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Abstract: FR-PO406

Effects of Chronic Renal Impairment on Glucose Homeostasis: Role of Class II PI3K-C2β

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Alliouachene, Samira, Queen Mary University , London, United Kingdom
  • Kieswich, Julius Edward, Queen Mary University , London, United Kingdom
  • Yaqoob, Muhammad M., Queen Mary University , London, United Kingdom

Group or Team Name

  • Diabetic Kidney Disease group
Background

Chronic kidney impairment may result in multiple metabolic derangements leading to insulin resistance and Type 2 diabetes. However the underlying mechanisms involved in the crosstalk between the kidney and insulin target tissues remains unknown. Therefore to help elucidate this we studied the effect of reduced kidney mass on whole-body glucose homeostasis in lean and obese mice.

Methods

Mice underwent unilateral nephrectomy (UniNX) or sham operation at 7-week old followed by either normal chow or high fat diet (HFD). 16 weeks after surgery, glucose homeostasis was assessed.

Results

Unexpectedly, despite mild proteinuria and uremia, glucose tolerance and insulin sensitivity were improved in UniNX animals both on normal and HFD without enhanced insulin secretion. This correlated with a significant increase in in vivo insulin stimulated-Akt signaling in metabolic tissues (liver, muscle and adipose tissue) both under normal and HFD in UniNX conditions. Furthermore, we observed a significant decrease of HFD-induced liver steatosis in UniNX animals. Taken together this unanticipated data show a beneficial impact of UniNX on glucose homeostasis.
To get greater insight into the molecular mechanisms involved, we investigated the role of the class II PI3K-C2β, a lipid kinase previously reported as a potential drug target for insulin sensitization. We observed that class II PI3K-C2β inactivation positive effect was accentuated by UniNX with a significant improvement of glucose metabolism and a complete protection against HFD-induced obesity and hepatic steatosis. In conclusion this study highlights an unexpected beneficial synergistic effect of PI3K-C2β inactivation and UniNX to protect against obesity, insulin resistance and hepatic steatosis.

Conclusion

Taken together this data reveal the possibility that kidney donors taking PI3K-C2β inhibitors could be fully protected against obesity, insulin resistance and diabetes. This study could encourage living kidney donations in addition to improving our understanding of the molecular mechanisms involved in the crosstalk between the kidney and insulin target tissues.

Funding

  • Government Support - Non-U.S.