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Christoffer Laustsen
Hyperpolarized 13C MagneticResonance Treatment
ResponseMonitoring: A New Paradigm forMultiorgan Metabolic
Assessmentof Pharmacological Interventions?Diabetes
2016;65:3529–3531 | DOI: 10.2337/dbi16-0055
Metformin is one of the most used hyperglycemic
controltherapeutics in patients with diabetes, although the
exactmechanism of action is still not fully understood
(1,2).Metformin is the preferred antihyperglycemic drug in
pa-tients with type 2 diabetes; its use in patients with type1
diabetes is limited however (3,4). A potential seriousside effect
of metformin treatment is lactic acidosis, whichhas reduced the
applicability in renal-impaired patients;however, this has been
questioned recently (5,6). Thesetogether support further
investigations of, first, the exactmechanism of action and, second,
the noninvasive methodsfor monitoring the treatment, in particular
the organ-specificmodulations imposed by metformin and their
complex in-terorgan interactions, which historically have been
especiallydifficult to assess.
This is particularly true in diseases where several organsare
simultaneously affected, such as the cardio-renal syn-drome, where
dysfunction of one organ affects the other andvice versa and where
the use of pharmacological inter-ventions in the treatment of one
organ can have detri-mental effects on the other and vice versa
(7,8). Thus theunderstanding of the organ-specific phenotypic
character-istics in diabetes and the therapy-induced alterations
isessential in the development of new treatments.
In this issue of Diabetes, the study by Lewis et al.
(9)demonstrates that a metformin-induced redox change andfollowing
redistribution of the lactate and pyruvate poolsvia lactate
dehydrogenase (LDH), which reflect a shift in thecosubstrates
[NAD+]:[NADH], products [lactate]:[pyruvate],LDH concentration,
and/or activation or inhibition of LDHitself, are directly
monitored both acutely and chronically,with similar reprogrammed
metabolic patterns.
Interestingly, the study finds an organ-specific meta-bolic
pattern with an increased lactate production in theliver compared
with the heart and potentially more impor-tant an increased lactate
production following acute infu-sion of metformin (45 min prior to
the examination),which was sustained during the full chronic period
of4 weeks of oral metformin treatment.
The study indicates that metformin reduces the glucogenicpathway
(increased lactate pool) and in turn that no aerobicalterations are
observed. Thus in spite of the acute andchronic metformin
treatment–induced metabolic shift, boththe liver and heart maintain
normal oxidative metabolism.The whole-cell [NAD+]:[NADH] do not
reflect the altered re-dox state, whereas a tendency to redox
alterations was seen inthe mitochondrial
[acetoacetate]:[b-hydroxybutyrate] in theliver, similar to what has
previously been seen in liver (2).The major finding of Lewis et al.
(9) is the [lactate]:[pyruvate]redox dependency on the
[1-13C]pyruvate:[1-13C]lactate con-version is already present
acutely, and thus it is very likelythat this change will be
indicative of the [lactate]:[pyruvate]redox at 4 weeks, allowing
for prognostic determination ofthe response to metformin if the
redox state is associatedwith the outcome of metformin treatment
(Fig. 1).
A potential limitation in the translation of hyper-polarized MR
to the clinic is that the metabolic conversionassociated with
hyperpolarized MR examinations arelimited to apparent rate constant
mapping, and severalfactors determine the accurate rate constant.
This can belargely overcome by investigating the same patient
severaltimes, thus acting as his or her own control. This
isparticularly relevant in monitoring the effects of treat-ments
and development of diseases over time (10).
MR Research Centre, Department of Clinical Medicine, Aarhus
University, Aarhus,Denmark
Corresponding author: Christoffer Laustsen, [email protected].
© 2016 by the American Diabetes Association. Readers may use
this article aslong as the work is properly cited, the use is
educational and not for profit, and thework is not altered. More
information is available at
http://www.diabetesjournals.org/content/license.
See accompanying article, p. 3544.
Diabetes Volume 65, December 2016 3529
COMMENTARY
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The prognostic potential of using hyperpolarized MRto detect
organ-specific metabolic fingerprints in relation todiseases, and
in particular the acute response to therapeuticinterventions, and
coupling them to the outcome of chronictreatment is a tremendous
opportunity for researchers andclinicians.
The recent successful translation of
hyperpolarized[1-13C]pyruvate MR examinations in prostate cancer
patients
(11) has paved the way for the use in other patient
groups(12–15), such as patient with diabetes. It is now time
toinvestigate the potential for this novel tool to aid in
theassessment of diabetes, associated complications, and
thetreatment of these.
The hyperpolarized 13C MRI methodology, dynamic nu-clear
polarization MRI, increases the signal of an inject-able biomarker
substrate, often [1-13C]pyruvate, more than
Figure 1—An altered redox state following acute and chronic
metformin treatment is observable with hyperpolarized
[1-13C]pyruvate MR,originating from an increased
[lactate]:[pyruvate] in both the liver and heart (observable as
[1-13C]lactate:[1-13C]pyruvate). Only the chronicmetformin-treated
liver showed an altered mitochondrial redox via the
[acetoacetate]:[b-hydroxybutyrate]. ACAC, acetoacetate;
b-HB,b-hydroxybutyrate.
3530 Commentary Diabetes Volume 65, December 2016
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10,000 times (11–14). The inherent low signal originatingfrom
the in vivo pool of carbons (approximately 1% of allcarbons are
13C) is almost MRI invisible, and thus the label-ing in a specific
molecular position with the nonradioactiveisotope 13C in
combination with the increased signal of thebiomarker substrate
(.10,000 times) enables the injectionof the biomarker and
subsequent monitoring of the dynamicdistribution and following
enzymatic fate of the substrate in-side cells into its metabolic
derivatives, such as [1-13C]lactate,[1-13C]alanine, and 13CO2/H
13CO32 in real time.This dynamic measurement of the metabolism
of 13C-
labeled substrates is inherently radiation free and is
con-veniently performed in combination with the standardMRI
examination. A limiting factor is the decay of thesignal, which
limits the investigations to fast metabolicprocesses (currently
less than 2 min). The use of hyper-polarized [1-13C]pyruvate MRI
provides an opportunity tocombine the flexibility and safety of
MR-based imagingwith an exceptional signal-to-noise ratio.
Exploration ofinjectable 13C-labeled substances has only recently
en-tered human trials (11).
Acknowledgments. C.L. acknowledges support from Danish
ResearchCouncil for Independent Research.Duality of Interest. No
potential conflicts of interest relevant to this articlewere
reported.
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diabetes.diabetesjournals.org Laustsen 3531
