Westernized Diet–Induced Insulin Resistance in Mice Is Associated with Focal Duodenal Hyperplasia

Abstract

Westernized diet (WD; high fat and sugar) induces an insulin resistant state associated with obesity and type 2 diabetes (T2D). Duodenal exclusion surgery in obese T2D patients implicates the duodenum as a key GI region involved in insulin resistance. To identify adaptive changes of pathophysiological relevance, detailed analyses of the GI tract was undertaken following exposure of mice to WD. Metabolic indices and stereological characteristics of the whole gut, mucosal surface and transcriptome were investigated in C57BI/6J male mice fed either chow (lean) or WD (60% fat; 20% sugar) for 7 or 13 weeks (10 mice/cohort). Compared to lean, WD gained more weight and had higher plasma glucose, insulin and total cholesterol (Table) with differences greater at 13 vs. 7 weeks. Unlike other intestinal segments, focal hyperplasia was observed in the duodenum with increased weight and surface area (∼40%). The hyperplastic duodenum was characterized by increased chromogranin-A staining of enteroendocrine (EE) cells. Transcriptomic analysis revealed differences between WD and lean groups (both 7 and 13 weeks) with enrichment for genes involved in lipid and glucose metabolism. Exposure to WD induces adaptive responses in duodenal mucosa, EE cell population, and transcriptome. These findings suggest a potential role of the duodenum in insulin resistance and may explain the insulin-sensitizing effect of duodenal exclusion. Disclosure S. Ghosh: Consultant; Self; Fractyl Laboratories, Inc. F. Rubino: Advisory Panel; Self; Fractyl Laboratories, Inc.. Consultant; Self; Fractyl Laboratories, Inc., Ethicon US, LLC.. Speaker's Bureau; Self; Ethicon US, LLC.. Consultant; Self; Medtronic. Advisory Panel; Self; GI Dynamics Inc.. Consultant; Self; GI Dynamics Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Ethicon US, LLC.. P. Wismann: None. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. H. Rajagopalan: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Board Member; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc. D. Maggs: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Spouse/Partner; Gelesis. Employee; Spouse/Partner; Gelesis.