Ketones, Muscle Metabolism, and SGLT2 Inhibitors

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Abstract The growing epidemic of Type 2 Diabetes (T2DM), with approximately 36 million patients in the United States alone, requires the active engagement of scientists from a variety of disciplines. Pharmaceuticals are being developed for the management of glucose metabolism, regulation of insulin sensitivity, and various other pathophysiological factors of T2DM. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been recently developed to help manage blood sugar and have proven effective for various components of metabolic syndrome. In SGLT2i trials, cardiovascular outcomes emphasized a marked reduction of heart failure and decreases in adverse cardiac events in diabetics with prior heart disease. It is speculated, from studies showing elevated fasting ketone concentration in diabetics taking SGLT2i compared to controls, that a preference for a compensatory ketone metabolism is both kickstarted by SGLT2i’s and enhances cardiovascular metabolic performance. The goal of the research in this proposal is to develop quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) capabilities for the evaluation of various cardiac functional parameters and in-vivo measurement of phosphorus metabolites and intramyocellular lipids in human skeletal muscle and myocardium. These studies will be implemented through a protocol created using phantom test models and validated in human subjects. Aim 1. To use cardiac MRI and 1H-MRS to measure differences in intramyocellular lipids content and pericardial lipid volume for the comparison of cardiovascular performance between normal glucose tolerant subjects and subjects with T2DM. In Aim 2, we shall use phosphorus-31 MRS (31P-MRS) and hydrogen-1 (1H-MRS) to measure metabolite concentrations in skeletal muscle of normal glucose tolerant and T2DM subjects. In Aim 3, we shall develop 31P-MRS to measure metabolite concentrations in myocardium and to evaluate, in conjunction with 1H-MRS, cardiac metabolite concentrations in normal glucose tolerant subjects and subjects with T2DM.