Abstract: TH-PO703

Endothelial Dysfunction in High Fat Diet Fed Diabetic Mice Is Dependent on Ketohexokinase

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Doke, Tomohito, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Ishimoto, Takuji, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Hayasaki, Takahiro, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • Kawabe, Mayumi, Nagoya City University , Nagoya, Japan
  • Lanaspa, Miguel A., University of Colorado Denver, Aurora, Colorado, United States
  • Johnson, Richard J., University of Colorado Denver, Aurora, Colorado, United States
  • Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Nagoya, Japan
Background

The metabolism of both dietary and endogenously produced fructose via activated polyol pathway by ketohexokinase (KHK) has been reported to induce metabolic syndrome, a cluster of hyperglycemia, hypertension, and obesity, and also hyperuricemia attributed to ATP depletion and activation of nucleotide degradation pathway in human and rodents. Metabolic syndrome is associated with vascular dysfunctions. KHK have two splicing variant, KHK-C and KHK-A. The aim of this study is to determine the role of KHK in the development of vascular dysfunction in diabetes.

Methods

Diabetes was induced by low-dose streptozotocin in male wild-type (WT), KHK-A knockout mice (KHK-A KO), and both KHK-C and KHK-A knockout mice (KHK-A/C KO). Then they were fed high fat diet (45% fat). At 24 weeks, blood, urine, and tissue samples including aorta were collected. Biochemical analysis, urinary nitrate/nitrite measurement, and metabolomic analysis of urine was done. The relaxing effects of acetylcholine (ACh) and effects of NO synthase inhibitors, N-nitro-L-arginine (LNA), on the contractions by phenylephrine (PE) were measured in endothelium-intact aortas.

Results

The level of blood glucose, body weight and blood pressure was similar among diabetic mice. However, urinary nitrate/nitrite concentration was significantly lower in diabetic WT and diabetic KHK-A KO compared with diabetic KHK-A/C KO. Whereas ACh-induced relaxation in the aortas did not show significant difference among diabetic mice, PE-induced contractions with pretreatment of LNA (LNA/PE ratio) was significantly decreased in both diabetic WT and diabetic KHK-A KO compared to A/C KO mice, indicating endothelial dysfunction was alleviated in diabetic KHK-A/C KO mice. Metabolomic analysis revealed the significant correlations between LNA/PE ratio and urinary metabolites. Especially, urinary uric acid was inversely correlated with LNA/PE ratio in diabetic mice.

Conclusion

Vascular dysfunction was attenuated in diabetic KHK-A/C KO compared with WT and KHK-A KO. These results suggest that endothelial dysfunction in high fat fed diabetic mice might be due to fructose metabolism dependent on KHK-C.