Abstract
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.
Highlights
Diabetes mellitus (DM) is a metabolic disorder characterized by loss and dysfunction of pancreatic β cells along with insulin resistance, resulting in multiple long-term complications [1, 2]
The proportion of dedifferentiated cells that retain chromogranin A (ChgA) immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially 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
Summary
Diabetes mellitus (DM) is a metabolic disorder characterized by loss and dysfunction of pancreatic β cells along with insulin resistance, resulting in multiple long-term complications [1, 2]. The information from cadaveric sample analyses does not account for either the extent or the mechanism by which β cell dedifferentiation contributes to the β cell deficit and its progression during the entire disease course of diabetes Elucidating this issue is a key challenge owing to the difficulty in obtaining long-term access to human pancreatic samples of appropriate quality for analyses, in conjunction with the necessary medical history and metabolic profiles. We took advantage of the opportunity to examine pancreatic samples from Japanese patients with and without diabetes undergoing partial pancreatectomy, for resection of pancreaticobiliary neoplasms, to examine the hypothesis that islet remodeling with dedifferentiation is a pathologic mechanism underlying long-standing disease progression. Our work reveals the involvement of dedifferentiation in β cell dysfunction and loss during the course of diabetes progression
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