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Biomedical subjects

A G Ziegler

Publications and source records attributed to A G Ziegler.

At least 19 recordsLinked to original sources
PubMed1992

Involvement of dendritic cells in early insulitis of BB rats.

In this study, subsets of mononuclear infiltrates in pancreatic islets of BB rats at different stages of insulitis were determined by various monoclonal antibodies against rat lymphoid cells, including a mouse monoclonal IgM antibody that distinguishes between macrophages and dendritic cells (mAb 1F119). 1F119+ dendritic cells were absent in and around islets of Wistar control rats. In BB rats, the first alteration of islets detectable by immunohistochemistry when compared with normal islets was the enhanced expression of 1F119 antigen around and in the islets (17% 1F119+ islets). At disease stage 1 (i.e. no leukocyte infiltration after HE staining), lymphocytes and macrophages were almost absent. At disease stage 2 (leukocyte infiltration < 20 cells), a more intense form of dendritic cell infiltration was seen (stage 1 versus stage 2, P < 0.0001). In addition, ED2+ and ED3+ cells were present around the islets (50% of islets were infiltrated with 1F119+ cells versus 16% with ED2+, 19% with ED3+, 11% with W3/25+ cells, and 11% with OX8+ cells, P < 0.0001). At disease stage 3 (> 20 cells), a clear increase of ED2+ and ED3+ macrophages and of W3/25+ and OX8+ T-lymphocytes in the infiltrates was observed. These observations suggest a role for antigen presenting dendritic cells in the initiation of immune reaction in type 1 diabetes of BB rats.

Animals↗
PubMed1992

Natural course of remission in IDDM during 1st yr after diagnosis.

OBJECTIVE: To describe the natural course of clinical remission in insulin-dependent diabetes mellitus (IDDM) when insulin dose is minimized without loss of target glycemia and to identify factors that predict clinical remission. RESEARCH DESIGN AND METHODS: Ninety-five patients, who were placebo-treated control subjects in the Canadian-European multicenter randomized trial of cyclosporin A in recent-onset IDDM, were studied. RESULTS: The mean insulin dose decreased during the first months after diagnosis, with a nadir at 3 mo, when 27% of the patients did not require insulin to maintain target glycemia. At 1 yr, 10% of patients still did not need insulin. Patients not receiving insulin who had glycosylated hemoglobin within the normal range were called remitters. Mean basal and glucagon-stimulated C-peptide values were significantly (P less than 0.025) higher in remitters than nonremitters at the start of the study. Therefore, all patients were divided into those with values above the mean stimulated C-peptide (0.4 nM) and those with values below the mean at entry. The probability of entering a remission with a stimulated C-peptide greater than 0.4 nM was 10 times as high (P less than 0.05) as for those with a stimulated C-peptide below this level. Surprisingly, the beginning and end of the remission were associated with neither major changes in C-peptide levels nor islet cell antibody and insulin-antibody titer. A more rapid loss of stimulated C-peptide occurred in patients who lacked HLA-DR3 and -DR4 (P less than 0.05 at mo 9). CONCLUSIONS: This study shows a higher spontaneous clinical remission rate than expected during the 1st yr after diagnosis. Preserved beta-cell function at entry predicts a greater chance of entering a remission, and a more rapid loss of beta-cell function was seen in patients without HLA-DR3 and -DR4.

Adult↗
PubMed1991

[Insulin autoantibodies and islet cell antibodies in recently appearing diabetes mellitus type I. Association with age of manifestation and HLA phenotype].

Insulin autoantibody (IAA) and islet cell antibody (ICA) titres were measured in 108 newly diagnosed type I diabetics (49 male, 59 female, mean age 20 [1-38] years) and 103 non-diabetic controls (41 male, 62 female, mean age 23 [16-46] years). IAA titres in the controls were normally distributed, with a mean of 5 +/- 11 nU/ml. The upper limit of normal was established as 49 nU/ml (mean + 4 standard deviations). Raised IAA and ICA titres were present in 45% and 44% of type I diabetics, respectively, with 59% positive for either IAA or ICA or both. IAA were markedly age-dependent, being positive in 70% (26 out of 37) of diabetics under the age of 15 years, and in 32% (23 out of 71) at the age of 15 years or more (P = 0.0004). There was a less marked difference for ICA titres (positive in 62% of patients less than 15 years, and in 35% of those of 15 years of older; P less than 0.01). IAA were significantly more common in HLA DR4 positive patients than in HLA DR4 negative patients (56% vs 11%; Pc less than 0.00015). With regard to age a significant association between IAA and HLA DR phenotype was present only in homozygous (Pc less than 0.03) and heterozygous (P less than 0.0003) patients aged 15 years or older. By contrast, ICA was not significantly correlated with HLA phenotype. These data suggest a genetic predisposition for the development of IAA.

Adolescent↗
PubMed1991

HLA-associated insulin autoantibody formation in newly diagnosed type I diabetic patients.

To assess a possible HLA association with anti-insulin autoantibodies (IAAs) in human insulin-dependent (type I) diabetes, 51 newly diagnosed type I diabetic patients (mean age 22 +/- 8 yr) were typed for HLA-DR and HLA-DQ and studied for IAAs before exogenous insulin therapy with a competitive radioimmunoassay (normal range less than or equal to 49 nU/ml). The level of IAAs in 16 patients exceeded our upper limit of normal, and 18 had high-titer islet cell antibodies (ICAs; greater than or equal to 40 Juvenile Diabetes Foundation U). A striking association with HLA-DR4 (DQw3) in both the prevalence and the level of IAAs was found (IAA positivity in patients with DR4/4 vs. DR4 heterozygous vs. non-DR4: 90 vs. 29%, corrected [c] P less than 0.01, vs. 5%, Pc less than 0.0001; IAA positivity in patients with DR4 vs. non-DR4: 50 vs. 5%, Pc less than 0.005; IAA level in patients with DR4/4 vs. DR4 heterozygous vs. non-DR4: 111 vs. 17 nU/ml, Pc less than 0.01, vs. 20 nU/ml, Pc less than 0.0001; IAA level in patients with DR4 vs. non-DR4: 45 vs. 20 nU/ml, Pc less than 0.01). In contrast, none of the DR3+ subjects had IAAs above normal range, except in conjunction with DR4 (DR3 vs. non-DR3: 12 vs. 42%, Pc less than 0.05). However, there was no significant relationship between DR3 and IAAs after correcting for the number of DR4 alleles. No relationship was seen between age of onset, IAA level, and HLA typing in our population, and no relationship was found between ICA positivity and HLA antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Changes of vitamin D3 serum concentrations at the onset of immune-mediated type 1 (insulin-dependent) diabetes mellitus.

Several hormones such as 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3), alpha-MSH, or ACTH have been found to interact extensively with the immune system. In view of the immune-mediated nature of Type 1 (insulin-dependent) diabetes mellitus, 49 recently diagnosed diabetic patients were investigated in terms of serum 1,25-(OH)2D3-levels, 25-hydroxyvitamin D3(25-(OH)D3), alpha-MSH and ACTH, and compared with 42 healthy controls. A marked decrease of 1,25-(OH)2D3-levels was found at onset of Type 1 (insulin-dependent) diabetes compared to normal controls (39 +/- 2 vs 55 +/- 4 pg/ml, p less than 0.01). Grouping patients according to season (winter or summer) of diabetes onset and blood sampling, it was demonstrated that the decrease of 1,25-(OH)2D3 was primarily present during summer and due to a loss of the seasonal rhythm of this hormone observed in healthy controls (summer: patients vs controls 41 +/- 2 vs 63 +/- 4 pg/ml, p less than 0.001; winter: 37 +/- 3 vs 33 +/- 3 pg/ml, n.s.). Serum concentrations of 25-(OH)D3 were closely correlated with those of 1,25-(OH)2D3, both in controls (r = 0.55, p less than 0.002) and diabetic patients (r = 0.41, p less than 0.05), yielding a similar loss of seasonal variation also of this vitamin D3 metabolite in Type 1 (insulin-dependent) diabetic patients. No difference was found in the mean and median values of alpha-MSH and ACTH between IDDM patients and controls, although patients exhibited much higher variation of alpha-MSH levels than did controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1990

Risk of progression to diabetes of low titer ICA-positive first-degree relatives of type I diabetics in southern Germany.

In a prospective study to evaluate the prevalence and predictive potential of circulating cytoplasmatic islet cell antibodies (ICA) and competitive insulin autoantibodies (CIAA), we screened 406 non-diabetic first-degree relatives of patients with Type I diabetes mellitus (n = 154 for CIAA). The prevalence of ICA was 2.5% (10/406) and of CIAA 0.6% (1/154) in ICA- and 10% (1/10) in ICA+ relatives at initial screening. The titer of ICA positivity in all relatives varied between 1:1 and 1:4. Values of elevated CIAA were 256 nU/ml of the CIAA+/ICA+, and 97 nU/ml of the CIAA+/ICA- relatives (normal range less than or equal to 39 nU/ml). Sera for repeat ICA and CIAA determination was obtained, and 70% of relatives were found to be again ICA+ after 1.5 years, 40% after 3 years, and 10% after 5.7 years. Both CIAA+ relatives were found to be again CIAA+ on follow-up. Intravenous glucose tolerance tests (IVGTT) were performed in all antibody-positive relatives. No decrease in first-phase insulin secretion (1 + 3 min) below the 1st percentile was observed in any of the ICA+ relatives during follow-up. No ICA+, but one CIAA+/ICA- relative had developed Type I diabetes after 5.6 years of follow-up. In summary, these results indicate that low titer ICA (less than 40 JDF units) are often transient and relatives with low titer ICA rarely progress to Type I diabetes. Elevated CIAA appear to be constant over time and associated with increased progression to overt diabetes.

Adolescent↗
PubMed1990

Low-pigment skin type and predisposition for development of type I diabetes.

To ascertain whether skin pigmentation type and sensitivity to ultraviolet (UV) light are associated with susceptibility to type I (insulin-dependent) diabetes, 55 type I diabetic patients were examined, 38 new-onset and 17 long-term cases. They were compared to 72 control subjects of the same geographic region and nationality. To evaluate the individual skin pigmentation type, a standardized questionnaire was developed. Reactivity to UV light was determined by a stepwise-graded UV irradiation. Significantly more diabetic patients in southern Germany had blue eyes than nondiabetic control subjects (55 vs. 26%, P less than 0.01), and significantly more diabetic patients had a low-pigment eye color (blue or green) than control subjects (66 vs. 38%, P less than 0.01). In addition, more fair skin color was noted among diabetic versus control subjects (84 vs. 60%, P less than 0.01). In response to UV irradiation, diabetic patients more often showed an increased UV-light sensitivity than control subjects (83 vs. 23%, P less than 0.001). The relative risk for susceptibility to type I diabetes in subjects with low-pigment eye color was 3.1, in subjects with fair skin type 3.4, and in subjects with increased UV-light sensitivity 5.8. The highest risk for the development of diabetes was seen in subjects who had low-pigment eye color and/or increased UV-light sensitivity (95 vs. 51%, P = 0.00002, odds ratio 17.4). We conclude that a low-pigment skin type may predispose for the development of type I diabetes.

Adult↗
PubMed1990

Predicting type I diabetes.

Currently, there are three markers that are being studied with the potential to give a high positive predictive value for the development of type I diabetes (insulin-dependent diabetes caused by autoimmune beta-cell destruction) and that can be utilized to predict the disease in susceptible relatives: 1) high-titer cytoplasmic islet cell antibodies, 2) insulin autoantibodies detected with fluid-phase radiobinding assays, and 3) first-phase insulin release after intravenous glucose less than 1st percentile. With the combination of these assays, it seems to be possible to identify first-degree relatives with a high probability of developing type I diabetes within a limited time span (i.e., less than 10 yr). The ability to predict type I diabetes with selected assays will allow trials for prevention of diabetes and trials to assess whether prediction will decrease morbidity and mortality at onset of diabetes.

Autoantibodies↗
PubMed1989

Production of insulin antibodies by mice rejecting insulin transfected cells.

Antibodies to insulin appear prior to the development of Type I diabetes and their concentration may correlate with the rate of autoimmune beta cell destruction. In order to study potential mechanisms involved in the production of antibodies to insulin, we transplanted different strains of mice with histoincompatible non-islet cells (AtT20-Ins and NIH-3T3-Ins) synthesizing homologous insulin, in contrast to immunization with non-transfected cells and insulin in Freund's adjuvant. The pituitary cell line (AtT20) and the fibroblast cell line (NIH-3T3) were transfected with the rat insulin-II gene (which encodes an insulin molecule identical to that of mouse insulin-II). No antibodies to insulin were found after subcutaneous injection of AtT20-control cells (without the integrated rat insulin gene) or after injection of rat insulin complete Freund's adjuvant. After subcutaneous injections of living AtT20-Ins or NIH-3T3-Ins cells producing insulin (40 to 60 ng insulin/10(6) cells per injection) in two strains (BALB/cJ, C3H/HeJ) but not in a third (SJL/J), antibodies to insulin rapidly appeared. In addition, when AtT20-Ins cells were transplanted into Wistar-Furth rats, insulin antibodies appeared in three out of four animals. The level of antibodies induced was similar to the concentrations of insulin antibodies of prediabetic NOD mice. This finding suggests that during the immune destruction of a cell synthesizing insulin, humoral 'tolerance' to insulin can be rapidly abrogated. Genetic control of this response is suggested by the difference between response of BALB/cJ and C3H/He vs SJL/J.

Animals↗
PubMed1989

Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes.

Cytoplasmic islet cell antibody-negative (ICA-; less than 20 Juvenile Diabetes Foundation units, n = 1670) and ICA+ (n = 42) first-degree relatives of type I (insulin-dependent) diabetic individuals were studied for competitive insulin autoantibodies (CIAAs) with a radioassay. Overall, 3.7% of first-degree relatives (64 of 1712) were CIAA+. Of ICA- relatives, 2.7% (45 of 1670) exceeded the upper limit of our normal CIAA range (greater than 39 nU/ml), and 45% (19 of 42) of ICA+ relatives exceeded this normal range. Follow-up serums for repeat CIAA determination have been obtained from 16 of the nondiabetic CIAA+/ICA- individuals (time between samples, 0.4-5.8 yr). Fourteen of these 16 (87%) CIAA+/ICA- relatives were found to still be positive on follow-up, and 2 of the relatives who were positive on the first determination were negative on their follow-up test. With a mean follow-up of approximately 2 yr, 4 of 45 (9%) of the CIAA+/ICA- relatives, 5 of 23 (22%) of the ICA+/CIAA- relatives, and 12 of 19 (63%) of the CIAA+/ICA+ relatives developed diabetes. Life-table analysis indicated that, overall, 53% of CIAA+ relatives become diabetic after 5 yr of follow-up versus 65% of ICA+ relatives. Also by life-table analysis, the predicted risk after 5 yr of follow-up for progression to diabetes is 17% for CIAA+/ICA- relatives, 42% for ICA+/CIAA- relatives, and 77% for CIAA+/ICA+ relatives. The highest rate of progression to diabetes was found in ICA+ relatives with CIAA levels greater than 150 nU/ml (100% projected to be diabetic within 5 yr, P less than .008 vs. ICA+/CIAA- relatives).

Autoantibodies↗
PubMed1989

Radioassay determination of insulin autoantibodies in NOD mice. Correlation with increased risk of progression to overt diabetes.

In an initial cross-sectional study, 29 female and 25 male nondiabetic weaned nonobese diabetic (NOD) mice of various ages (age range 30-300 days, mean 108 +/- 10 days) and 11 unweaned NOD pups were evaluated for competitive insulin autoantibodies (CIAAs) with a fluid-phase radioassay. Eleven of 54 (20%) weaned NOD mice had CIAA levels above the range (greater than 39 nU/ml) of 81 control mice. The group of NOD mice that progressed to diabetes had a significantly higher level of CIAAs than NOD mice that did not progress to diabetes (NOD mice progressing to diabetes: CIAA 63 +/- 12 nU/ml; NOD mice not progressing to diabetes: CIAA 8 +/- 4 nU/ml; P less than .02). Seven of 11 (64%) NOD mice having CIAA concentrations exceeding the normal range progressed to diabetes, whereas only 4 of 43 (9%) NOD mice progressed to diabetes without detection of elevated CIAAs (Fisher's exact test, P less than .0005). The relative risk of progressing to overt diabetes with CIAA levels greater than 39 nU/ml was therefore 17 (P less than .005), giving a positive predictive value of 64%, a negative predictive value of 91%, and an overall accuracy of 85%. None of 11 unweaned NOD pups had CIAA levels above the normal range (mean -9.4 +/- 4.9 nU/ml). At 6 wk of age, 37% of female NOD mice were CIAA+, whereas none of the male animals exceeded the normal range at this age (38 +/- 13 vs. 5 +/- 6 nU/ml, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[The effect of the beta 1 selective beta blocker, betaxolol, on metabolism in type II diabetics].

The effects of the highly beta 1-selective beta-blocker betaxolol (Kerlone) on carbohydrate and lipid metabolism in type II diabetic subjects were compared in a cross over study with those of a diuretic (xipamide-triamterene combination, Neotri). Betaxolol significantly lowered blood pressure with a tendency to better efficacy than the diuretic. The betaxolol-induced decrease in heart rate could be a contributing factor in attenuating the progression of atherosclerosis. No significant alterations were observed in postprandial blood glucose, glycosylated haemoglobin and 24-h urinary glucose excretion. The lack of noticeable influence on the carbohydrate metabolism during 4-week therapy is presumably related to the high beta 1-selectivity of betaxolol. Considering that diabetic hypertensive patients are at high risk for atherosclerosis it appears also favourable that betaxolol did not increase triglyceride levels and even decreased total cholesterol. The protective effect of beta-Blockers has been well established in the secondary and primary prevention of cardiovascular diseases. Especially diabetic patients might be expected to benefit from this therapy, if given preferably as beta 1-selective blocker that impairs carbohydrate and lipid metabolism in lesser extent.

Adrenergic beta-Antagonists↗
PubMed1989

Impact of blood pressure on diabetic retinopathy.

Although an elevated blood pressure has been proposed as one of the major risk factors for the development and acceleration of diabetic retinopathy, demonstration of an unequivocal association between high blood pressure and retinopathy is lacking. Recent epidemiologic, cross-sectional studies indicated a close relationship between elevated systolic blood pressure and diabetic retinopathy, particularly in NIDDM subjects. In IDDM patients, the association with diastolic blood pressure was more pronounced. In the few prospective studies with sufficient number of individuals and acceptable documentation of retinal changes, in addition to poor metabolic control elevated blood pressure emerged as one of the best predictors of the development of severe deterioration of diabetic eye disease. In the Joslin study the risk of progression to severe forms of diabetic retinopathy increased exponentially with hemoglobin A1c and was dramatically different in patients with diastolic blood pressure below versus above 70 mmHg. It was hypothesized that a very low diastolic blood pressure is associated with some mechanisms which are protective against progression of eye lesions. Treatment and adequate control of hypertension is strongly recommended in all diabetic patients, the optimal level of blood pressure reduction, however, is yet to be determined.

Blood Pressure↗
PubMed1988

Left ventricular relaxation and filling pattern in diabetic heart muscle disease: an echocardiographic study.

In order to study left ventricular function digitized M-mode-echocardiograms were analyzed. 34 patients with insulin-dependent diabetes mellitus (mean age 37.8 years, mean diabetes history 21.5 years) were compared with 35 healthy individuals (mean age 40.9 years). Only patients with negative exercise-ECG, normal 2-D-echocardiogram and normal systemic arterial blood pressure were enclosed. In diabetics the time-constant Te of free wall endocardial retraction was significantly prolonged (76.8 +/- 21.2 ms versus 64.0 +/- 7.9 ms in normals, p less than 0.005), the dimension change during early diastole (dD DS-ERF) was significantly reduced (54.5 +/- 13.1% versus 69.8 +/- 9% in normals, p less than 0.001) and the dimension change during atrial contraction phase (dD ACP) was significantly enlarged (23.4 +/- 14.4% versus 14.3 +/- 6.4% in normals, p less than 0.001). These data suggest that impaired left ventricular diastolic function can be found in patients with long standing insulin-dependent diabetes mellitus.

Adolescent↗
PubMed1988

Loss of Ia-positive epidermal Langerhans cells at the onset of type 1 (insulin-dependent) diabetes mellitus.

Immunocompetent antigen-presenting Langerhans cells were investigated in skin biopsies of 20 short-term Type 1 (insulin-dependent) diabetic patients and compared with 17 matched normal control subjects. Langerhans cells in epidermal sheet preparations were visualized with a monoclonal anti-HLA DR antibody using indirect immunofluorescence. A significant decrease of Langerhans cells/mm2 body surface area was found in 10 patients immediately at the onset of diabetes compared to 10 patients with 6 months duration of diabetes and to normal control subjects (401 +/- 30 vs 559 +/- 43 vs 611 +/- 33, p less than 0.01 and p less than 0.002). There was no significant difference in the number of Langerhans cells between patients with 6 months duration of diabetes and control subjects. Examination of the most likely precursor of Langerhans cells, the blood monocytes, indicated an increase of monocyte counts in Type 1 diabetic patients after 6 months duration (344 +/- 37 cells/microliters vs 191 +/- 31 in control subjects, p less than 0.05) and an inverse correlation between the number of Langerhans cells in skin with the number of monocytes in peripheral blood (at onset: r = -0.73, p less than 0.01, after 6 months of diabetes: r = -0.61, p less than 0.05). In addition, a positive correlation between Langerhans cells and daily insulin dose was noted in patients after 6 months of diabetes (r = 0.76, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗