Hyperpolarized ¹³C Magnetic Resonance Treatment Response Monitoring: A New Paradigm for Multiorgan Metabolic Assessment of Pharmacological Interventions?

Metformin is one of the most used hyperglycemic control therapeutics in patients with diabetes, although the exact mechanism of action is still not fully understood (1,2). Metformin is the preferred antihyperglycemic drug in patients with type 2 diabetes; its use in patients with type 1 diabetes is limited however (3,4). A potential serious side effect of metformin treatment is lactic acidosis, which has reduced the applicability in renal-impaired patients; however, this has been questioned recently (5,6). These together support further investigations of, first, the exact mechanism of action and, second, the noninvasive methods for monitoring the treatment, in particular the organ-specific modulations imposed by metformin and their complex interorgan interactions, which historically have been especially difficult to assess.

This is particularly true in diseases where several organs are simultaneously affected, such as the cardio-renal syndrome, where dysfunction of one organ affects the other and vice versa and where the use of pharmacological interventions in the treatment of one organ can have detrimental effects on the other and vice versa (7,8). Thus the understanding of the organ-specific phenotypic characteristics in diabetes and the therapy-induced alterations is essential 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 and following redistribution of the lactate and pyruvate pools via lactate dehydrogenase (LDH), which reflect a shift in the cosubstrates [NAD+]:[NADH], products [lactate]:[pyruvate], LDH concentration, and/or activation or inhibition of LDH itself, are directly monitored both acutely and chronically, with similar reprogrammed metabolic patterns.

Interestingly, the study finds an organ-specific metabolic pattern with an increased lactate production in the liver compared with the heart and potentially more important an increased lactate production following acute infusion of metformin (45 min prior to the examination), which was sustained during the full chronic period of 4 weeks of oral metformin treatment.

The study indicates that metformin reduces the glucogenic pathway (increased lactate pool) and in turn that no aerobic alterations are observed. Thus in spite of the acute and chronic metformin treatment–induced metabolic shift, both the liver and heart maintain normal oxidative metabolism. The whole-cell [NAD+]:[NADH] do not reflect the altered redox state, whereas a tendency to redox alterations was seen in the mitochondrial [acetoacetate]:[β-hydroxybutyrate] in the liver, 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 conversion is already present acutely, and thus it is very likely that this change will be indicative of the [lactate]:[pyruvate] redox at 4 weeks, allowing for prognostic determination of the response to metformin if the redox state is associated with the outcome of metformin treatment (Fig. 1).

A potential limitation in the translation of hyperpolarized MR to the clinic is that the metabolic conversion associated with hyperpolarized MR examinations are limited to apparent rate constant mapping, and several factors determine the accurate rate constant. This can be largely overcome by investigating the same patient several times, thus acting as his or her own control. This is particularly relevant in monitoring the effects of treatments and development of diseases over time (10).

The prognostic potential of using hyperpolarized MR to detect organ-specific metabolic fingerprints in relation to diseases, and in particular the acute response to therapeutic interventions, and coupling them to the outcome of chronic treatment is a tremendous opportunity for researchers and clinicians.

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 to investigate the potential for this novel tool to aid in the assessment of diabetes, associated complications, and the treatment of these.

The hyperpolarized ¹³C MRI methodology, dynamic nuclear polarization MRI, increases the signal of an injectable biomarker substrate, often [1-¹³C]pyruvate, more than 10,000 times (11–14). The inherent low signal originating from the in vivo pool of carbons (approximately 1% of all carbons are ¹³C) is almost MRI invisible, and thus the labeling in a specific molecular position with the nonradioactive isotope ¹³C in combination with the increased signal of the biomarker substrate (>10,000 times) enables the injection of the biomarker and subsequent monitoring of the dynamic distribution and following enzymatic fate of the substrate inside cells into its metabolic derivatives, such as [1-¹³C]lactate, [1-¹³C]alanine, and ¹³CO₂/H¹³CO₃− in real time.

This dynamic measurement of the metabolism of ¹³C-labeled substrates is inherently radiation free and is conveniently performed in combination with the standard MRI examination. A limiting factor is the decay of the signal, which limits the investigations to fast metabolic processes (currently less than 2 min). The use of hyperpolarized [1-¹³C]pyruvate MRI provides an opportunity to combine the flexibility and safety of MR-based imaging with an exceptional signal-to-noise ratio. Exploration of injectable ¹³C-labeled substances has only recently entered human trials (11).