Effects of Pyruvate Dehydrogenase Kinase Inhibition in Type 2 Diabetes

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) exhibit renal protective effects in CKD, but the mechanisms remain unclear. Studies of the renal translatome showed that SGLT2i markedly reduced the expression of pyruvate dehydrogenase kinase 4 (PDK4) in diabetic mice. Pyruvate dehydrogenase kinases are a family of 4 enzymes that regulate glucose and lipid metabolism and may have an important role in diabetes. In this study, we examined the effects of SGLT2i, pan PDK inhibition, and specific PDK4i on db/db mice. Methods: Db/db mice (6 weeks old) were randomized into 5 groups: Vehicle control, SGLT2i Dapagliflozin (Dapa, 1 mg/kg), Dichloroacetate, a pan PDK inhibitor (DCA, 400 mg/kg), Dapa + DCA, and PDK4i (15 mg/kg). Treatments were given by oral gavage for 15 weeks. Db/m background mice were used as control. Body weight, blood glucose (unfasted/fasted), and urine markers (lactate, glucose, protein) were monitored for over 15 weeks of treatment. Results: Dapa, DCA, or PDK4i caused moderate reduction in unfasted BG. Dapa+DCA caused significant reduction in unfasted BG to baseline levels. In fasted animals, Dapa or Dapa+ DCA reduced BG to baseline. The effect of PDK4i on BG in fasted animals remained unchanged compared to the unfasted state. While the Vehicle, Dapa, DCA, and PDK4i groups showed a robust increase in BW that plateaued by the end of treatment, the Dapa+DCA group showed a remarkable and persistent increase in BW. Furthermore, Dapa+DCA group and DCA group showed increased proteinuria by the end of treatment compared to other groups. Finally, the DCA group (and to a lesser extent the Dapa+DCA) exhibited higher urinary d-lactate compared to other groups throughout the duration of the study. Conclusion: Our results show that pan PDK inhibition has unique and potentially detrimental effects on BW and metabolic profile of diabetic mice compared to selective PDK4 inhibition. Whether selective PDK4 inhibition with or without SGLT2 inhibition is beneficial in the diabetic setting remains to be determined. Funding: NIDDK Support