Abstract
Obesity is characterized by increased gut serotonin signaling, which has been shown to enhance hepatic gluconeogenesis favoring hyperglycemia and adipose tissue lipolysis promoting raised levels of free fatty acids and, thus, peripheral insulin resistance. Little is known about the potential involvement of the human gut serotonin system in the pathophysiology of type 2 diabetes. We investigated the transcriptional profile of key enzymes, receptors and transporters in the serotonin system in intestinal biopsies sampled using double-balloon enteroscopy from the duodenum, the jejunum, throughout the remaining small intestine with 30 cm intervals, the ileocecal region, the cecum, the four segments of the colon and the rectum in 12 individuals with type 2 diabetes and 12 gender, age and body mass index-matched healthy controls. Global gene expression analysis was performed on all biopsies, and intestinal expression profiles of genes involved in the serotonin system were mapped and compared between the two groups. We used false discovery rate adjustment to correct for multiple testing. Patients with type 2 diabetes exhibited 2-fold increased mRNA encoding the serotonin-synthesizing enzyme TPH1 in the sigmoid colon (P = 0.027) and the rectum (P < 0.001), and lower levels of mRNA encoding the transporter responsible for reuptake of serotonin in enterocytes, SERT (P = 0.038), and the serotonin-metabolizing enzymes MAOA (P = 0.001) in the distal small intestine and MAOB in the cecum (P = 0.013), the ascending colon (P = 0.020) and the transverse colon (P = 0.011). Our findings provide the first detailed transcriptional profile of key factors in the serotonin system along the entire intestinal tract in humans and lend support to previous animal and human studies suggesting that increased gut serotonin signaling may be involved in the development of dysmetabolic conditions including type 2 diabetes. Disclosure C. Legart: None. C. A. Hagemann: None. A. Ellegaard: None. D. Keating: None. T. Jorsal: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
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