We examined pancreas biopsy specimens from 18 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients to elucidate the mechanism underlying beta cell destruction. Pancreas islets were seen in all patients and insulitis in eight patients. Infiltrating mononuclear cells consisted of CD4+T, CD8+T, B lymphocytes, and macrophages. Among them, CD8+T lymphocytes were predominant and macrophages followed. The expression of MHC class I antigens was increased in islet and endothelial cells in nine patients. MHC class II expression was increased in endothelial cells of the same patients. The expression of intercellular adhesion molecule-i was increased in endothelial cells in two of the nine patients with MHC hyperexpression; in one of them, lymphocyte functionassociated antigen-3 expression was also increased. Out of the eight patients with insulitis, seven showed MHC class I hyperexpression, whereas 2 of the 10 patients without insulitis showed the phenomenon (P < 0.05). The relation between insulitis and the hyperexpression of adhesion molecules was not evident. In conclusion, we revealed the close relation between CD8+T lymphocyte-predominant insulitis and MHC class I hyperexpression in islet cells. This suggests that infiltrating CD8 'T lymphocytes recognize islet autoantigens in association with increased MHC class I molecules and act as major effector cells in autoimmune response against islet cells in IDDM pancreases. The role of adhesion molecules in the pathogenesis of IDDM still remains to be elucidated. (J. Clin. Invest. 1993.

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.

OBJECTIVEWe have already reported that A1C is elevated because of iron deficiency in late pregnancy among nondiabetic pregnant women. This report examined whether the same phenomenon is observed in pregnant women with diabetes.RESEARCH DESIGN AND METHODSThis longitudinal study was conducted in 17 pregnant women with diabetes (20–35 weeks of pregnancy). A1C, serum glycated albumin, erythrocyte indexes, and iron metabolism indexes were measured.RESULTSA1C levels were significantly increased in late pregnancy, whereas serum glycated albumin showed no significant changes. Glycated albumin/A1C ratio, mean corpuscular hemoglobin, serum transferrin saturation, and serum ferritin were significantly decreased in late pregnancy. Serum transferrin saturation showed a significant positive correlation with glycated albumin/A1C ratio.CONCLUSIONSA1C levels, but not serum glycated albumin levels, are elevated in late pregnancy because of iron deficiency in diabetic women. Serum glycated albumin may offer an adequate marker for glycemic control during pregnancy.

Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 µg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of ␤-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing ␤-cell volume, primarily through accelerated neogenesis from ductal lining cells.

To better understand the pathogenesis of type 1 diabetes, we have developed pancreatic biopsy under laparoscope for recent-onset type 1 diabetic patients. The patients included 29 acute-onset type 1 diabetic patients, 5 latent-onset type 1 diabetic patients, and 1 type 2 diabetic patient. Their median age was 28 years, and the duration of diabetes at the time of biopsy was ϳ3 months. In 31 of 35 patients, we could obtain the pancreas tissue by punching. No serious complications, such as heavy bleeding, peritonitis, or pancreatitis, have been experienced. Pneumoderma was observed in two patients, and abdominal dull pain had continued for 2 days in two patients. However, special treatment was not necessary for these complications. T-cell-predominant infiltration to islets (insulitis) and hyperexpression of major histocompatibility complex class I antigens on islet cells were the two major findings and were observed in 17 of 29 recent-onset type 1 diabetic patients. These findings could be regarded as evidence of immune attack against ␤-cells, and their presence was closely correlated with the presence of either anti-GAD or anti-IA-2 antibodies (P ‫؍‬ 0.02). In conclusion, pancreatic biopsy under laparoscope is a safe procedure without serious complications, according to our findings, for detecting in situ autoimmune phenomenon in recent-onset type 1 diabetic patients.

To clarify the regeneration process of pancreatic beta-cells, we established a new mouse model of diabetes induced by selective perfusion of alloxan after clamping the superior mesenteric artery. In this model, diabetes could be induced by the destruction of beta-cells in alloxan-perfused segments, while beta-cells in nonperfused segments were spared. Intraperitoneal glucose tolerance tests showed glucose intolerance, which gradually ameliorated and was completely normalized in 1 year with a concomitant increase of insulin content in the pancreas. Histological examination showed neo-islet formation in the alloxan-perfused segment and the proliferation of spared beta-cells in the nonperfused segment. In the alloxan-perfused segment, despite a marked reduction of islets in size and number at an early stage, both the number of islets, including islet-like cell clusters (ICCs), and the relative islet area significantly increased at a later stage. Increased single beta-cells and ICCs were located in close contact with duct cell lining, suggesting that they differentiated from duct cells and that such extra-islet precursor cells may be important for beta-cell regeneration in beta-cell-depleted segment. In addition to beta-cells, some nonhormone cells in ICCs were positive for nuclear insulin promoter factor 1, which indicated that most, if not all, nonhormone cells positive for this factor were beta-cell precursors. In the nonperfused segment, the islet area increased significantly, and the highest 5-bromo-2-deoxyuridine-labeling index in beta-cells was observed at day 5, while the number of islets did not increase significantly. This indicated that the regeneration of islet endocrine cells occurs mostly through the proliferation of preexisting intra-islet beta-cells in the nonperfused segment. In conclusion, the regeneration process of beta-cells varied by circumstance. Our mouse model is useful for studying the mechanism of regeneration, since differentiation and proliferation could be analyzed separately in one pancreas.

Our finding suggests that for Japanese women, smoking and working may be important public health issue targets for the prevention of early spontaneous abortions.

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