Online-Only_Supplemental_Materials_Rev3.pdf (1.03 MB)

Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes

Download (1.03 MB)
figure
posted on 22.02.2021, 08:01 by Tatsuya Fukuda, Ryotaro Bouchi, Takato Takeuchi, Kikuko Amo-Shiinoki, Atsushi Kudo, Shinji Tanaka, Minoru Tanabe, Takumi Akashi, Kazuhiro Hirayama, Toshitaka Odamaki, Miki Igarashi, Ikuo Kimura, Katsuya Tanabe, Yukio Tanizawa, Tetsuya Yamada, Yoshihiro Ogawa
OBJECTIVE

To elucidate the pathogenesis of post-pancreatectomy diabetes (PPDM).

RESEARCH DESIGN AND METHODS

Forty-eight patients without diabetes undergoing either pancreatoduodenectomy (PD) (n = 20) or distal pancreatectomy (DP) (n = 28) were included. 75-g oral glucose tolerance test was performed every 6 months. Microbiome composition and short-chain fatty acids in feces were examined before and 6 months after surgery. The association of histological characteristics of the resected pancreas with PPDM were examined.

RESULTS

During follow-up (median, 3.19 years), 2 out of 20 PD patients and 16 out of 28 DP patients developed PPDM. Proteobacteria relative abundance, plasma GLP-1, and fecal butyrate levels increased only after PD. Postsurgical butyrate levels were correlated with postsurgical GLP-1 levels. With no significant difference in the volume of the resected pancreas between the surgical procedures, both β-cell and α-cell areas in the resected pancreas were significantly higher in DP patients than in PD patients. In DP patients, the progressors to diabetes showed pre-existing insulin resistance compared with non-progressors, and both increased α- and β-cell areas were predictors of PPDM. Furthermore, in DP patients, α-cell and β-cell areas were associated with ALDH1A3 expression in islets.

CONCLUSIONS

We postulate that a greater removal of β-cells contributes to the development of PPDM after DP. Islet expansion along with pre-existing insulin resistance is associated with high cellular-plasticity, which may predict the development of PPDM after DP. In contrast, PD is associated with alterations of gut microbiome and increases in SCFA production and GLP-1 secretion, possibly protecting against PPDM development.

Funding

This work was funded by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K-19507), the Japan Foundation for Applied Enzymology, Takeda Science Foundation, and AstraZeneca. The study funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, or preparation.

History