Incidence Of Insulin-dependent Diabetes Mellitus Research Articles

Body Mass Index (BMI) and Its Influence on the Cardiovascular and Operative Risk Profile in Coronary Artery Bypass Grafting Patients: Impact of Inflammation and Leptin.

Background Obesity is related to coronary artery disease (CAD) and worse outcomes in coronary artery bypass graft (CABG) patients. Adipose tissue itself is an endocrine organ that secretes many humoral mediators, such as adipokines, which can induce or reduce inflammation and oxidative stress. Objectives We investigate the relationship between the body mass index (BMI), inflammation, and oxidative stress by measuring serum levels of leptin, interleukin-6, and 3-nitrotyrosine in CABG patients and correlate their levels to the cardiovascular and operative risk profiles. Methods and Results 45 men (<75 years) with a median BMI of 29 (21-51) kg/m2, who were diagnosed with CAD and scheduled for elective CABG, were included after applying the following exclusion criteria: prior myocardial infarction, reoperation, female gender, and smoking. Patients' blood samples were taken preoperatively. Several markers were measured. We found significant correlations between leptin and BMI (p < 0.0001) as well as between leptin and 3-nitrotyrosine (p = 0.006). Interleukin-6 was correlated with C-reactive protein (p < 0.0001) and with the incidence of insulin-dependent diabetes mellitus (p = 0.036), arterial hypertension (p = 0.044), reduced left ventricular function (p = 0.003), and severe coronary calcification (p = 0.015). It was also associated with significantly longer extracorporeal bypass time (p = 0.009). Postoperative deep sternal wound infections could be predicted by a higher BMI (p = 0.003) and leptin level (p = 0.001). Conclusions There seems to be a correlation between inflammatory processes and cardiovascular morbidity in our cohort. Further, the incidence of deep sternal wound infections is related to a higher BMI and leptin serum level.

Safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in adolescents aged 12–15 years: Interim analysis of a large community-randomized controlled trial

ABSTRACTThis community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12–15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0–82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2–91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03–1.24] and 0.16 [95% CI: 0.03–0.55], respectively).

Abstract PR046

Background & Objectives: Currently, the most commonly used model to predict cardiac risk before non-cardiac or vascular surgery is the Revised Cardiac Risk Index (RCRI), but some studies have pointed out that the Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) is a better predictor of cardiac complications. The objective of this study was to assess which index indicates intraoperative hemodynamics instability (IHI) and a higher incidence of following comorbidities (FC). Materials & Methods: The medical records of 101 patients, underwent carotid endarterectomy under cervical plexus block during a 3 month period at our institution, were retrospectively reviewed. RCRI and VSG-CRI were used to classify patients into 3 groups: low (I), medium (II) and high risk group (III). IHI was defined as an increase/decrease in systolic and diastolic blood pressure or heart rate for ≥20% from basal value, for 2 minutes. The incidence of FC such as insulin-dependent diabetes mellitus (IDDM), chronic heart failure (CHF), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), old age and smoking, were compared among groups. Results: According to RCRI, group I consisted of 26 patients (25.74%), group II of 68 (67.33%) and group III of 7 (6.93%). On the other hand, according to VSG-CRI, group I consisted of 52 patients (51.49%), group II of 35 (36.63%) and group III of 12 (11.88%). No statistically significant differences in blood pressure alterations (systolic and diastolic) and heart rate were noted among groups classified by the RCRI and VSG-CRI. The incidence of IDDM, CHF and CAD were significantly higher in III group compared to the other two groups classified by RCRI (p=0.004, p=0.005, p=0.0001, respectively). In line with VSG-CRI, age and the incidence of CHF and CAD were significantly higher in group III compared to the other two groups (p<0,0001, p<0.0001). The incidence of COPD and smoking were statistically higher in the medium group compared to the other two groups, in accordance to VSG-CRI as well (p=0,008, p=0.03). Conclusion: VSG-CRI showed greater representation of the incidences of FC in high (3 FC) and medium risk group (2 FC), compared to RCRI which showed the presence of the only 3 FC in high risk group. Follow-up is necessary to confirm better predictive value of VSG-CRI.

Synthesis of Diosgenin-Ibuprofen Derivatives and Their Activities against Insulin-Dependent Diabetes Mellitus

The synthesis and anti-diabetes activities of diosgenin-ibuprofen derivatives were investigated. Ibuprofen (IBU) was chemically coupled with diosgenin either directly or through amino acid esters linkers. The effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) generation were assessed. The results showed spirost-5-en-3β-yl (2-(4-isobutyl-phenyl)-propionate) (4) was of better activity to suppress the production of NO in the supernatant of LPS-stimulated RAW264.7 cells. In vivo investigation on nonobese diabetic (NOD) mice indicated that compound 4 decreased the incidence of insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) of NOD mice which suggested a potential activity of compound 4 against type 1 diabetes.

Outbreak of Escherichia coli and diabetes mellitus

Sir, The present global public health issue on the outbreak of Escherichia coli is the world's focus. The infection started in Germany and spread widely in Europe.[1] The pathogenic E. coli infection can cause severe diarrhea as well as other more serious presentations. In some severe cases, infected with E. coli, O157: H7, renal complications such as hemolytic uremic (HUS) syndrome can be expected. HUS is known for its relationship with diabetes mellitus. Due to pancreatic injury,[2] the increased incidence of insulin-dependent diabetes mellitus in pediatric patients infected with O157: H7 E. coli is reported.[1,3] It usually accompanies renal failure, which is a complication of HUS.[1–5] Suri et al. mentioned that “Survivors with diarrhea-associated HUS have a significantly increased incidence of diabetes due to complete insulin deficiency, which may recur several years after the initial infection.”[1] As a conclusion, Suri et al. proposed following up for diabetes among the affected patients during acute illness and in long term after severe infection.[4] In addition to the copresentation with HUS, E. coli is also reported for its relationship to development of peritonitis in diabetic patients. In an animal model study, it is proved that endothelin-1 played important role in development of peritonitis, and increased plasma endothelin-1 concentrations was common in E. coli septic peritonitis.[6] In conclusion, a certain relationship between diabetes mellitus and E. coli infection is evidenced. In the present E. coli outbreak, the importance of diabetes mellitus, as a possible comorbidity, should not be forgotten.

The Incidence of Insulin-Dependent Diabetes Mellitus in Urban Districts of Shanghai (1989-1993)

Article The Incidence of Insulin-Dependent Diabetes Mellitus in Urban Districts of Shanghai (1989-1993) was published on July 1, 1996 in the journal Journal of Pediatric Endocrinology and Metabolism (volume 9, issue 4).

Four‐year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.

New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis

New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment.Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis.New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n = 1636) or cyclosporine (n = 1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p < 0.00001), an effect observed in renal (9.8% vs. 2.7% p < 0.00001) and nonrenal (11.1% vs. 6.2%; p < 0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p < 0.00001).The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.

Influence of tacrolimus plus mycophenolate mofetil regimens on acute rejection rate and diabetes mellitus development in renal transplant recipients

In this study we investigated the influence of a tacrolimus (TAC) plus mycophenolate mofetil (MMF) immunosuppressive regimen on the acute rejection rate and side effect profile in renal transplant recipients.The study included 80 living-related and 40 cadaveric donor renal transplant recipients (82 men, 38 women) of mean age 35 ± 10 years (range, 16 to 58) who were operated between August 1999 and September 2002. The mean HLA mismatches was 3 ± 1 (range, 0 to 5). All patients received prednisolone, MMF (2 g/d for the first 14 days posttransplant and then 1 g/d) plus TAC (0.2 mg/kg/d). They were followed for the development of rejection attacks and side effects. Diabetes mellitus developed in 13 patients (9 men, 4 women; 10.8%). Initially, patients required insulin therapy but after 6 months, 5 recipients no longer needed insulin therapy and were switched to oral hypoglycermic agents and diet control. Hypertension was diagnosed in 58 patients (48.3%). Neither gender nor donor origin (P = .14; P = .79, respectively) produced a significant difference in diabetes mellitus development.Biopsy proven acute rejection episodes were observed in 16 out of 120 patients (13.3%). Six out of 120 patients lost their grafts throughout the study period including one death because of suicide, one because of cytomegalovirus disease and hemophagocytic syndrome, one due to posttransplant lymphoproliferative disease and two to a cardiac arrhythmia. Only one patient lost his graft due to acute accelerated vascular rejection. Biopsy-proven chronic rejection appeared in one patient.In conclusion, although the incidence of insulin-dependent diabetes mellitus during posttransplant 6 months, seems high it decreased to 1.6% upon reduction of the TAC dosage. TAC plus MMF immunosuppression seems effective and safe in terms of acute rejection rates and side effect profiles.

Pedal Arterial Bypass for Limb Salvage in Patients with Diabetes Mellitus

Objective: to evaluate pedal bypass grafting in patients with diabetes mellitus with critical limb ischaemia.Patients and Method: from 1994 to 1999, 49 consecutive pedal bypass grafts were performed in 46 patients with a median age of 69 years (range 37–85 years). The incidence of insulin-dependent diabetes mellitus was 87%. The distal anastomosis was located at the dorsalis pedis artery in 36, at the inframalleolar posterior tibial artery in 9 and at the plantar artery in 4 cases, respectively.Results: one patient died perioperatively. Two bypass occlusions and one major amputation accounted for a primary patency rate of 96% and a limb salvage rate of 98% at 30 days, respectively. During a median follow-up of 28 months (range 1–70 months), 21 patients died of nonrelated causes. Three additional graft occlusions and 4 major amputations were noted resulting in a primary patency rate of 89% and a limb salvage rate of 87% at 48 months, respectively.Conclusion: Pedal bypass grafting utilising the greater saphenous vein with in-situ technique is a reliable and effective procedure to achieve durable limb salvage in patients with diabetes mellitus.

HLA alleles and IDDM in children in Hungary: a comparison with Finland

It has been postulated that variation in the distribution of human leukocyte antigen (HLA)-encoded susceptibility alleles for insulin-dependent diabetes mellitus (IDDM) is the genetic basis for variation in the incidence of the disease between populations. The aim of this study was to characterize HLA-encoded susceptibility to IDDM in Hungary and to identify whether HLA-DRB1/DQ-encoded susceptibility could account for the five times lower incidence of disease in Hungary compared with Finland. The haplotypes DRB1∗03-DQA1∗05-DQB1∗02 (DRB1∗03-DQ2) and DRB1∗04-DQA1∗0301-DQB1∗0302 (DRB1∗04-DQ8) were significantly associated with disease in both populations. Three genotypes incorporating either or both of these haplotypes accounted for over 70% of the diabetic population in both races. The combined background frequency and the degree of risk as measured by odds ratios of these HLA-DRB1-DQ genotypes were not significantly different in the two countries. Comparison of the DRB1∗0401-DQ8 haplotype between the two races suggested a role for HLA-B alleles in susceptibility. These data indicate that the susceptibility associated with high risk DRB1-DQ genotypes alone is insufficient to account for the fivefold variation in incidence of IDDM between Hungary and Finland. Other genetic and/or environmental influences must be involved.

IDDM and early exposure of infant to cow's milk and solid food.

Associations studies were attempted between the type of feeding, duration, and time of starting of solid foods in infancy and the incidence of insulin-dependent diabetes mellitus (IDDM). The study subjects comprised 52 IDDM patients and 52 control subjects matched for sex, age, social status, country, geographical location and selected from pediatric departments of different hospitals in Tehran. Diabetic children (21 boys, 31 girls) were of the ages of 1.5 to 14 years. Information about the pattern of their feeding at the first two years of life were collected through questionnaires administered to the mothers. The questionnaire was designed to evaluate the duration of complete or partial breast-feeding and the age at which dietary products containing cow's milk were introduced into the diet. A large proportion of the diabetic children rather than the control children had been breast-fed, and the risk of IDDM among children who had not been breast-fed was below unity. No significant difference in the duration of breast-feeding was observed between diabetic and control group. Our data do not support the existence of a protective effect of breast-feeding on the risk of IDDM, nor do the data indicate that early exposure to cow's milk and dairy products has any influence on the development of IDDM.

Genetic epidemiology of type 1 diabetes mellitus in Taiwan

Some environmental and genetic factors play important roles in etiopathogenesis of type 1 or insulin-dependent diabetes mellitus (IDDM). HLA genes, the IDDM1 locus located the human chromosome 6, were found to be associated with insulin-dependent diabetes mellitus. However, the incidence of IDDM varied greatly among various populations. To evaluate the pathogenetic factors contributing to the development of IDDM in Taiwan, HLA typing was performed in a group of IDDM unrelated individuals and IDDM pedigrees along with the normal controls from the northern Taiwan. DNA genotypes of class II HLA were done by polymerase-chain-reaction based oligotyping techniques. We confirmed that class II HLA genes were significantly associated with IDDM in Taiwan. To study detailed molecular structure of class II HLA molecules and disease association, we examined several amino acid residues on DQα and DQβ chains and the molecular mechanisms to explain the heterozygotic effect of the DR3/DR4 and DR3/DR9 in the Chinese population. Linkage analysis in our pedigrees confirmed the association between HLA and IDDM in population association studies. Among the several class II alleles, a closer segregation of HLA-DQB1*0401 to the affected persons might suggest that HLA-DQB1*0401 itself or an allele closely linked to the DQB1 locus was the IDDM-predisposing allele in Taiwanese. For IDDM2 ( INS) region, association with IDDM was not found due to that more than 90% of the population carried class I alleles. In our collection of IDDM, we found few cases (2.4%) carried mitochondrial DNA mutation. Our studies in Taiwanese confirm a multigenetic nature for IDDM.

HLA-DR and -DQ associations with insulin-dependent diabetes mellitus in a population of Turkey

Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) has been shown to be associated with MHC in many studies. To extend this data with a population with relatively low IDDM incidence, MHC DRB, DQA, and DQB have been investigated by polymerase chain reaction and sequence specific oligonucleotide probe hybridization (PCR/SSO) in 178 IDDM patients from Turkey and compared to 248 healthy controls. Significant differences are detected between IDDM and control groups in the frequencies of DRB1∗0402 DQA1∗03 DQB1∗0302 (28.1% vs. 5.2%, p < 0.0001, OR: 7.1) and DRB1∗0301 DQA1∗0501 DQB1∗02 (57% vs. 18.1%, p < 0.0001, OR: 6.1). Among the negative associations, the most strong ones are with DRB1∗1401 DQA1∗0101 DQB1∗0503 (0.6% vs. 8.9%, p < 0.0001, OR: 0.1), DRB1∗1502 DQA1∗0103 DQB1∗0601 (1.1% vs. 7.7%, p = 0.0023, OR: 0.1), DRB1∗1301 DQA1∗0103 DQB1∗0603 (0.6% vs. 6.9%, p = 0.0039, OR: 0.2) and DRB1∗1101 DQA1∗0501 DQB1∗0301 (3.9% vs. 12.1%, p < 0.0001, OR: 0.2). When the DRB, DQA or DQB genotypes of the susceptible alleles are compared, the most strong susceptibility marker of the disease is found to be DRB1∗0301/∗04 (31.4% vs. 2.8%, p < 0.0001, OR: 15.8) and among these, heterozygote genotype DRB1∗0301/∗0401 (4.5% vs. 0, p = 0.0008, OR: 24.8). These results confirm the positive associations with IDDM previously observed in other Caucasian populations and reveal many negative and strong associations which maybe underlining several characteristics that distinguish Turkish diabetics form other Caucasians.

Functional status of the immune system after chronic administration of 2'-deoxycoformycin in the BB rat.

Insulin-dependent diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic beta cells with the primary mechanism being cell mediated. The BB rat develops insulitis and IDDM with many features analogous to the disease in man. In previous studies we reported that weekly administration of 2'-deoxycoformycin (dCF) for four months reduces significantly the incidence of IDDM in the BB rat by 70%, and that the animals remain free of diabetes for a minimum of two months after drug withdrawal. Since the diabetes-prone BB rat is lymphopenic, with a reduction of both CD4 and CD8 cells, the continuous failure of dCF treated animals to develop diabetes may have been due to generalized immunosuppression. To test this possibility, the ability of dCF treated diabetes-free BB rats to mount an immune response after challenge with Ovalbumin was examined five months after drug withdrawal. The results showed that the post-immunization levels of total IgG and specific IgG in these animals did not differ from those observed in non-dCF treated controls nor those of control diabetes-resistant non-lymphopenic BB rats. Moreover, FACS analysis indicated no change in the percentages of total numbers of CD4+ or CD8+ cells between the two groups of animals. Histological assessment of the pancreata of the post-dCF treated animals showed varying degrees of mononuclear cell infiltrates in the islets. These data demonstrate that treatment by dCF is not permanent, and may require intermittent or continuous administration to prevent development of diabetes. Further studies are needed to determine the mechanism of action of dCF in this model of IDDM.

HLA class II immunogenetics and incidence of insulin-dependent diabetes mellitus in the population of Cantabria (Northern Spain)

HLA class II genes were analyzed to study IDDM susceptibility in Cantabria (Northern Spain). Patients showed highly significant increases in DRB1∗0301 (RR = 4.581, p < 0.00005), DRB1∗0401 (RR = 2.6, p < 0.05), DRB1∗0402 (RR = 8.78, p < 0.05) and DRB1∗0405 (RR = 14.73, p < 0.005). Highly significant diferences were in the DQA1∗0301 (RR = 3.62, p < 0.000005) and DQA1∗0501 (RR = 2.13, p < 0.05) alleles. DQB1∗0201 (RR = 4.1, p < 0.00005) and DQB1∗0302 (RR = 5.42, p < 0.000005) alleles were also significantly increased. A significant increase in DRB1∗0402-DQA1∗0301-DQB1∗0302 (RR = 16.18, p < 0.05), DRB1∗0405-DQA1∗0301-DQB1∗0302 (RR = 16.12, p < 0.05), DRB1∗0301-DQA1∗0501-DQB1∗0201 (RR = 4.58, p < 0.00005) and DRB1∗0401-DQA1∗0301-DQB1∗0302 (RR = 4.36, p < 0.005) was apparent in the diabetic group, while the DRB1∗1501-DQA1∗0102-DQB1∗0602 and DRB1∗1401-DQA1 ∗0104-DQB1∗05031 protective haplotypes (RR = 0.17 and 0.09, p < 0.0005 and 0.05, respectively) were significantly lower in patients. The absence of Asp57 and the presence of Arg52 were associated with disease in a dose-dependent manner. Several genotypes encoding the identical DQα52/DQβ57 phenotype carried very different RRs. Finally, the Cantabrian population has the highest incidence of IDDM reported for Spain (15.2 of 100.000 in the 0–14 age group, Poisson’s 95% CI: 10.6–19.3).

The role of environmental factors in insulin-dependent diabetes mellitus: an unresolved issue.

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by the destruction of the insulin-secreting beta cells found in the islets of Langerhans. Reduced beta-cell mass results in overt diabetes, requiring lifelong exogenous insulin administration and the possibility of numerous sequelae. Incidence and development of IDDM depend upon a variety of genetic and nongenetic factors. Environmental factors such as chemicals, diet, and infection are suspected to influence the development of disease. This review describes the work performed to date to elucidate the role of these environmental factors in IDDM.

Inhibition of Diabetes in NOD Mice by Idiotypic Induction of SLE

The present study was undertaken to investigate whether active induction of systemic lupus erythematosus (SLE) in non-obese diabetic (NOD) mice could affect their development of insulin-dependent diabetes mellitus (IDDM). NOD mice were immunized with a human IgM mAb carrying the 16/6 idiotype (MIV-7) or with control human IgM. The mice were bled monthly and tested for SLE-associated autoantibodies in the serum and for the presence of leukopenia, thrombocytopenia, proteinuria and immunoglobulin deposits in the kidneys. The development of diabetes was determined by a blood glucose level exceeding 15mM on two consecutive weekly determinations and by the presence of insulitis in the pancreas. The NOD mice immunized with MIV-7 developed high and persistent levels of autoantibodies, including anti-DNA, anti-histones and anti-cardiolipin, untreated mice and those immunized with normal human IgM did not produce these autoantibodies. The MIV-7-immunized mice also manifested an elevated erythrocyte sedimentation rate, leukopenia, thrombocytopenia and significant proteinuria, as well as deposits of Ig in their kidney glomeruli. Thus, NOD mice immunized with MIV-7 developed both autoantibodies and clinical features of SLE. The MIV-7-treated mice, however, showed a significantly lower incidence of IDDM (25%vs . 90%, P<0.003), accompanied by amelioration of the insulitis. The present study indicates that the induction of SLE by idiotypic immunization can protect NOD mice from developing IDDM, pointing to the importance of immune dysregulation in shift from one autoimmune disease to another.

DNA immunization to prevent autoimmune diabetes.

Mice expressing lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a transgene in their beta cells develop insulin-dependent diabetes mellitus (IDDM) only after LCMV infection. Inoculation of plasmid DNA encoding the insulin B chain reduced the incidence of IDDM by 50% in this model. The insulin B-chain DNA vaccination was effective through induction of regulatory CD4 lymphocytes that react with the insulin B chain, secrete IL-4, and locally reduce activity of LCMV-NP-autoreactive cytotoxic T lymphocytes in the pancreatic draining lymph node. In contrast, similar vaccination with plasmids expressing the LCMV viral ("self") protein did not prevent IDDM, because no such regulatory cells were induced. Thus, DNA immunization with plasmids expressing self-antigens might constitute a novel and attractive therapeutic approach to prevent autoimmune diseases, if the antigens are carefully preelected for an ability to induce regulatory lymphocytes in vivo.

Diabetes and enterovirus autoimmunity in glacial Europe

The incidence of insulin-dependent diabetes mellitus (IDDM), a chronic disease with a well-known genetic basis, is highest in Scandinavian and Sardinian populations. The high incidence of IDDM in Scandinavia and Sardinia, which were genetically isolated from the spread of agriculturists in Europe about 8000 years ago, suggests that an IDDM-susceptible genotype(s) may have been beneficial in Europe more than 8000 years ago. In glacial times, Europe had an extremely cold climate that was frequently interrupted by episodes of warming. When enteroviruses were locked in the ice and permafrost, glacial Europeans would have had little immunity to these viruses. Each time the climate warmed, enteroviruses would have spread through increased amounts of melt water. With a genetic ability to mount an autoimmune defense, the IDDM genotype(s) would have been beneficial in glacial Europe as a defense against all enteroviruses, including those that had co-evolved to mimic host tissue.