Endocrine Abstracts

Type 2 diabetes causes excess cardiovascular mortality and microvascular disease. Therefore, the results of the EMPA-REG OUTCOME trial were received with great excitement, since this was the first trial with cardiovascular end points to show a benefit for persons suffering from type 2 diabetes. The striking benefit of a 38% reduction in cardiovascular mortality during SGLT2 inhibitor treatment was surprising and exceeded what was expected based on the relatively modest reductions in glycemic levels, blood pressure and body weight observed in the trial. Therefore, alternative explanations for the cardioprotective effects are sought. It has been suggested that the increase in circulating ketone bodies, observed during SGLT2 inhibitor treatment, could mediate these effects by acting as a superfuel for the heart. This remains controversial since experimental evidence regarding the metabolic effects of SGLT2 inhibitor treatment is limited, however, we have recently demonstrated a striking effect with a 50% reduction in glucose uptake during ketone infusion. In our ongoing study, we continue to investigate the hypothesis, that the increase in circulating ketone bodies will reduce oxygen consumption and improve the efficiency of the heart by increasing ketone body oxidation at the expense of FFA and glucose oxidation. We are doing this in a randomized, placebo-controlled crossover study in persons with type 2 diabetes. Using a novel combination of PET tracer techniques, we measure oxygen consumption, energy efficiency, and FFA and glucose oxidation in the heart. Uniquely, this allows previously inaccessible in-vivo measurement of cardiac substrate metabolism. The results of the study will provide new important mechanistic insight into the role of ketone bodies in the cardioprotective effects of SGLT2 inhibitors. A beneficial effect of an increase in ketone bodies could lead to development of targeted treatment to promote ketogenesis in people suffering from type 2 diabetes or ischemic heart disease.