is a key regulator of fatty acid oxidation
and glucose uptake in the heart, it also raises the important
question as to whether metformin has direct actions on cardiac
energy metabolism. The identification of novel AMPK inhibitors
may also have important therapeutic potential in the treatment
of ischemic heart disease.
Gary Lopaschuk
Dipyridamole-induced increased glucose
uptake in patients with
single-vessel coronary artery disease assessed with PET
Araujo LI, McFalls EO, Lammertsma AA, Jones
T, Maseri A. J Nucl Cardiol. 2001;8:417–420.
The aim of this study was to determine the relationship between
vasodilatation-induced ischemia and post-stress glucose uptake.
Coronary vasodilators may induce myocardial ischemia due to coronary
steal through collateral circulation or transmural blood flow
redistribution with diminished subendocardial perfusion. Myocardial
ischemia can be demonstrated by increased glucose uptake as previously
shown in patients with exercise-induced ischemia. We studied 11
patients with single-vessel disease and no history of myocardial
infarction. Five patients had no collateral circulation, and six
had angiographic evidence of collateral vessels. We measured myocardial
blood flow (MBF) and glucose uptake at baseline and after the
administration of dipyridamole (0.56 mg/kg) with PET, using 15O
water and 18F-fluorodeoxyglucose (FDG) as perfusion and glucose
tracers. MBF at baseline was 0.82 ± 0.13 mL/g per min in normal
areas and 0.80 ± 0.15 mL/g per min in areas supplied by stenotic
arteries. MBF during dipyridamole was 2.05 ± 0.66 and 1.19 ± 0.66
mL/g per min in normal areas and areas with stenotic arteries,
respectively (P £ 0.001). FDG uptake at baseline was 1.36 ± 0.55
in normal areas and 1.57 ± 0.62 in areas supplied by stenotic
arteries. FDG uptake after dipyridamole infusion was 1.79 ± 1.1
and 4.04 ± 0.84 in normal areas and areas with stenotic arteries,
respectively (P £ 0.001). MBF and FDG uptake were not different
between patients with collateral circulation and those without
collateral circulation. Increased myocardial glucose uptake was
consistently observed after dipyridamole administration in those
areas with diminished coronary vasodilatory capacity. The similar
MBF and FDG findings in patients with and without collateral circulation
may indicate that transmural blood flow redistribution appears
to be a possible mechanism of dipyridamole-induced myocardial
ischemia.
Commentary
Traditionally, the use of FDG has been limited to the assessment
of myocardial viability. Patients with left ventricular dysfunction
who show relatively preserved or increased FDG uptake in the dysfunctional
areas (viable tissue), are likely to recover in function after
revascularization.
From animal experimental studies it is known that during episodes
of myocardial ischemia, uptake and turnover of glucose are increased
in comparison with the nonischemic state. This observation forms
the basis of the present study and of previous studies. In 1986,
Camici et al[1] showed that patients with chronic
coronary artery disease had an increased FDG uptake in the ischemic
areas (hot spot imaging) after stress testing. In 2000, Abramson
et al[2] compared the use of sestamibi SPECT
and FDG PET after stress to detect coronary artery disease in
women. The data suggested that FDG stress imaging was superior
to conventional perfusion imaging due to avoidance of breast-related
attenuation problems of perfusion imaging in women. Finally, in
the present study, Araujo et al studied single-vessel coronary
artery disease patients with FDG and perfusion PET after dipyridamole
stress. The authors also found increased FDG uptake in the areas
with decreased perfusion reserve and a stenosed coronary artery.
Thus, the available evidence suggests that FDG uptake is increased
in post-stress ischemic tissue and this approach may be used as
an alternative to detect coronary artery disease and ischemic
tissue in patients. The interesting point is that this technique
relies on a truly metabolic marker of ischemia rather than on
using a flow tracer which indirectly points to the presence of
ischemia; also that FDG can be used by both PET and SPECT systems,
allowing widespread use in clinical research and practice. Nevertheless,
much research needs to be done before it can be applied in cardiological
practice. First, the data need to be confirmed in large clinical
trials and the potential superior diagnostic and prognostic value
of hot spot FDG stress imaging and its cost-effectiveness need
to be established.
REFERENCES
Increased uptake of 18F-fluorodeoxyglucose in
postischemic myocardium of patients with exercise-induced angina.
Camici P, Araujo LI, Spinks T, Lammertsma AA, Kaski JC, Shea MJ,
Selwyn AP, Jones T, Maseri A.
Regional myocardial perfusion and exogenous glucose uptake were
assessed with rubidium-82 (82Rb) and 18F-2-fluoro-2-deoxyglucose (FDG)
in 10 normal volunteers and 12 patients with coronary artery
disease and stable angina pectoris by means of positron emission
tomography. In patients at rest, the myocardial uptake of 82Rb and
FDG did not differ significantly from that measured in normal
subjects. The exercise test performed within the positron camera
in eight patients produced typical chest pain and ischemic
electrocardiographic changes in all. In each of the eight patients
a region of reduced cation uptake was demonstrated in the 82Rb
scan recorded at peak exercise, after which uptake of 82Rb
returned to the control value 5 to 14 min after the end of the
exercise. In these patients, FDG was injected in the recovery
phase when all the variables that were altered during exercise,
including regional myocardial 82Rb uptake, had returned to control
values. In all but one patient, FDG accumulation in the regions of
reduced 82Rb uptake during exercise was significantly higher than
that in the nonischemic regions, i.e., the ones with a normal
increment of 82Rb uptake on exercise. In the nonischemic areas,
FDG uptake was not significantly different from that found in
normal subjects after exercise. In conclusion, myocardial glucose
transport and phosphorylation seem to be enhanced in the
postischemic myocardium of patients with exercise-induced
ischemia.
PMID: 3486725 [PubMed - indexed for MEDLINE]
Comment in:
Stress perfusion/metabolism imaging: a pilot
study for a potential new approach to the diagnosis of coronary
disease in women.
Abramson BL, Ruddy TD, deKemp RA, Laramee LA, Marquis JF,
Beanlands RS.
Division of Cardiology, St Michaels' Hospital, Toronto, Ontario,
Canada. abramsonb@smh.toronto.on.ca
BACKGROUND: The diagnosis of coronary artery disease (CAD) in
women continues to be a challenge. F-18 deoxyglucose (FDG)
positron emission tomography (PET) has been used for detection of
myocardial ischemia at rest. Little has been reported about FDG
stress imaging. The aim of this pilot study was to assess stress
FDG PET imaging for defining CAD in a group of women referred for
chest pain. METHODS: Stress FDG imaging was performed in 19 women
(mean age 59 +/- 10 years). All had abnormal stress testing before
entering the study. FDG and 2-methoxy-2-methylpropyl isonitrile
were injected at peak stress (treadmill n = 8, dipyridamole n =
11) followed by PET and single photon emission computed tomography
image acquisitions. Myocardial ischemia was defined by regions
that demonstrated both a defect on perfusion imaging and increased
FDG uptake relative to uptake in normal perfusion zones.
Defect/normal zone FDG ratios were also determined. Coronary
angiography was performed on all patients. RESULTS: Average, or
mean, body mass index was high at 29.2 +/- 5 kg/m2. Nine of 19
patients had significant CAD. Eight of 9 with CAD had FDG-defined
ischemia. Nine of the 10 without CAD had negative FDG images
(sensitivity 89%, specificity 90%). The average defect/normal zone
FDG ratio was greater in patients with CAD than in those without
(2.4 +/- 1.9 vs 0.9 +/- 0.4, P < .05). CONCLUSIONS: Regional FDG
uptake in areas of perfusion defects with stress increased in this
group with CAD. These pilot data suggest that stress FDG PET may
be diagnostically helpful in obese female patients. This novel
approach may complement current methods of CAD detection in women
and warrants further study.
PMID: 10888390 [PubMed - indexed for MEDLINE]
Frans Visser
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