TY - JOUR
T1 - Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes
AU - Amo-Shiinoki, Kikuko
AU - Tanabe, Katsuya
AU - Hoshii, Yoshinobu
AU - Matsui, Hiroto
AU - Harano, Risa
AU - Fukuda, Tatsuya
AU - Takeuchi, Takato
AU - Bouchi, Ryotaro
AU - Takagi, Tokiyo
AU - Hatanaka, Masayuki
AU - Takeda, Komei
AU - Okuya, Shigeru
AU - Nishimura, Wataru
AU - Kudo, Atsushi
AU - Tanaka, Shinji
AU - Tanabe, Minoru
AU - Akashi, Takumi
AU - Yamada, Tetsuya
AU - Ogawa, Yoshihiro
AU - Ikeda, Eiji
AU - Nagano, Hiroaki
AU - Tanizawa, Yukio
N1 - Funding Information:
The authors thank all staff members of the Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, and the Department of Diagnostic Pathology, Yamaguchi University Hospital, for their contributions. This study was supported by a Grant-in-Aid for Scientific Research (grant number 16K09752 and 20K08887) (to K Tanabe) and a Grant-in-Aid for Scientific Research (grant number 19H03710) from Takeda Science Foundation (to YT). KAS is supported by a Grant-in-Aid for Scientific Research (grant number 19K07506), a Japan Diabetes Society Junior Scientist Development Grant supported by Novo Nordisk Pharma Ltd., a Grant for Front Runner of Future Diabetes Research, and Grants for young researchers from the Japan Association for Diabetes Education and Care and from MSD Life Science Foundation, Public Interest Incorporated Foundation. The funding agencies had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2021, Amo-Shiinoki et al.
PY - 2021/1/11
Y1 - 2021/1/11
N2 - Dedifferentiation has been implicated in β cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. To elucidate this, we analyzed surgically resected pancreatic tissues of 26 Japanese subjects with diabetes and 11 nondiabetic subjects, who had been overweight during adulthood but had no family history of diabetes. The diabetic subjects were subclassified into 3 disease stage categories, early, advanced, and intermediate. Despite no numerical changes in endocrine cells immunoreactive for chromogranin A (ChgA), diabetic islets showed profound β cell loss, with an increase in α cells without an increase in insulin and glucagon double-positive cells. The proportion of dedifferentiated cells that retain ChgA immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially during disease progression. The increased dedifferentiated cell ratio was inversely correlated with declining C-peptide index. Moreover, a subset of islet cells converted into exocrine-like cells during disease progression. These results indicate that islet remodeling with dedifferentiation is the underlying cause of β cell failure during the course of diabetes progression in humans.
AB - Dedifferentiation has been implicated in β cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. To elucidate this, we analyzed surgically resected pancreatic tissues of 26 Japanese subjects with diabetes and 11 nondiabetic subjects, who had been overweight during adulthood but had no family history of diabetes. The diabetic subjects were subclassified into 3 disease stage categories, early, advanced, and intermediate. Despite no numerical changes in endocrine cells immunoreactive for chromogranin A (ChgA), diabetic islets showed profound β cell loss, with an increase in α cells without an increase in insulin and glucagon double-positive cells. The proportion of dedifferentiated cells that retain ChgA immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially during disease progression. The increased dedifferentiated cell ratio was inversely correlated with declining C-peptide index. Moreover, a subset of islet cells converted into exocrine-like cells during disease progression. These results indicate that islet remodeling with dedifferentiation is the underlying cause of β cell failure during the course of diabetes progression in humans.
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U2 - 10.1172/jci.insight.143791
DO - 10.1172/jci.insight.143791
M3 - Article
C2 - 33427207
AN - SCOPUS:85099279096
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 1
M1 - e143791
ER -