Profound Metabolic Benefits Observed in an Eight -Week GK Rat Study of a Novel Orally Administered Polymeric Duodenal Exclusion Therapy: Implications for Type 2 Diabetes (T2D) Therapy

Background: Roux-en-Y gastric bypass surgery produces significant weight loss and improvement in T2D and insulin resistance, attributed predominantly to duodenal exclusion. To mimic this effect non-invasively, we developed an 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 therefore hypothesized that such treatment would result in significant improvement in glycemia and weight loss in a rodent model of type 2 diabetes. Methods: Goto-kakizaki (GK) rats were gavaged daily for 8 weeks. The treatment group (n = 7) received 1.5 ml of GLY-POL (8 wt %) solution and control group (n=7) received saline. Five metabolic responses were evaluated weekly: body weight, food intake, oral glucose (oGTT) and mixed meal tolerance (mMTT) tests, and HOMA-IR. Results: oGTT performed after chronic GLY-POL therapy produced a profound reduction of post-prandial glycemia (PPG) (incremental area under curve (iAUC)  = 60 – 70%, p<0.0005) compared to control; the PPG reduction amplified with duration of therapy through the study period. Similar robust reduction in PPG iAUC was evident during mMTT (iAUC  > 55%, p < 0.005). Fasting plasma glucose was lower in GLY-POL group (p<0.05) with improvement in HOMA-IR (p<0.005). GLY-POL therapy resulted in 6% weight loss compared to control (p<0.005), without a difference in food intake between the groups. Conclusion: Our results confirm a key role for chronic duodenal exclusion in improving the systemic metabolic milieu. Chronic once daily oral GLY-POL therapy results in a profound reduction in FPG, PPG, insulin resistance and weight loss. 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; Self; Glyscend Inc. S. Kulkarni: None. J. S. Petersen: Employee; Self; Glyscend Inc. S. Polomoscanik: Employee; Self; Glyscend Inc. P. J. Pasricha: Stock/Shareholder; Self; Glyscend. K. Colbert: Employee; Self; Glyscend Inc., LifeSprout, Inc. T. H. Jozefiak: Employee; Self; Glyscend Inc., Stock/Shareholder; Self; GLYCOLOGIX LLC. J. Vora: Advisory Panel; Self; Bayer Inc., Other Relationship; Self; AstraZeneca. M. Vieira: Employee; Self; AstraZeneca. T. Carlson: None. L. Liu: None. Funding National Science Foundation (1521347)