sensor to treat
New activators of AMPK
have beneficial effects in
type 2 diabetes mellitus
By D. Grahame Hardie
Obesityoccurs when whole-bodyenergy intake exceeds energy expenditure for prolonged periods. This is a major public health issue because obesity increases the risk of disorders such as type 2 diabetes mellitus (T2DM).
The liver and muscle store excess energy
in the form of fat, leading to resistance to
the hormone insulin. Released when blood
glucose rises after meals, insulin normally
promotes glucose uptake by muscle and re-presses glucose production by the liver, thus
rapidly returning blood glucose to normal.
However, this process is impaired in insulin-resistant individuals, who may eventually
develop persistently elevated blood glucose
(i.e., T2DM), which can cause debilitating or
life-threatening complications. Because the
energy sensor AMPK (adenosine monophosphate–activated protein kinase) promotes
muscle glucose uptake by insulin-independent mechanisms, it was proposed in 1999
that AMPK-activating drugs might represent a novel approach to treating T2DM (1).
Representing the culmination of more than
15 years of developing this concept, a study
by Myers et al. (2) on page 507 of this issue
and a study by Cokorinos et al. (3) show that
compounds that bind to a unique site on
AMPK can promote glucose uptake by muscle, and hence reverse elevated blood glucose
in animal models of T2DM.
AMPK senses cellular energy status by
monitoring the levels of AMP, ADP, and ATP
(adenosine mono-, di-, and triphosphates)
(4). ATP and ADP can be likened to the
chemicals in a rechargeable battery, with a
high ATP:ADP ratio being equivalent to a
Division of Cell Signalling and Immunology, School of Life
Sciences, University of Dundee, Dundee DD1 5EH, Scotland,
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each of which have native salamanders. Immediate research into modes of transmission, susceptible species and habitats, and
available treatment options enabled accurate
risk assessments to inform policy (12). Importation of salamanders through the pet trade
posed the greatest risk of pathogen introduction, and this threat led to lobbying for an
importation ban by academics, government
officials, and nongovernment organizations,
supported by the private sector. Resulting
legislation banned the import of 20 salamander genera; a voluntary moratorium by the
Pet Industry Joint Advisory Council included
additional genera. This example illustrates
the power of multiple stakeholders to implement meaningful regulations and voluntary
measures in a timely fashion in order to reduce the threat from chytrid fungi.
At the time of writing, salamander chytrid
fungus has not been detected in the United
States. However, this does not reduce the
need for a more comprehensive and perma-
nent legislative solution to wildlife health is-
sues and a mature postinvasion plan should
the fungus be detected. Both prevention and
options for mitigation need to be part of a
considered response to this threat. Further-
more, recent reports that the salamander
chytrid fungus can infect hosts other than
salamanders suggest that it may emerge even
in areas without native salamander fauna,
such as Australia and southern Africa (12).
Many areas of the globe still remain naïve
to emerging parasitic chytrid fungi (see the
figure). For example, disease surveys in New
Guinea suggest that its frog fauna (which
represents 6% of global frog species) may
not yet have been exposed to amphibian chy-
trids, despite the fact that this remote island
is climatically suitable for the parasitic fungi
(13). Although the data are sparse, they sug-
gest that New Guinea may be one area where
preemptive disease mitigation could save
species such as Litoria auae (see the photo)
from decline and possible extinction.
There is a distinct opportunity for rapid,
preemptive action for policy, legislation,
and management informed by a strategic
investment to protect the biodiversity of
remaining refuges from parasitic chytrid
fungi. Although significant outcomes arose
from preemptive responses to the threat
of the salamander chytrid fungus in the
United States, greater impact (such as from
comprehensive and permanent legislative
solutions) is still hindered by lack of disease
policy, fragmented management responsi-
bility, multiple competing objectives, and
few effective options for postemergence
control (14). These problems are likely to be
magnified in developing countries, where
many species are undescribed and their
ecology is unknown, providing an addi-
tional hurdle to effective conservation. Aid
and scientific expertise from international
sources must flow to regions that are a last
remaining refuge for a large proportion of
the world’s amphibian species.
Comparatively cheap measures, such as
lobbying for protective legislation to avoid
introduction of wildlife diseases and strategically developing early response plans, will
be more effective than post hoc attempts
at species salvation. Estimates for effective
conservation of 29 threatened frog species
in Australia were costed at AU$15 million
over 5 years (15). Wildlife disease is often
an additional threat to species already exposed to overexploitation, habitat loss, and
climate change; approaches to conservation
need to be approached strategically. Efficient
management of remaining refugia requires
immediate collaboration among scientists,
policy-makers, managers, and local landowners together with commitment and funds.
By acting now to identify remaining refugia,
document fauna, improve biosecurity, and
plan contingency responses, funds, and species can be saved long term. j
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The frog species Litoria auae is endemic to Papua
New Guinea, where no parasitic chytrid fungi have
been detected to date.