OR33-3 Exenatide suppresses Keap-1 and stimulates expression of Nrf-2 depended genes

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR33-Insulin Signaling & Inflammation
Basic
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:45 AM
Room 303 (Moscone Center)
Husam Ghanim1, Ajay Chaudhuri2, Sandeep S Dhindsa*3, Sanaa Abuaysheh4, Kelly Green4, Nitesh D Kuhadiya5, Cherie Lisa Vaz1, Anupam Ohri6 and Paresh Dandona7
1SUNY at Buffalo, Buffalo, NY, 2The State Univeristy of New York, University at Buffalo, 3SUNY at Buffalo, Amherst, NY, 4SUNY at Buffalo, 5University at Buffalo, Buffalo, NY, 6SUNY at Buffalo, Williamsville, NY, 7State Univ of NY, Buffalo, NY
Nuclear factor erythroid 2-related factor (Nrf)-2 is an anti-oxidant transcription factor that when released from its inhibitor, Keap-1, translocates to the nucleus and binds to anti-oxidant response elements (ARE) of several anti-oxidant genes. It has been shown recently that Nrf-2 might be involved in protection from the development of diabetic nephropathy in mice with streptozotocin induced diabetes. Since we have previously demonstrated that exenatide exerts rapid and potent anti-oxidant and anti-inflammatory effects in diabetic patients, we investigated the effect of exenatide treatment on Nrf-2/Keap-1 system. Twenty four obese type 2 diabetics were randomized to receive either exenatide 10μg twice daily (n=12, mean HbA1c:8.6±0.4%) or placebo twice daily (n=12, mean HbA1c:8.5±0.3%) for 12 weeks. Fasting blood samples were obtained at baselines and at 3, 6 and 12 weeks later. Mononuclear cells (MNC) were isolated and tested for expression of related genes. Following exenatide, HbA1c fell to 7.4±0.5% (P<0.05) and there was no weight loss. Exenatide treatment also suppressed Keap-1 protein by 21±8% and increased the mRNA expression of NQO-1, GST-1P and HO-1 by 51±15%, 42±10% and 39±10%, respectively (P<0.05). Exenatide also increased expression of p21 (a competitor of Keap-1 that stabilizes Nrf-2) by 68±26%. In addition, exenatide suppressed TGF-1β (a fibrogenic cytokine involved in the pathogenesis of diabetic nephropathy) concentrations by 20±7% (from12.93±0.57 to 10.37±1.04ng/ml, P<0.05). We conclude that exenatide treatment in type 2 diabetics suppresses Keap-1 and stimulates the expression of Nrf-2 regulated anti-oxidant enzymes. Although these observations are in MNC and not in the kidney it might be relevant to renal pathophysiology since the monocyte/macrophage has an important pro-inflammatory role in the pathogenesis of diabetic glomerulopathy. Further clinical investigations on the effect of exenatide and other GLP-1 mimetics on diabetic nephropathy are clearly needed.

Nothing to Disclose: HG, AC, SSD, SA, KG, NDK, CLV, AO, PD

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