Pancreatic Biopsy as a Procedure for Detecting In Situ Autoimmune Phenomena in Type 1 Diabetes

Imagawa, Akihisa; Hanafusa, Toshiaki; Tamura, Shinji; Moriwaki, Masamitsu; Itoh, Naoto; Yamamoto, Keiji; Iwahashi, Hiromi; Yamagata, Kazuya; Waguri, Masako; Nanmo, Takao; Uno, Shigeyuki; Nakajima, Hitoshi; Namba, Mitsuyoshi; Kawata, Satoshi; Miyagawa, Jun Ichiro; Matsuzawa, Yūji

doi:10.2337/diabetes.50.6.1269

Cited by 132 publications

(50 citation statements)

References 23 publications

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“…Immunohistochemistry and morphometry Pancreatic sections from patients and controls were prepared and stained with haematoxylin and eosin, as reported previously [4,5]. Each pancreatic biopsy specimen was 20-40 mg. To visualise pancreatic beta cells and alpha cells, sections were stained by the indirect immunoperoxidase technique, using one of the following primary antibodies: guinea-pig anti-insulin (Dako Japan, Kyoto, Japan) or rabbit anti-glucagon (generously provided by Dr Iwasa, Takeda Chemical, Osaka, Japan).…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

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Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment

et al. 2005

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Aims/hypothesis: We have previously reported that fulminant type 1 diabetes is characterised by an absence of diabetes-related antibodies and a remarkably abrupt onset. However, little is known about the mechanism of beta cell destruction in this diabetes subtype, and to obtain insights into the aetiology of the disease, we investigated residual endocrine cells and the expression of Fas and Fas ligand in fulminant type 1 diabetes. Methods: Residual beta and alpha cells were morphologically assessed in pancreatic tissue obtained by biopsy from five patients with recent-onset fulminant type 1 diabetes and five patients with recent-onset typical autoimmune type 1 diabetes. In addition, the expression of Fas and Fas ligand was evaluated by immunohistochemistry. Results: In fulminant type 1 diabetes, beta and alpha cell areas were decreased significantly, compared with autoimmune type 1 diabetes and control subjects. In contrast, the alpha cell area was not decreased significantly in autoimmune type 1 diabetes, compared with that in control subjects. No Fas expression in islets and Fas ligand expression in CD3 + cells in the exocrine pancreas were found in the fulminant type 1 diabetic patients who underwent this evaluation. Conclusions/ interpretation: Our study showed that beta and alpha cells are damaged in fulminant type 1 diabetes. In addition to the lack of Fas and Fas ligand expression, the results suggest that the mechanism of beta cell destruction in fulminant type 1 diabetes is different from that in autoimmune type 1 diabetes.

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Section: Subjects Materials and Methodsmentioning

confidence: 99%

“…The insulin-or glucagon-positive cell area was expressed as a percentage of the total area of the section. To examine Fas and Fas ligand expression and the infiltration of CD3 + T cells, we performed immunohistochemical analysis, as reported previously [4,5].…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment

et al. 2005

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“…Pancreatic biopsies were performed in three of 12 patients within 5 months of the onset of diabetes, as reported previously [15]. Patients were under local anaesthesia, and a standard laparoscopic technique was used (Olympus, Tokyo, Japan).…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

T lymphocyte response against pancreatic beta cell antigens in fulminant Type 1 diabetes

et al. 2004

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Aims/hypothesis. Fulminant Type 1 diabetes is a novel subtype of Type 1 diabetes that involves the abrupt onset of insulin-deficient hyperglycaemia. This subtype appears to be non-autoimmune because of the absence of diabetes-related autoantibodies in the serum, and of insulitis in pancreatic biopsy specimens. The pathogenesis of the disease is still unknown. In this study, we investigated whether T cell autoimmune responses are involved in fulminant Type 1 diabetes. Methods. Cellular immune responses to beta cell autoantigens were studied by enzyme-linked immunospot (ELISPOT) assay in 13 fulminant Type 1 diabetic patients and 49 autoantibody-positive autoimmune Type 1 diabetic patients. Results were compared with those of 18 Type 2 diabetic patients, six secondary diabetic patients (diabetes due to chronic pancreatitis) and 35 healthy controls. Results. Nine of 13 (69.2%) GAD-reactive Th1 cells, and three of 12 (25%) insulin-B9-23-reactive Th1 cells were identified in fulminant Type 1 diabetic patients by ELISPOT, as in autoantibody-positive Type 1 diabetic patients. Four fulminant Type 1 diabetic patients possessed the highly diabetes-resistant allele DR2, three of whom had GAD-reactive Th1 cells in the periphery. Conclusions/interpretation. Peripheral immune reaction was observed in 69.2% of fulminant Type 1 diabetic patients, indicating that autoreactive T cells might contribute, at least in part, to the development of fulminant Type 1 diabetes.

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“…The prediabetic period in humans is characterized by the presence of islet cell autoantibodies (2), which seem to have a close correlation with histological evidence of autoimmunity (3). There are already subtle changes in ␤-cell function during this period, including both disproportionately elevated proinsulin/insulin levels (4, 5) and a preferential loss of the first phase insulin secretion in response to an intravenous glucose challenge (6 -9).…”

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The Cytokine Interleukin-1β Reduces the Docking and Fusion of Insulin Granules in Pancreatic β-Cells, Preferentially Decreasing the First Phase of Exocytosis

Ohara‐Imaizumi

Cardozo²,

Kikuta

et al. 2004

Journal of Biological Chemistry

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The prediabetic period in type I diabetes mellitus is characterized by the loss of first phase insulin release. This might be due to islet infiltration mediated by mononuclear cells and local release of cytokines, but the mechanisms involved are unknown. To determine the role of cytokines in insulin exocytosis, we have presently utilized total internal reflection fluorescence microscopy (TIRFM) to image and analyze the dynamic motion of single insulin secretory granules near the plasma membrane in live ␤-cells exposed for 24 h to interleukin (IL)-1␤ or interferon (IFN)-␥. Immunohistochemistry observed via TIRFM showed that the number of docked insulin granules was decreased by 60% in ␤-cells treated with IL-1␤, while it was not affected by exposure to IFN-␥. This effect of IL-1␤ was paralleled by a 50% reduction in the mRNA and the number of clusters of SNAP-25 in the plasma membrane. TIRF images of single insulin granule motion during a 15-min stimulation by 22 mM glucose in IL-1␤-treated ␤-cells showed a marked reduction in the fusion events from previously docked granules during the first phase insulin release. Fusion from newcomers, however, was well preserved during the second phase of insulin release of IL-1␤-treated ␤-cells. The present observations indicate that IL-1␤, but not IFN-␥, has a preferential inhibitory effect on the first phase of glucose-induced insulin release, mostly via an action on previously docked granules. This suggests that ␤-cell exposure to immune mediators during the course of insulitis might be responsible for the loss of first phase insulin release.Accumulating evidence over the past 30 years suggests that ␤-cells are destroyed by an autoimmune process in type 1 diabetes mellitus (T1D) 1 (1). The prediabetic period in humans is characterized by the presence of islet cell autoantibodies (2), which seem to have a close correlation with histological evidence of autoimmunity (3). There are already subtle changes in ␤-cell function during this period, including both disproportionately elevated proinsulin/insulin levels (4, 5) and a preferential loss of the first phase insulin secretion in response to an intravenous glucose challenge (6 -9). Of note, ␤-cell suppression precedes ␤-cell death in T1D, as suggested by results obtained in islets isolated from prediabetic non-obese diabetic mice (10, 11) or from a patient who died immediately after diagnosis of T1D (12). This initial ␤-cell functional suppression might be due to exposure to cytokines. Indeed, our previous observations (13) indicate that islet exposure to cytokines under in vitro conditions reproduce the disproportionately elevated proinsulin/insulin levels observed in prediabetic patients. Moreover, microarray analysis of purified ␤-cells or insulin-producing INS-1 cells cultured in the presence of IL-1 ␤ or IL-1␤ ϩ IFN-␥ showed inhibition of the expression of several genes involved in the exocytosis of insulin granules, including SNAP-25, and Rab3 (14,15). This raised the intriguing possibility that cytokines could also co...

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Pancreatic Biopsy as a Procedure for Detecting In Situ Autoimmune Phenomena in Type 1 Diabetes

Cited by 132 publications

References 23 publications

Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment

Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment

T lymphocyte response against pancreatic beta cell antigens in fulminant Type 1 diabetes

The Cytokine Interleukin-1β Reduces the Docking and Fusion of Insulin Granules in Pancreatic β-Cells, Preferentially Decreasing the First Phase of Exocytosis

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