Evidence of Primary β-Cell Destruction by T-Cells and β-Cell Differentiation From Pancreatic Ductal Cells in Diabetes Associated With Active Autoimmune Chronic Pancreatitis

Abstract

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 about pathological changes of islet and exocrine pancreas in ACP. 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 ␤-cells. The subsets of T-cells infiltrated to the islets were mainly CD8 ϩ . Islet ␤-cell volume was decreased; the mean percentage area of ␤-cells in the islets in four cases with ACP were 16% (range 13-20) (P ϭ 0.0015 vs. type 2 diabetic patients, 48% , n ϭ 8; P ϭ 0.0002 vs. nondiabetic control subjects, 58% [39 -77], n ϭ 7). Preserved ductal cells were surrounded predominantly by CD8 ϩ or CD4 ϩ T-cells. Some cytokeratin 19 -positive ductal cells contained insulin and glucagon, representing upregulated differentiation of islet cells from ductal cells. Insulin promoter factor-1 (IPF-1) was hyperexpressed in insulin-containing ductal cells. RESEARCH DESIGN AND METHODSCONCLUSIONS -Diabetes associated with ACP is caused by T-cell-mediated mechanisms primarily involving islet ␤-cells as well as pancreatic ductal cells. In ACP, ductal islet precursor cells were associated with IPF-1 hyperexpression, suggesting a critical role of IPF-1 on islet cell differentiation and eventual ␤-cell restoration. Diabetes Care 24:1661-1667, 2001D iabetes occurs in ϳ50% of patients with chronic pancreatitis (1,2). Although chronic pancreatitis is often related to excessive alcohol consumption, in Ͼ25% of patients with chronic pancreatitis, the disorder is not related to alcohol (1,2). Autoimmune-mediated mechanisms often underlie such nonalcoholic impairment of the pancreas, so-called "autoimmune chronic pancreatitis" (ACP) (3-7). ACP is characterized by diffuse swelling and severe fibrosis associated with mononuclear cell infiltration involving the exocrine pancreas (3-7). The disorder can induce severe pancreatic swelling or tumor formation, with malabsorption and often cholestasis, and is sometimes misdiagnosed as pancreatic carcinoma or lymphoma. Patients with ACP are sometimes subjected to pancreatectomy or chemotherapy (6,7). Recently, we have reported that a large proportion of patients with ACP had diabetes and responded well to corticosteroid therapy, and after treatment, those patients had normal or mild glucose intolerance with improved insulin response (8). Current knowledge is limited regarding the changes in both affected endocrine as well as exocrine pancreas. In this study, we report the findings of the affected pancreas of patients with diabetes associated with ACP on a morphological, immunological, and morphometric bases. RESEARCH DESIGN AND METHODS SubjectsOur cohort study of ACP was performed between 1993 and 1999 and included 2,483 Japanese patients with suspected chronic pancreatitis and symptoms of abdominal and/or back pain, m...

Pancreatectomy with islet autotransplantation for the treatment of severe chronic pancreatitis: the first 40 patients at the leicester general hospital

“…One of the major disadvantages with pancreatectomy is that the patient will become diabetic if a total resection is performed or may be at risk of developing diabetes following partial resection. However, it should also be taken into consideration that a relatively high proportion of patients with CP will go on to develop diabetes, with various studies quoting between one third to one half of CP patients developing either insulindependent diabetes mellitus (IDDM), noninsulin-dependent diabetes mellitus (NIDDM), or impaired glucose tolerance (IGT) (3)(4)(5).…”

Endocrine pancreatic insufficiency in chronic pancreatitis

“…Diabetes associated with autoimmune CP is an uncommon clinical entity, probably caused by T-cell-mediated mechanisms primarily involving islet ␤ -cells as well as pancreatic ductal cells [60,61] . Initial reports correlated some cases of CP with Sjogren's syndrome and primary sclerosing cholangitis, on a common basis of an unknown autoimmune mechanism [62,63] .…”

Amylase α-2A Autoantibodies

“…ϩ or CD8 ϩ T-cells in the inflammatory process, which might induce diabetes in AIP (6). In addition, treatment with prednisolone improved insulin secretion and glycemic control in AIP patients (5).…”