Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis
S. Tanaka et al., Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis, DIABET CARE, 24(9), 2001, pp. 1661-1667
OBJECTIVE - Diabetes associated with autoimmune chronic pancreatitis (ACP)
is a subtype of diabetes that is responsive to corticosteroid treatment of
progressive endocrine and exocrine dysfunction. However, little is known ab
out pathological changes of islet and exocrine pancreas in ACP.
RESEARCH DESIGN AND METHODS - We examined pancreatic specimens obtained on
biopsy from four diabetic men with ACP (mean [range]: age 62 years [48-78],
duration of ACP 3 months [1-5], duration of diabetes I month [0-3]) morpho
logically, immunohistochemically, and morphometrically.
RESULTS - The pancreatic specimens in all cases exhibited inflammatory cell
infiltration surrounding ductal cells and extensive fibrosis. Some islets
were infiltrated with mononuclear cells with disrupted beta -cells, The sub
sets of T-cells infiltrated to the islets were mainly CDS'. Islet beta -cel
l volume was decreased; the mean percentage area of beta -cells in the isle
ts in four cases with ACP were 16% (range 13-20) (P = 0.0015 vs. type 2 dia
betic patients, 48% [27-73], n = 8; P = 0.0002 vs. nondiabetic control subj
ects, 58% [39-77], n = 7). Preserved ductal cells were surrounded predomina
ntly by CD8(+) or CD4(+) T-cells. Some cytokeratin 19-positive ductal cells
contained insulin and glucagon, representing upregulated differentiation o
f islet cells from ductal cells. Insulin promoter factor-1 (IPF-1) was hype
rexpressed in insulin-containing ductal cells.
CONCLUSIONS - Diabetes associated with ACP is caused by T-cell-mediated mec
hanisms primarily involving islet beta -cells as well as pancreatic ductal
cells. In ACP, ductal islet precursor cells were associated with IPF-1 hype
rexpression, suggesting a critical role of IPF-1 on islet cell differentiat
ion and eventual beta -cell restoration.