Abstract
Type II diabetes and pre-diabetes are widely prevalent among adults. Elevated serum glucose levels are commonly treated by targeting hepatic gluconeogenesis for downregulation. However, direct measurement of hepatic gluconeogenic capacity is accomplished only via tracer metabolism approaches that rely on multiple assumptions, and are clinically intractable due to expense and time needed for the studies. We previously introduced hyperpolarized (HP) [2-13C]dihydroxyacetone (DHA) as a sensitive detector of gluconeogenic potential, and showed that feeding and fasting produced robust changes in the ratio of detected hexoses (6C) to trioses (3C) in the perfused liver. To confirm that this ratio is robust in the setting of treatment and hormonal control, we used ex vivo perfused mouse livers from BLKS mice (glucagon treated and metformin treated), and db/db mice. We confirm that the ratio of signal intensities of 6C to 3C in 13C nuclear magnetic resonance spectra post HP DHA administration is sensitive to hepatic gluconeogenic state. This method is directly applicable in vivo and can be implemented with existing technologies without the need for substantial modifications.
Highlights
Diabetes is a widely prevalent ailment affecting more than 10% of adults in the United States, with about 20% of those undiagnosed
A further 34% of the adult population are pre-diabetic based on fasting glucose or A1C levels [1]
The inability to directly measure hepatic gluconeogenesis has hampered the development of alternative treatments and leaves the clinician uncertain of treatment efficacy at a mechanistic level
Summary
Diabetes is a widely prevalent ailment affecting more than 10% of adults in the United States, with about 20% of those undiagnosed. The ratio of integrals of hexose resonances to three- and four-carbon metabolites derived from HP DHA (identified in Figure 2) is sensitive to de novo hepatic glucose production We have demonstrated that hyperpolarized DHA is sensitive to modulations of hepatic glucose output and propose a simple metric to distinguish gluconeogenic and non-gluconeogenic livers
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