818-P: Chronic Oral Polymeric Duodenal Exclusion Therapy Has Profound Metabolic Benefits in a T2D Rat Model and Affects Duodenal Morphological Enteroplasticity Similar to RYGB surgery: Implications for T2D Therapy

Abstract

Background: RYGB surgery has significant weight loss and improvement in glycemia, attributed predominantly to duodenal exclusion. To mimic this effect non-invasively, we developed oral, gut-restricted, inert polymer (GLY-POL) that interacts with mucus in the proximal small intestine to form a dynamic barrier excluding the duodenal lining from luminal contents. We hypothesized that such treatment would result in significant metabolic improvement and affect morphologic enteroplasticity similar to RYGB. Methods: Goto-kakizaki (GK) rats were gavaged with GLY-POL daily for 8-weeks (n=7 per group) . Metabolic responses were evaluated weekly (BW, food intake, oGTT, mMTT, HOMA-IR) . Duodenal morphometric analysis (villus height and crypt depth) was performed in excised duodenum after study completion. Results: There was profound metabolic improvement with chronic GLY-POL therapy; oGTT (iAUC ↓ = 60 - 70%, p<0.0005) , mMTT (iAUC ↓ > 55%, p < 0.005) , HOMA-IR improvement (p<0.005) , 6% weight loss (p<0.005) . There was no difference in food intake between the groups. There was a significant reduction in the duodenal villus height (p<0.0001) and crypt depth (p<0.0001) in treated rats compared to controls. Conclusion: Our results confirm a key role for chronic duodenal exclusion oral GLY-POL therapy in improving the systemic metabolic milieu with profound reduction in FPG, PPG, insulin resistance and weight loss. Duodenal villus morphological changes are likely due to nutritional depletion from the GLY-POL lining. Similar cellular structural changes have been reported in the bypassed portion of the small intestine after RYGB surgery. GLY-POL therapy offers the potential for a novel non-invasive approach for glycemic and weight control in T2D patients that mimics the effects of gastric bypass without the adverse effects associated with this surgery. Disclosure A.Nimgaonkar: Employee; Glyscend Inc. M.Fineman: None. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. F.Guerina: Employee; Glyscend Inc. S.L.Kelleher: Research Support; Glyscend Inc. T.Carlson: Employee; Glyscend Inc. K.Colbert: Stock/Shareholder; Glyscend Inc., LifeSprout. S.Polomoscanik: None. J.S.Petersen: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc. P.J.Pasricha: Consultant; Vanda, Other Relationship; Teva Pharmaceutical Industries Ltd., Stock/Shareholder; Glyscend Inc., Neurogastrx, P4M.