Background and Aims: Roux-en-Y gastric bypass (RYGB) surgery significantly improves glucose metabolism independently of surgery-induced weight loss; partly due to the increased postprandial secretion of the insulinotropic gut hormone glucagon-like peptide 1 (GLP-1). Mouse studies have shown that intestinally derived ketone bodies inhibit GLP-1 secretion from enteroendocrine L cells, and it was recently suggested that RYGB-induced downregulation of intestinal ketogenesis contributes to the increased GLP-1 secretion after RYGB. We investigated the intestinal expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses before and after RYGB.

Materials and Methods: Twenty obese individuals underwent mixed meal tests and anterograde enteroscopy with gut mucosal biopsy retrieval before and 3 months after RYGB. A global gene expression analysis was performed on the mucosal biopsies. Here, we report the expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses.

Results: We observed a significant 7.6-fold downregulation of the gene encoding 3-hydroxy-3- methylglutaryl-CoA synthase 2 (HMGCS2) (the rate-determining enzyme in ketogenesis) in the alimentary limb after RYGB. The proglucagon gene encoding GLP-1 was significantly upregulated after surgery and postprandial plasma GLP-1 responses increased significantly after RYGB.

Conclusions: RYGB-induced downregulation of intestinal HMGCS2 gene expression in obese individuals may indicate reduced intestinal ketogenesis; supporting the notion (originating from animal studies) that reduced ketone body-mediated inhibition of L cells constitute a contributor to postprandial hypersecretion of GLP-1 after RYGB.

Disclosure

C. Legart: None. T. Jorsal: None. C.A. Hagemann: Employee; Self; Gubra. D. Worm: None. C.B. Juhl: None. A.R. Andries: None. C. Zhang: Employee; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

© 2020 by the American Diabetes Association
2020
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.