T-cell insulitis found in anti-GAD65+ diabetes with residual beta-cell function. A case report.

CASE HISTORY: We recently encountered a 65-year-old anti-GAD+ diabetic woman with residual beta-cell function who was proved to have T-cell insulitis. The proportion of CD4+ and CD8+ cells varied among individual islets, although CD4+ cells tended to be the predominant T-cell type in the islets examined. All of the islets examined still contained insulin, suggesting that beta-cell mass may have been preserved. DISCUSSION: It is well known that lymphocytic infiltration of pancreatic islets, a condition referred to as "insulitis," is seen in acute-onset type 1 diabetes at autopsy and in biopsy specimens. However, there have been no proven cases of insulitis in type 1 diabetes with residual beta-cell function. We believe that this is the first type 1 diabetic patient with residual beta-cell function who was proven to have T-cell insulitis. This novel evidence will contribute to the proper classification and treatment of diabetes and to a better understanding of the pathophysiology of type 1 diabetes.

Elevated serum IP-10 levels observed in type 1 diabetes.

OBJECTIVE: Although most patients with type 1 diabetes are considered to have T-cell-mediated autoimmune disease, a method of measuring of pancreatic beta-cell-specific T-cell function in cases of type 1 diabetes has yet to be established. Here, we focused on interferon-inducible protein-10 (IP-10), a chemokine that promotes the migration of activated T-helper 1 (Th1) cells and measured serum IP-10 levels in patients with human type 1 diabetes, which is regarded as a Th1-mediated disease. RESEARCH DESIGN AND METHODS: Serum samples were obtained from diabetic patients, and the levels of autoantibodies (GAD and insulinoma-associated protein-2 [IA-2]) and IP-10 were measured. Diabetic patients positive for either or both of the autoantibodies were classified as Ab+ type 1, and those negative for both were classified as Ab type 1. To evaluate islet antigen-specific responses, peripheral blood from patients stimulated with or without GAD was used, and intracellular cytokine staining for flowcytometry was performed. RESULTS: The Ab+ and Ab- type 1 groups both showed a significantly higher serum IP-10 level than the healthy subjects (P < 0.001 and P < 0.05, respectively), and the IP-10 level in the recent-onset Ab+ subgroup was significantly higher than that in the established (longstanding) Ab+ subgroup (P < 0.002). Furthermore, there was a significant positive correlation between the serum IP-10 level and the number of GAD-reactive gamma-interferon-producing CD4+ cells in the Ab+ type 1 group (P < 0.007). CONCLUSIONS: Our findings demonstrate that measurement of serum IP-10 concentrations is useful in patients with type 1 diabetes.

Balance of GAD65-specific IL-10 production and polyclonal Th1-type response in type 1 diabetes.

It has been proposed that cytokine responses of memory CD4+ cells change from a T-helper 2 (Th2)-to a T-helper 1 (Th1)-dominant response as the disease progresses in non-obese diabetic (NOD) mice. However, the regulation of Th1/Th2 balance in spontaneous diabetes development in this model is not well understood. In this study, higher glutamic acid decarboxylase 65 (GAD65)-specific IL-10 production was observed at 10-12 weeks in NOD mice, and a marked increase of Th1-type response (IFN-gamma production) upon polyclonal (anti-CD3 antibody) stimulation was observed just before diabetes development along with a decline of GAD65-specific IL-10 production. Moreover, there was a clear negative correlation between IL-10 level upon GAD65 stimulation and log(IFN-gamma) level upon anti-CD3 antibody stimulation (r=-0.999, p<0.001). These results suggest that the balance between GAD65-specific IL-10 production and polyclonal Th1-type response may regulate the onset of hyperglycemia in type 1 diabetes in NOD mice.

Secretion of GIP in responders to acarbose in obese Type 2(NIDDM) patients.

Acarbose has been shown to reduce postprandial hyperglycemia and to improve lipid parameters in diabetics via its inhibitory effects on intestinal alpha-glucosidases. Response to acarbose may therefore be dependent upon gastric or pancreatic hormone function. To test this hypothesis, we treated 27 mild type 2 (NIDDM) Japanese diabetics who were mildly obese with low-dose acarbose (150 mg/day) for 3 months. We then performed a responder analysis to determine specific hormonal responses that may be associated with a good response to acarbose. At the end of the treatment period, a total of 15 evaluable patients was grouped as responders (n=6) and nonresponders (n=9) based on an effective decrease in postprandial glucose levels (>30 mg/day) and glycosylated hemoglobin (HbA1c) levels (>0.5%). There were no differences between the two groups in demographic variables or mean postprandial glucose levels at baseline. There was a small but significant increase in postprandial cholecystokinin (CCK) in responders, and fasting gastric inhibitory peptide (GIP) levels were significantly increased in responders and all patients after treatment. Serum leptin levels were reduced by treatment in our mildly obese responders and this was associated with a significant decrease in body weight. These results suggest that treatment with low-dose acarbose may reduce hyperglycemia in mild type 2 Japanese patients and may improve metabolic control by regulating hormones involved in glycemic control and digestive absorption. Acarbose may provide a safe adjunct to help treat insulin resistance in type 2 patients.

[A case of tropical eosinophilia associated with pleural effusion].

A 52-year-old man was admitted to Keio University Hospital for determination of the etiology of a bilateral pleural effusion associated with marked eosinophilia (10200 cells/mm3). He had been in Vietnam for three years and had returned to Japan in May 1993. He was suffering from tropical eosinophilia, as clearly indicated by eosinophilia, elevation of serum IgE level (708 IU/ml), the presence of anti-dirofilarial antibodies, and the absence of microfilaria in the blood. The pleural effusion was an exudate and 51% of the cells in the effusion were eosinophils. In the effusion, no parasites were detected but anti-dirofilarial antibodies were found (the titer was as high as that in the serum). Diethylcarbamazine was given, and a steroid had to be superimposed because of wheezing. These treatments successfully reduced the bronchoconstriction, eosinophilia and accumulation of pleural effusion. Tropical eosinophilia has generally been thought not to be associated with pleural effusion. This is only the third case report of tropical eosinophilia with authentic pleural effusion.