Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin

PLoS One. 2012;7(5):e36675. doi: 10.1371/journal.pone.0036675. Epub 2012 May 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Proliferation* / drug effects
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Glucagon / genetics
  • Glucagon / metabolism
  • Glucagon-Secreting Cells* / cytology
  • Glucagon-Secreting Cells* / drug effects
  • Glucagon-Secreting Cells* / metabolism
  • Homeodomain Proteins / genetics
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin-Secreting Cells / drug effects
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred C57BL
  • Regeneration / drug effects
  • Somatostatin / genetics
  • Somatostatin / metabolism
  • Somatostatin-Secreting Cells* / cytology
  • Somatostatin-Secreting Cells* / drug effects
  • Somatostatin-Secreting Cells* / metabolism
  • Streptozocin / pharmacology*
  • Trans-Activators / genetics


  • Homeodomain Proteins
  • Insulin
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Somatostatin
  • Streptozocin
  • Glucagon