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Abstract: FR-PO417

The Use of Type 2 Hypoglycemic Agents in Type 1 Diabetic Animals: Unveiling Novel Signaling Pathways

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Dia, Batoul, American University of Beirut, Beirut, Lebanon
  • Bou assi, Patricia, American University of Beirut, Beirut, Lebanon
  • El mouhayyar, Christopher, American Univeristy of Beirut , Naccache, Lebanon
  • Barakat, Rasha, Universite Paris Descartes, Amioun, Lebanon
  • Mahjoub, Neamah, American University of Beirut, Beirut, Lebanon
  • Eid, Assaad Antoine, American University of Beirut/Faculty of Medicine, Beirut, Lebanon
Background

Diabetic nephropathy (DN) is the leading cause of end stage renal disease. The AMPk activator, metformin, or the GLP1-agonist, liraglutide are hypoglycemic agents that are typically prescribed to type 2 diabetic patients. With their distinct mechanisms of action, these hypoglycemic drugs are utilized in our study to dissect the molecular pathway through which DN may ensue in type1 diabetes. Oxidative stress is known to be the unifying mechanisms that mediates the pathogenesis of DN, however, the role of the DUOX subfamily of enzymes, a poorly studied cellular source of reactive oxygen species (ROS), and their mechanism of action has not been previously characterized in DN. In this study, we aim to examine the expression of DUOXs in the diabetic renal system and reveal their crosstalk with AMPK/GLP-1 signaling in type 1 diabetic animals.

Methods

Monotherapy and combination therapy of metformin and liraglutide were used to assess their effects on glomerular injury in STZ-induced type-1 diabetic animals. ROS production, proteins and mRNA levels of DUOX, AMPK, mTOR, and autophagy markers were examined and correlated with morphological alterations observed histologically in addition to albuminuria.

Results

Our results showed that metformin or liraglutide monotherapy or their combination did not affect glycaemia. However, a decrease in albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis was evident, especially when the drugs were used in combination. Elevated ROS production correlated with NADPH oxidase activity in diabetic animals compared to non-diabetic animals. The administration of the metformin or liraglutide was shown to partially reverse DUOX-derived ROS production, the expression of fibronectin, COL IV, nephrin, DUOX1, DUOX2, AMPK, mTOR and autophagy markers LC3A and LC3B in the type 1 diabetic animals. An effect that was more pronounced when the drugs were used in combination.

Conclusion

These findings shed light on the crosstalk between the AMPK and GLP1 signaling pathways with the NADPH-oxidases and their role in restoration of autophagy, a potential reno-protective mechanism in DN.