Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes.
OBJECTIVE
In adults, the rate of beta cell replication is normally very low, but recent evidence suggests that it may increase during insulitis. We therefore studied tissue from donors with recent-onset type 1 diabetes to establish whether islet cell proliferation is increased during the disease process.


METHODS
Paraffin-embedded pancreatic sections from ten donors with recent-onset type 1 diabetes and a range of relevant controls were stained by immunohistochemical techniques with antibodies against the proliferation markers Ki67 and minichromosome maintenance protein-2 (MCM-2). A combination staining technique involving immunoperoxidase and immunofluorescence methods was developed to quantify the numbers of alpha and beta cells with Ki67-positive nuclei and to investigate the relationship between insulitis and islet cell proliferation.


RESULTS
In non-diabetic control donors, only 1.1 +/- 0.3% (mean +/- SEM) of islets contained one or more Ki67(+) islet cells, whereas this proportion was increased markedly in recent-onset type 1 diabetes (10.88 +/- 2.5%; p < 0.005). An equivalent increase in Ki67(+) staining occurred in alpha and beta cells and was correlated positively with the presence of insulitis. A significant increase in the labelling of islet cells from type 1 diabetic donors was also seen when MCM-2 staining was employed. Increased islet cell proliferation was not evident in three donors with longer duration type 1 diabetes or in ten type 2 diabetic donors.


CONCLUSIONS
Alpha and beta cells undergo a marked increase in proliferation during the progression of type 1 diabetes in humans. The results imply that islet cell proliferation is re-initiated in response to the autoimmune attack associated with type 1 diabetes.
Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry (University of Exeter), Tamar Science Park, Derriford, Plymouth, UK.
A
A
Willcox
S J
SJ
Richardson
A J
AJ
Bone
A K
AK
Foulis
N G
NG
Morgan
D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007223:Infant; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2