To elucidate the pathogenesis of post-pancreatectomy diabetes (PPDM), we carried out a prospective observational study in patients without diabetes undergoing partial pancreatectomy, investigating the effects of gut microbiota, incretins, and short-chain fatty acids (SCFAs) on postsurgical glucose metabolism. In addition, we analyzed histologically the resected pancreas to investigate whether increased cellular-plasticity and expansion of the islets could predict the development of PPDM. Forty-eight patients without diabetes, who underwent either pancreatoduodenectomy (PD) (n=20) or distal pancreatectomy (DP) (n=28), were included. To assess the post-surgical glucose metabolism, 75-g oral glucose tolerance test (OGTT) was performed every 6 months. Microbiome composition and SCFAs in feces were examined before and 6 months after the surgery. We also underwent immunostainings of insulin, glucagon, and ALDH1A3 (a progenitor cell marker) in the resected pancreatic samples obtained from patients following DP. During the follow-up (median 2.50 years), 2 out of 18 patients with PD and 16 out of 28 patients with DP developed PPDM. Microbiota shifted to a higher relative abundance of Proteobacteria after PD. After PD, fecal butyrate and plasma GLP-1 concentrations were significantly increased, which were not increased after DP. In all patients, postsurgical change in butyrate was strongly correlated with increased GLP-1 secretion. In DP patients, expansion of both α- and β-cell areas in the resected pancreas were significantly associated with the development of PPDM, and HR (95% CI) of ALDH1A3 positive cells (%) for PPDM was 1.127 (1.000-1.270). This study demonstrates that incidence of PPDM is much lower after PD than that after DP, which may be explained by marked changes in intestinal environment after PD. On the other hand, high cellular-plasticity and expansion of the islets in the resected pancreas can predict the development of PPDM after DP.

Disclosure

R. Bouchi: None. T. Fukuda: None. T. Takeuchi: None. K. Amo-Shiinoki: None. K. Tanabe: None. Y. Tanizawa: None. T. Yamada: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Ogawa: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker’s Bureau; Self; Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation.

Funding

Ministry of Education, Culture, Sports, Science and Technology of Japan (15K19507); Japan Foundation for Applied Enzymology; Takeda Science Foundation; AstraZeneca

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