Increased apoptosis of lactotrophs in streptozotocin-induced diabetic rats is followed by increased proliferation.
Poorly controlled diabetes mellitus can result in decreased prolactin production and thus problems with lactation, reproduction, and other physiological processes. This may be due to a loss of lactotrophs, as we have previously shown that long-term (8 weeks) poorly controlled streptozotocin-induced diabetes results in increased death of lactotrophs and that this most likely occurs through the activation of caspase-8 and the extrinsic cell death cascade. However, cell proliferation is also increased in the anterior pituitary at this time, although the cell type undergoing this proliferation and whether it is a response to the increased cell death remains unknown. In order to determine the time-course of increased cell death and proliferation in the anterior pituitary and if this is related to changes in tumor necrosis factor (TNF)-alpha, a cytokine involved in the activation of the extrinsic cell death pathway, rats were killed at 1, 4, 6, and 8 weeks after the induction of diabetes. Cell death was significantly increased after 4 weeks, as was caspase-8 activation, although circulating levels of TNF-alpha were increased as early as 1 week. Pituitary levels of TNF-alpha did not change significantly until 8 weeks after diabetes onset. Similarly, Western-blot analysis of proliferating cell nuclear antigen showed that anterior pituitary cell proliferation increased significantly 8 weeks after diabetes onset, with the majority of proliferating cells, as detected by BrdU incorporation, corresponding to lactotrophs. These results suggest that the increased death of lactotrophs in poorly controlled diabetic rats is followed by increased proliferation of this cell type, even when no treatment is given.
Arroba
Ana I
AI
Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.
Lechuga-Sancho
Alfonso M
AM
Frago
Laura M
LM
Argente
Jesús
J
Chowen
Julie A
JA
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D001973:Bromodeoxyuridine / Q000032:analysis; D053181:Caspase 8 / Q000378:metabolism; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015151:Immunoblotting / Q000379:methods; D052682:Lactotrophs / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010903:Pituitary Gland, Anterior / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015415:Biomarkers; D018809:Proliferating Cell Nuclear Antigen; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8; D001973:Bromodeoxyuridine