Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to Insulin-dependent diabetes mellitus (IDDM)

Abstract: Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecule in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-length cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing analysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along with that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from various ethnic groups and in healthy unrelated Japanese and Norwegian individuals. The allelic and haplotypic distributions in each population revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients were analyzed. DQB1*0301 was negatively associated with IDDM in both ethnic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB1*0302 positive populations, which represented a positive association with IDDM in both ethnic groups, DRB1*0401, *0404, *0802 haplotypes increased in the patients, whereas DRB1*0406 haplotype decreased. Considering about the hierarchy in DRB1 alleles with IDDM susceptibility (DRB1*0401>*0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the combination of DR-associated susceptibility and DQ-associated susceptibility and by the DQ-associated resistance which is a dominant genetic trait.     

Increased CD5-positive B lymphocytes in type I diabetes.

CD5+ B lymphocytes have been implicated in the production of polyspecific and monospecific antibodies that bind self-antigens, and increased proportions of this B cell subset occur in patients with some autoimmune diseases. We investigated the proportion of peripheral blood CD5+ B lymphocytes in type I diabetic patients. Compared with 18 age-matched healthy subjects, 11 out of 28 (39.2%) type I diabetic patients had increased proportions of circulating CD5. B lymphocytes with no alterations in the numbers of circulating B and T lymphocytes. Although all patients with increased CD5 B lymphocytes also had serum islet cell antibodies and/or insulin autoantibodies, the occurrence of increased proportions of CD5+ B lymphocytes and serum autoantibodies was not significantly correlated. Increased proportions of CD5+ B lymphocytes was not related to the time elapsed since the clinical onset of diabetes. In addition, regardless of being increased or normal, the proportion of CD5+ B lymphocytes appeared as a relatively constant phenotype after 1 year of follow-up studies at 3-month intervals in eight patients. Although the significance of these findings remains to be established, the possibility exists that CD5+ cells play a role in the pathogenesis of type I diabetes.     

全身性红斑狼疮、银屑病和胰岛素依赖性糖尿病病人补体成份BfSS亚型的检测

用薄层聚丙烯酰胺凝胶等电聚焦方法对62例全身性红斑狼疮(SLE)、61例寻常型银屑病(PV)及17例胰岛素依赖性糖尿病(IDDM)病人补体第二途径成份B因子SS型的亚型分布及基因频率进行了检测。结果表明,SLB病人BfSS亚基因频率分别为,S_A0.516,S_B0.484;PV为:S_A0.492,S_B0.508,IDDM为:S_A0.676,S_B0.324。与正常人(S_A0.414,S_B0.586)比较,三种疾病的S_A亚基因频率均有不同程度的增高,并伴有S_B亚基因频率的降低。统计结果表明,IDDM与正常人的差异显著(P<0.01),SLE次之(P<0.05),PV不著(P>0.1)。此外,这三种疾病病人BfS_A-S_A亚型的表型频率(分别为30.6%、31.1%和41.1%)都显著高于正常19.3%),统计学表明差异均显著(P<0.05)。     

Lack of Autoimmune Serological Reactions in Rodent Models of Insulin Dependent Diabetes Mellitus

Spontaneous insulitis with insulin-dependent diabetes mellitus (IDDM) in rodent models, the BB rat and NOD mouse, has clarified the pathogenesis of and guided decisions on interventional therapy for human IDDM. However, the occurrence in such models of a standard marker of human IDDM, autoantibodies to β islet cell constituents, has been controversial. Hence we assessed diabetes-prone rodents for the frequencies of raised levels of auto-antibodies to glutamic acid decarboxylase GAD (anti-GAD), insulin and heat shock protein 65 (HSP-65) in relation to levels in non-diabetes-prone animals and levels in human diabetic sera. Assays were performed sequentially at various ages of life. The immunoassays used for anti-GAD and anti-insulin were those validated for sensitivity and specificity for detection of the corresponding autoantibodies in human IDDM sera at international workshops. Positive controls included human IDDM sera with reactivity with GAD or insulin and, for mouse anti-GAD, the highly reactive monoclonal antibody, GAD-6. The results were that levels of autoantibodies in diabetes-prone BB rats or NOD mice to the ‘IDDM-relevant’ autoantigens in our panel did not exceed levels in control rats or mice, and were much lower than levels in humans with IDDM. We conclude that the BB rat and NOD mouse represent a model, but not a facsimile, of human IDDM and that therapeutic successes in such models should be interpreted with caution in relation to interventional therapy for human IDDM.     

Type 1 (insulin-dependent) diabetes mellitus diagnosed during pregnancy: a clinical and prognostic study

Summary The study concerns the clinical outcome and later prognosis (regarding permanent insulin treatment) of patients who develop insulin-dependent diabetes mellitus during pregnancy (which is different from gestational diabetes). Sixty-three such patients (27±1 (SEM) years old) were delivered at the Copenhagen Centre for Diabetes and Pregnancy during the years 1966–1980. Obstetric complications such as toxaemia were seen in 9.5% of these study patients and the perinatal mortality was 6.3%, both percentages being higher than in the general population (1.1%,p<10^–7 and 1.0%,p<10^–3, respectively), but similar to those observed in patients with Type 1 diabetes diagnosed before pregnancy. In contrast, the frequency of malformations was 1.6%, the same as in the general population (1.4%), but lowerthan that seen in patients with long-standing diabetes (8.3%,p<0.05). At follow-up examination 8±1 years after diagnosis all patients were diabetic; 77% were insulin treated, having no or virtually no residual B-cell function, and were clearly Type 1 diabetic patients. After delivery 80% of the patients had a remission period (median 256 days) without insulin treatment. This remission period was absent or shortest in patients with the following characteristics (p0.03): low age, first parity, not overweight, and high blood glucose level at diagnosis. These prognostic parameters should be considered in obligatory, clinical follow-up plans for such patients.     

Erythrocyte sodium-lithium countertransport is not different in Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary We studied erythrocyte sodium-lithium countertransport in 33 patients with Type 1 (insulin-dependent) diabetes mellitus with diabetic nephropathy, 18 patients with Type 1 diabetes without diabetic nephropathy and in 42 nondiabetic patients with various other renal diseases. No significant differences were found in sodium-lithium countertransport between these three groups (median (range) 322 (162–676) vs 321 (189–627) vs 300 (142–655) mol·1 cells^–1·h^–1). We conclude, that sodium-lithium countertransport cannot be used as a marker for diabetic nephropathy.     

Renal functional reserve in insulin dependent diabetic children

Abstract Background: Microalbuminuria has been shown to be predictive for clinical diabetic nephropathy. Renal functional reserve (RFR), as a response to protein loading in a short period of time, is a parameter to assess the ability of kidneys to increase the glomerular filtration rate (GFR). The aim of this study was to predict the early phase of diabetic nephropathy by measuring urinary albumin level and RFR capacity in patients with insulin-dependent diabetes mellitus (IDDM).
Methods: Twenty-two patients with IDDM were studied: 11 with a disease duration of less than 5 years (group 1) and 11 with a disease duration of more than 5 years (group 2). As the control group, 15 healthy children (group 3) were included in the study. At the beginning of the study, glucose was measured and the urinary albumin/creatinine ratio was calculated. Average glycosylated hemoglobin (HbA₁c) over 1 year was determined. After protein loading (red meat containing 2 g/kg of protein), the creatinine clearance was calculated at each hour for a duration of 4 h. The RFR was accepted as the peak percentage increase in GFR over the baseline value.
Results: Although metabolic control in group 2 was better, the RFR in group 2 was significantly lower than in group 1 (P < 0.05). Urinary microalbumin levels between the groups did not differ (P < 0.05). In two patients in whom microalbuminuria was detected, the RFR was much lower.
Conclusions: Detecting lower RFR levels in patients with normal urinary albumin excretion, as well as in patients with microalbuminuria, may support the idea that the RFR capacity is more sensitive than microalbuminuria in assessing the early phase of diabetic nephropathy.     

儿童Ⅰ型糖尿病发病相关危险因素分析

[目的]探讨Ⅰ型糖尿病可能的相关因素.[方法]采用1：2配对原则应用单因素和多因素回归分析对新乡市中心医院儿科住院和门诊患者1999年1月～2004年1月50名患者.100名对照者进行研究.[结果]单因素分析表明窒息、体重过大或过轻、易患感冒、胃肠道感染、腮腺炎、不明原因发热、药物中毒为主要因素.多因素回归分析示窒息,体重过大或过小、感冒、胃肠道感染、呼吸道感染为高危因素.[结论]窒息、体重过大或过轻、发热、感冒、胃肠道感染、药物中毒是高危因素,增强儿童预防保健是关健.     

How to Apply the Experience from the Diabetes Control and Complications Trial to Children and Adolescents?

The Diabetes Control and Complications Trial (DCCT) taught us to set target blood glucose (BG) and glycohaemoglobin (GHb) goals, to ensure safety regarding hypogly-caemia, to be flexible with insulin and meal planning and to offer frequent contact with diabetes educators, dieticians, psychologists and social workers as well as with diabe-tologists skilled in intensified management. Insulin dosage should be individualized based upon frequent BG monitoring results. Co-ordinated multidisciplinary health care teams provide optimum problem-solving rather than disaster control working with children, adolescents and their families. The patient and the family should form the central core of the diabetes team with outpatient follow-up every month and frequent telephone contact between visits. GHb should be obtained at least every 1–2 months to provide feedback as based on the DCCT intensified treatment cohort. Insulin lispro helps minimize hypoglycaemia and makes insulin administration more convenient and timely. Barriers to improvement should be identified: learning problems, concomitant significant illnesses (epilepsy, coeliac and thyroid disease, asthma) and family problems. Ensure age-appropriate transfer of self-care but continue adult supervision. Educate, motivate and re-educate. Meal planning includes not only carbohydrate counting but also maintaining normal lipids and energy needs for growth and development as well as strategies for activity compensation and hypoglycaemia prevention. Consideration of protein restriction may be required in adolescents with microalbuminuria. Individualized multidose insulin algorithms allow reactive (corrective) decisions based upon capillary BG results plus proactive (anticipatory) decisions to compensate for expected BG changes from changes in activity, food and/or illness using a multidose insulin schedule. The number of insulin injections does not define an intensified insulin treatment programme but rather the ability to target and achieve near-normal BG values as often as possible - without severe episodes of hypoglycaemia. Self BG monitoring is a key to success. Long-term monitoring should include not only frequent GHb but also at least annual fasting lipids, thyroid functions and microalbuminuria as well as dilated retinal exams, blood pressure, growth charting and Tanner staging.     

The immunogenicity of insulin preparation. Antibody levels before and after transfer to highly purified porcine insulin

Summary Ninety-two insulin-dependent diabetics (aged 4–20 years, mean±SD: 13±4) with a duration of diabetes from 2 to 17 years (7±3) were transferred from Lente or NPH (5 × crystallised insulin) to Monotard insulin (highly purified insulin). Total serum immunoreactive insulin levels and concentrations of antibodies against insulin, porcine proinsulin, a-component and pancreatic polypeptide were determined prior to [I] and at a mean of 220 [II], 460 [III], 830 [IV], and 1170 [V] days after the change. All but two subjects had insulin antibodies (IgG) at the start, with a mean value of 2864 U/ml. There was a significant fall in the mean insulin antibody level between [I] and [II] to 2165 U/ml (p<10^-7), followed by an increase between [II] and [III] whereafter a slight decrease was observed being significant between [III] and [IV], as well as between [IV] and [V] (p<0.05); some patients showed a constant fall over the entire period, while others showed fluctuations. Total serum insulin showed a similar pattern, with a mean value of 1141 U/ml at [I] declining to 522 U/ml at [V]. The percentage fall between [I] and [V] was greater (54%) than that in the insulin antibodies (30%). Antibodies against acomponent, proinsulin and pancreatic polypeptide were present in 96%, 72% and 41% of the patients respectively before the change in therapy. There was a decline in these antibodies between each sampling (p values between <10^-3 and 10^-8) and, at the end of the investigation antibodies against a-component were above the detection limit in only 4 patients, and none of the patients showed antibodies against proinsulin or pancreatic polypeptide. Thus, removal of the impurities, including the hormonal contaminants of insulin, leads to a slow fall in antibodies to insulin and a much faster disappearance of antibodies against acomponent, proinsulin and pancreatic polypeptide.