Abstract
The non-β endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing β-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of β-cell regeneration in adults, very little is known about the regeneration of the non-β endocrine cells such as glucagon-producing α-cells and somatostatin producing δ-cells. Previous studies have noted the increase of α-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-β-cells such as α-cells and δ-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ)-induced diabetes mouse model in detail. Our data showed the number of α-cells in each islet increased following STZ-mediated β-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, we found δ-cell numbers doubled by Day 6 following STZ treatment. These data suggest α- and δ-cell regeneration occurred rapidly following a single diabetes-inducing dose of STZ in mice. Using in vivo BrdU labeling techniques, we demonstrated α- and δ-cell regeneration involved cell proliferation. Co-staining of the islets with the proliferating cell marker Ki67 showed α- and δ-cells could replicate, suggesting self-duplication played a role in their regeneration. Furthermore, Pdx1+/Insulin− cells were detected following STZ treatment, indicating the involvement of endocrine progenitor cells in the regeneration of these non-β cells. This is further confirmed by the detection of Pdx1+/glucagon+ cells and Pdx1+/somatostatin+ cells following STZ treatment. Taken together, our study demonstrated adult α- and δ-cells could regenerate, and both self-duplication and regeneration from endocrine precursor cells were involved in their regeneration.
Highlights
The islets of Langerhans within the pancreas play a pivotal role in maintaining glucose homeostasis
STZ-mediated b-cell destruction Based on previous observations, we hypothesized that, similar to the insulin-producing b-cells, non-b cells such as glucagonproducing a-cells and somatostatin-producing d-cells in adults could regenerate, and the regeneration could accelerate in the event of b-cell loss
We chose 130 mg of STZ per kilogram body weight as the optimal dose for this study because it resulted in hyperglycemia in the mice within 2 days post injection, and allowed the mice to survive for approximately 2 weeks without any treatment
Summary
The islets of Langerhans within the pancreas play a pivotal role in maintaining glucose homeostasis. Each islet typically contains five endocrine cell types, which include glucagonproducing a-cells, insulin-producing b-cells, somatostatin-producing d-cells, pancreatic polypeptide-producing PP-cells, and ghrelin-producing e-cells. The reports on the precise appearance of the different lineages vary, it is generally found that most of the hormoneexpressing cells that comprise the islets rapidly emerge around E13.5–E15.5 in mice [4,5,6], a period often referred to as the secondary transition in pancreatic development [1]. Endocrine pancreas undergoes substantial remodeling, which involves significant apoptosis, replication, and neogenesis of islet cells [7,8,9]. There is little change in islet mass in adults except in response to physiological/ pathological changes such as pregnancy and obesity [10,11], while adaptive islet cell proliferation is severely restricted in aged mice [12]
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