Abstract
Despite being first published over 40 years ago, the combination of 13C nuclear magnetic resonance spectroscopy (NMR) and the isolated perfused liver preparation remains a unique and relevant approach in investigating the effects of pharmacological interventions on hepatic metabolism. The use of intact, perfused livers maintains many metabolic reactions at their respective rates in vivo, while the use of 13C-labelled substrates in combination with 13C NMR allows for a detailed study of specific pathways, as well as the design of robust assays which can be used to evaluate novel pharmacological agents. In this review article, we share some of the methods used to probe glucose metabolism, and highlight key findings and successes derived from the application of this specialized technique to the area of drug development for diabetes and related metabolic disorders.
Highlights
Throughout the recent decades, there have been numerous novel therapeutic agents approved for the treatment of diabetes and related metabolic disorders
Consistent with the heterogenous nature of the etiology of diabetes, these treatments elicit their therapeutic effects via modulation of different metabolic pathways such as insulin sensitivity [1], renal glucose reabsorption [2], glucose-dependent insulin secretion [3], and hepatic glucose production [4]
Another ubiquitous approach in the study of metabolic pathways is the use of nuclear magnetic resonance (NMR) spectroscopy with 13C-labelled stable isotopes
Summary
Throughout the recent decades, there have been numerous novel therapeutic agents approved for the treatment of diabetes and related metabolic disorders. A dose titration of glucagon itself in this assay (data not shown) yielded an EC50 of approximately 20 pM (70 ng/mL) which is consistent with in vivo data [16], highlighting the fact that the perfused liver recapitulates normal physiology.
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