Pyruvate-Enriched Oral Rehydration Solution Improves Glucometabolic Disorders in the Kidneys of Diabetic db/db Mice

Figure 4

Diagram of the underlying glucometabolic mechanisms on pyruvate protection against diabetic nephropathy. Oral pyruvate enters cytosol via the mitochondrial pyruvate carrier in diabetic db/db mice. Pyruvate reductive reaction with LDH reaction couples the NADH oxidation to NAD⁺ with increase of NAD⁺/NADH ratio, prompting glycolytic flux at G-3-PD step. Pyruvate also stimulates PK and inhibits AR activities, leading to inhibit the HG-promoted sorbitol pathway. All restore the inhibited anaerobic glycolytic pathway induced by HG. In mitochondria, pyruvate also reactivates the HG-declined PDH by direct inhibition of PDK, increasing PDHa/PDHt ratio and glucose oxidative phosphorylation in the TCA cycle metabolism, concomitantly reducing the blood glucose level. Oral pyruvate competitive inhibition of AR in sorbitol pathway increases NAD(P)⁺/NAD(P)H ratios. As a result, it restores the suppressed PPP, leading to increase of GSH/GSSG ratios in diabetic kidney. Red color: increase; blue color: inhibition; red/blue color: untested.