Kunihiro Doi

Immunogenetics of early-onset insulin-dependent diabetes mellitus among the Japanese: HLA, Gm, BF, GLO, and organ-specific autoantibodies — the J.D.S. study

The Japan Diabetes Society (JDS) conducted a multicenter study on the immunogenetics of early-onset insulin-dependent diabetes mellitus (IDDM) of the Japanese. Human leukocyte antigen (HLA), properdin factor B (BF), immunoglobulin heavy-chain complex (Gm), and glyoxalase of erythrocytes (GLO) were typed, and organ-specific autoantibodies, including islet cell antibody (ICA), were assayed in 159 Japanese IDDM patients and their family members and in 258 healthy Japanese controls. The HLA-DRw9 phenotype and HLA-Bw61/DRw9 haplotype were significantly increased among the patients with autoantibodies other than ICA but with no autoimmune diseases (RR = 5.84, cP less than 0.001; and RR = 7.45, P less than 0.001), whereas the HLA-DR4 phenotype and HLA-Bw54/DR4 haplotype were significantly increased in those without either the autoantibodies or autoimmune diseases (RR = 2.64, cP less than 0.001; and RR = 4.55, P less than 0.001). The HLA-DR4 phenotype was significantly increased in the patients with autoimmune thyroid diseases (RR = 6.21, cP less than 0.05). In all groups of patients, the HLA-DR2 phenotype was significantly decreased, and the relative risk of the HLA-DRw9/DR4 genotype was highest among all HLA-DR genotypes. No significant association was found between HLA type and the duration or incidence of ICA. Gm types of g and gft were significantly increased in the patients with the autoantibodies (RR = 2.11, P less than 0.05; and RR = 34.11, P less than 0.05), whereas the BF-F phenotype was significantly decreased in the patients either with or without autoantibodies (RR = 0.43, P less than 0.05; and RR = 0.46, P less than 0.05). There was no association between IDDM and GLO type. These data indicate that immunogenetic bases underlying IDDM of the Japanese are heterogeneous, as are those in Caucasians.

Prevalence and clinical features of diabetes mellitus secondary to chronic pancreatitis in Japan; a study by questionnaire

The prevalence and clinical features of diagnosed mellitus secondary to chronic pancreatitis (CP) were assessed from northern (Hokkaido) to southern (Okinawa) Japan by means of a questionnaire to elucidate whether WHO-classified malnutrition-related diabetes mellitus (MRDM) exists in Japan. Of a total 17,500 diabetic patients, only two (0.011%)-one fibrocalculous pancreatic diabetes (FCPD) and one protein-deficient pancreatic diabetes (PDPD) - exhibited MRDM characteristics. A total of 649 CP were collected and classified into 268 cases with chronic alcoholic pancreatitis (CAP), 150 cases with chronic calcified pancreatitis (CCP) and 231 cases with other CP. The prevalence of diabetes mellitus was found to be 50.7% in CAP, 72.7% in CCP and 22.8% in other CP. Among all diabetics, 56.6% was noninsulin-dependent (NIDDM) and 26.4% insulin-dependent (IDDM). IDDM was most frequent in CP. Satisfactory and less than satisfactory glycemic control was obtained in approximately three quarters of all subjects. Only one quarter showed poor glycemic control. Insulin treatment was frequent in CAP (52.2%) and CCP (61.7%), but less in other CP (27.5%). The prevalence of diabetic retinopathy was observed in 33.1% of all subjects, nephropathy 21.0% and neuropathy 36.3%, respectively. The prevalence of complications, including macroangiopathy tended to be higher in CAP and CCP (40.3 and 56.9%) than in other CP (31.4%).

Lymphocyte subpopulations and function in childhood IgA nephropathy.

In order to examine T lymphocyte function in childhood IgA nephropathy, 13 patients and 10 age-matched control subjects were studied. T lymphocyte function was examined in terms of in vitro immunoglobulin synthesis by peripheral blood mononuclear cells (PBMC) and CD4-depleted (suppressor-rich) and CD8-depleted (helper-rich) PBMC in both unstimulated and pokeweed mitogen (PWM) and Staphylococcus aureus Cowan I (SAC) stimulated cultures. T lymphocyte subpopulations were examined by two-color immunofluorescence analysis using Fluorescein-Activated Cell Sorter (FACS). Children with IgA nephropathy showed (1) a significant increase in IgA synthesis by PBMC with or without mitogen stimulation, (2) a significant increase in IgG and IgA synthesis by CD4-depleted (suppressor-rich) PBMC, (3) a significant increase in IgG and IgA synthesis by CD8-depleted (helper-rich) PBMC, and (4) a significant decrease in suppressor-inducer T cells (Leu3a+Leu8+). These results suggest that a decrease in suppressor-inducer T cells, impaired suppressor T cell function and hyperactivity of helper T cell function are responsible for the increase in IgA production in children with IgA nephropathy.

ICA and organ-specific autoantibodies among Japanese patients with early-onset insulin-dependent diabetes mellitus--the JDS study.

The Japan Diabetes Society (JDS) conducted a multicenter study on the immunogenetics of insulin-dependent diabetes mellitus (IDDM) among Japanese. The previous report of the JDS study described HLA types and other immunogenetic markers in Japanese patients with IDDM. In the present report, the autoimmunity of Japanese patients was studied by measuring ICA and other organ-specific autoantibodies in patients with different durations of IDDM. The prevalences of ICA were the highest in the first year after diagnosis (73.1%) and decreased to 58.0%, 18.3% and 2.8% in 1-5 years, 5-10 years and 10 years or more after diagnosis, respectively (P < 0.01), while the prevalences of the other organ specific autoantibodies increased gradually with duration of IDDM from 20% in the first year to 35% in 10 years or more after diagnosis (P < 0.05). There were no sex differences in the prevalences of ICA but those of other organ-specific autoantibodies were significantly higher in female patients than in male patients (P < 0.01). The prevalence of ICA was not correlated with sex, age at onset or HLA types. In one of the subjects, a girl, the titers of ICA increased in parallel with a decrease in insulin secretion before the development of overt IDDM and declined thereafter. These findings suggest that IDDM might develop when the autoimmunity specific to pancreatic islets is triggered in people with underlying autoimmunity as shown by the presence of organ-specific autoantibodies other than ICA.

Effects of long-term high-fiber diet on macrovascular changes and lipid and glucose levels in STZ-induced diabetic SD rats

The effects of long-term high-fiber diet on lipid and glucose levels and the histological changes in the coronary arteries and thoracic aorta in STZ-induced diabetic SD rats were investigated. During the first 4 weeks of the study period, all diabetic rats were given regular chow plus water after which, all were grouped according to the following diet regimen: group II, no added cholesterol and glucomannan; group III, no added cholesterol but with glucomannan supplement, group IV, with added cholesterol but no glucomannan supplement; and group V, with both cholesterol and glucomannan supplements. 15% weight of glucomannan and 1.5% weight of cholesterol in regular rat chow were used as supplements when indicated. Non-diabetic rats which received only regular chow served as the control group (group I). In the 18th week all rats were sacrificed and weight gain, glucose, total cholesterol, HDL-cholesterol, triglyceride and lipid peroxidase concentrations were determined. Selected portions of the heart and thoracic aorta were histologically examined. Weight gain was higher in rats supplemented with glucomannan than in those without glucomannan supplements, but the difference is not significant. A lowering tendency in glucose levels was likewise observed. Furthermore, total cholesterol and HDL-cholesterol levels were lower and higher, respectively in diabetic rats receiving glucomannan. Although the triglyceride levels were similar in all rats, lipid peroxidase levels were significantly lower in rats with high-fiber diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin 2/interleukin 2 receptor system in type 1 diabetes

There is increasing evidence that cellular immune abnormalities are involved in the pathogenesis of type 1 diabetes mellitus. The non-obese diabetic (NOD) mouse, a model of human type 1 diabetes, develops mononuclear cell infiltration of its pancreatic islets (insulitis), leading to /3 cell destruction and overt diabetes [l]. In recent studies, most of the islet-infiltrating cells in the NOD mouse were determined to be T cells by immunohistochemistry [2] and electron microscopy [3]. Furthermore, neonatal thymectomy [4], the administration of anti-thymocyte serum [5], or the transfer of the nude gene [6] has prevented insulitis and the development of diabetes in this animal model. These findings strongly suggest that T lymphocyte-mediated autoimmunity underlies the autoimmune phenomenon in NOD mice. Interleukin 2 (IL-2) is produced by antigenor mitogen-activated T lymphocytes and plays a central role in the development of the immune re-

Suppressor T-cell abnormality in NOD mice before onset of diabetes

To investigate the pathological role of suppressor T-cells in non-obese diabetic (NOD) mice, we stimulated splenic T-lymphocytes from diabetes-prone NOD mice with concanavalin A (ConA) and then evaluated their ability to suppress the lymphocyte-proliferative responses to mitogen and allogenic cells. Lymphocytes from NOD mice showed significantly less suppressor ability than did those from BALB/c mice and non-obese non-diabetic (NON) mice, the corresponding non-diabetic sister strain of the NOD mouse, both in the mitogen response and in the mixed lymphocyte reaction (MLR). We used monoclonal antibodies and flow cytometry to analyze the lymphocytic surface phenotypes, and found markedly fewer Lyt2+ T-lymphocytes (suppressor/cytotoxic T-lymphocyte) in the NOD mice than in both controls after exposure to ConA. These results suggest that suppressor T-cell activity is already depressed in NOD mice before diabetes begins and that a substantial decrease in the number of suppressor T-cells induced by ConA may explain this depressed suppressor activity. This impairment may contribute to the pathogenesis of type 1 diabetes in NOD mice.

Morphological study of nervous system in vacor-induced diabetic rats

Patients with Vacor diabetes mellitus frequently developed diabetic ketoacidosis and neuropathy in the early stage of the disease; however, the mechanism of the development of diabetes and its neurologic complications is not known. In this study, oral administration of 100 mg Vacor/kg of body weight was used in Wistar male rats. The rats were sacrificed 6 h after administration to avoid natural expiration. Light microscopy revealed focal hemorrhage and edematous change in the periventricular area of the brain, scattered hemorrhage in the posterior and anterior horns, spongy degeneration and demyelinization in th fasciculus gracilis and cuneatus of the white matter, early degenerative changes in the sciatic nerve, and no change of the vagus. Electron microscopy showed necrosis of the axon, myelin sheaths and glia cells in the spinal cord, while the organelles of the peripheral nerves were unchanged. These findings indicate that Vacor produces various neurotoxicities in the acute toxic phase.

Changing distribution of obesity index in freshmen students of Kobe University from 1975 to 1985

1. We determined changes of the mean levels of height, weight, BMI (body mass index) and blood pressure among Japanese freshmen students (n = 9708) of Kobe University for a period of 10 years (1975 to 1985). 2. We observed the distribution of obesity index calculated on Welfare Ministry’s standard body weight among Japanese freshmen students in 1975 and 1984. 3. We checked the body measurement and blood pressure of 1214 male students of Kobe University (1980); those who have no history of alcohol drinking, liver disease (except fatty liver) and glucosuria. 4. The blood samples were examined for SGGT, SGPT, cholinesterase (CHE), total cholesterol, triglyceride (TG), serum uric acid and fasting blood glucose. Fatty liver findings were observed using ultrasonographic method (TOSHIBA, SAL32B).

Recent status of insulin treatment of Japanese NIDDM

Diabetes mellitus is becoming more prevalent in Japan, particularly non-insulin-dependent diabetes mellitus (NIDDM). The prevalence remains lower than in the West, particularly the prevalence of insulin-dependent diabetes mellitus (IDDM), which is much lower. While the reasons are unknown, possibilities include differences in diet, environment, and heredity. As in other countries, hypoglycemic drug treatment is becoming more common in Japan. The recent report of UDGP [l] documented the side effects not only of insulin but also of oral hypoglycemic agents as well. The report led to many patients being switched from oral agents to insulin or to diet therapy. Insulin use has also increased with the distribution of human insulin and highly purified insulin and the superior diabetic control they make possible. The growing use of insulin has made it easier for us to ask patients about their treatment even if oral agents do not provide them with good control. This report presents data concerning patients with diabetes in 29 hospitals in the Kinki region (which includes Kyoto. Osaka, Hyogo, Shiga, Nara and