Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In some cases patients with Type 2 (non-insulin-dependent) diabetes mellitus fail to respond to treatment with oral hypoglycaemic agents. These patients may respond in the same way as Type 1 (insulin-dependent) diabetic patients. Cellular immune aggression (defined as the capacity of peripheral mononuclear cells to inhibit stimulated insulin secretion by dispersed rat islet cells), insulin autoantibodies, C-peptide response and HLA antigens were determined in 31 Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents and in 22 control subjects. Nine (29.03%) of the 31 Type 2 diabetic patients showed positive cellular immune aggression (2 SD below control group) and 22 (70.97%) presented no cellular immune aggression. There was a relationship between positive cellular immune aggression and each of the following parameters: age, body mass index and microangiopathy. No correlation was found between positive cellular immune aggression and glycaemia, HbA1, blood lipids or atherosclerosis. Patients with positive cellular immune aggression showed a significantly lower glucagon-stimulated C-peptide response vs those with no cellular immune aggression. Within a sub-group of patients who had never been treated with insulin, insulin autoantibodies were present in four of six patients with positive cellular immune aggression. DR2 antigen was found with decreased frequency in patients whereas no DR3/DR4 heterozygotes were observed. Our data support the hypothesis that a group of Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents presented autoimmunity towards pancreatic Beta cells.
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PMID:Cellular and humoural autoimmunity markers in type 2 (non-insulin-dependent) diabetic patients with secondary drug failure. 147 68

With an ultrasensitive noncompetitive enzyme-linked immunosorbent assay (ELISA), we tested the hypothesis that the presence of insulin autoantibodies in nondiabetic individuals is a normal event. Plasma and peripheral blood mononuclear cells were obtained from 50 nondiabetic whites for determination of insulin autoantibodies by ELISA and radioimmunoassay (anti-insulin IgG [AI-IgG] and 125I-labeled insulin bound [%]), islet cell antibodies, anti-nuclear antibodies and rheumatoid factor, and HLA class II-type antigens (DR, DRw, and DQ). The range of 125I-insulin binding was significantly less than was seen in pretreatment sera from individuals with diabetes (from -0.4 to 0.4% vs. -0.8 to 7.7%, respectively, P = 0.001). Eighty-eight percent of these nondiabetic individuals had significant levels of AI-IgG with preferential binding to human insulin. The geometric mean of AI-IgG concentrations in individuals with significant levels was 180 pM. Binding to human insulin was seen in 88%, to pork insulin in 42%, and to beef insulin in 24% of individuals (P less than 0.001 overall; P less than 0.05 where more bound to pork than beef insulin). Binding of AI-IgG to human insulin-coated plates was substantially inhibited by preincubation with human insulin (median inhibition 57.6%) with little if any inhibition by glucagon, C-peptide, albumin, or IgG. Four individuals had highly specific human AI-IgG as shown by immunoaffinity studies. AI-IgGs were significantly higher in individuals with the HLA haplotype DR4,DRw53,DQ3 and lower in individuals with DR5,DRw52,DQ1 (P = 0.03 for both).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presence of insulin autoantibodies as regular feature of nondiabetic repertoire of immunity. 193 23

The HLA haplotype and its relationships with clinical, biological and immunological parameters were analyzed in a group of 87 Spanish type 1 diabetic patients at the clinical onset of the disease. The frequency of HLA-B18, DR3 and DR4 antigens was significantly increased whereas DR2, DR5 and DR7 were decreased in comparison with 189 healthy unrelated controls without family history of diabetes. DR3 showed a maximum relative risk for diabetes (5.5) whereas DR4 had a lower one (4.0). HLA-DR4 patients were younger at the time of diagnosis than DR4 negative (16.7 vs 21.4 years). We found no statistically significant relationship between HLA antigens and the other variables studied including the presence of islet cell antibodies, complement fixing islet cell antibodies, insulin autoantibodies, organ-specific antibodies, fasting and maximal glucagon stimulated C-peptide levels, initial glycemia and glycosylated hemoglobin.
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PMID:HLA antigens in Spanish type 1 diabetic population. Correlations with clinical, biological and autoimmune markers. 207 84

The aim of this study was to determine which candidates were suitable for immunotherapy among adult insulin dependent diabetic patients of recent onset. A statistical analysis was performed using the results of a multicentre randomized trial of cyclosporine versus placebo after nine months of treatment. When the baseline characteristics of the patients in remission were compared with those not in remission, there was no difference observed either in initial residual beta-cell function (glucagon stimulated C-peptide level), or in immunological markers (T4 and T8 lymphocytes counts, Interleukin 2). The parameters showing the most difference were, in addition to treatment group, the duration of diabetes symptoms and body mass index at inclusion, and the HLA-DR phenotype. This was confirmed using a logistic regression analysis, in which these variables were found to be significantly related to remission. The probability of remission in each individual patient was then calculated using these variables in the mathematical function provided by the logistic model. Ninety eight out of 110 patients were correctly classified using this method. In addition, it must be noted that only subjects adequately treated by cyclosporine were still in complete remission after a one year follow-up. Conversely, it appeared that immunosuppression in subjects having a predicted probability of remission lower than 0.35 using the mathematical function, and being non-DR3, non-DR4 has to be avoided. These results will be useful in optimizing the recruitment of patients in on-going or future trials of immunotherapy in early diabetes.
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PMID:Probability of remission in individual in early adult insulin dependent diabetic patients. Results from the Cyclosporine Diabetes French Study Group. 226 35

Islet cell antibodies (ICAs), thyrogastric antibodies, and HLA-DR antigens were determined in 204 patients with type II (non-insulin-dependent) diabetes controlled with diet and/or oral hypoglycemic agents (NIR) and in 108 age-matched patients who required insulin to control their hyperglycemia (IR). beta-Cell function measured as C-peptide response to glucagon was evaluated in relation to the presence of ICAs and HLA-DR antigens. The IR patients differed from the NIR patients with respect to higher frequency of ICAs (P less than .001), thyroid antibodies (P less than .02), and the HLA antigen DR4 (P less than .02). The highest frequency of ICAs and thyroid antibodies was observed in female insulin-treated subjects (51.2 and 46.4%). Patients who were heterozygous for HLA-DR3/DR4 showed significantly higher frequency of ICAs (P less than .01) and complement-fixing ICAs (P less than .001) than patients without the heterozygous form DR3/DR4. Neither the presence of ICA alone nor DR3/DR4 alone was associated with a significant impairment of beta-cell function. However, when both ICA and DR3/DR4 were present in a diabetic individual, beta-cell function was markedly impaired (P less than .001), suggesting that both genetic and autoimmune factors are necessary to facilitate the process leading to beta-cell destruction of the patients. Our findings suggest that type II diabetes is a heterogeneous disorder including at least two major subgroups, which can be further characterized by HLA-DR antigens and organ-specific antibodies.
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PMID:Organ-specific autoimmunity and HLA-DR antigens as markers for beta-cell destruction in patients with type II diabetes. 327 59

Some patients do not fall neatly into the categories of Type 1 (insulin-dependent), Type 2 (non-insulin-dependent) or maturity onset diabetes of young people diabetes. The pedigree and characteristics of the family reported here illustrate this problem. Nine cases of diabetes are known in 4 out of 5 generations, with onset between 17-70 years. Treatment was with insulin in 5 (onset 17-29 years), tablets in 3 (onset 32-70 years), and in one diabetes occurred before the insulin era. Plasma C-peptide was 0.04-0.52 nmol/l (fasting) and 0.35-1.33 nmol/l (peak stimulation with glucagon). HLA typing, available in 7 diabetic patients showed DR2 or DR7 in all, DR4 in 2 and DR3 in none. Pancreatic islet cell antibodies were absent at diagnosis in the most recently diagnosed patient. Diabetic complications remain absent in two insulin-treated patients (duration 28 and 24 years), but have occurred extensively in the remainder. The form of diabetes in this family is therefore characterised by (a) strong family history (possible autosomal dominant with variable penetrance), (b) widely variable age of onset, (c) a variable degree of B cell reserve (d) no association with HLA DR3/4 and the presence of DR2 or DR7 and (e) no protection from complications.
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PMID:Familial diabetes mellitus with variable B cell reserve; analysis of a pedigree. 330 4

In order to study the heterogeneity of Type 2 (noninsulin-dependent) diabetes, we determined HLA antigens and measured B-cell function as C-peptide response to intravenous glucagon in 217 patients with onset of non-ketotic diabetes after the age of 40 years. Their HLA frequencies were compared with those of Type 1 (insulin-dependent) diabetic patients and of healthy blood donors. The Type 1 diabetic patients showed a typical HLA pattern, with increased frequencies of B15, DR3, DR4, B8/B15 and DR3/DR4 and decreased frequencies of B7 and DR2. The Type 2 diabetic patients could be distinguished from blood donors by increased frequencies of Cw4, DR4, DR5 and DR3/DR4, and from Type 1 diabetic patients by increased frequencies of B7, DR2, DR5 and decreased frequency of A9, Bw22 and DR4. Age at onset and body mass index were unrelated to HLA antigens, but the Type 2 diabetic patients with HLA-Cw4, DR5 and DR6 showed a strong family history for Type 2 diabetes. Type 2 diabetic patients with HLA-B8, DR4, B8/B15 and DR3/DR4 showed significantly lower C-peptide concentrations (p less than 0.05) than patients without these HLA antigens. In contrast, patients with DR5 and DRw8 presented with high C-peptide levels. Twelve patients who were positive for both DR3 and DR4 and 23 patients who were DR3/DR4 negative were followed with repeated C-peptide determinations during a period of three years. The C-peptide concentrations of the DR3/DR4 positive patients decreased during this period, whereas there was no change in C-peptide levels in the DR3/DR4 negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship between B-cell function and HLA antigens in patients with type 2 (non-insulin-dependent) diabetes. 354 54

'Secondary failure' of oral hypoglycemics, in non-insulin dependent diabetics, has been attributed to dietary non-compliance, inadequate drug dosage, metabolic stress, or true drug failure. Progressive loss of beta cell function is a suggested mechanism for true drug failure but on the basis of little documented evidence. In view of this, we have measured basal and glucagon-stimulated C-peptide levels, human leukocyte antigen (HLA) types, and islet cell antibodies in 20 non-insulin dependent diabetics with 'secondary failure' of oral agents. There were 16 females and four males with a mean ideal body weight of 1.30 units and mean duration of diabetes of 9.5 years. Fasting insulin (mean +/- SD: 15.1 +/- 10.6 mU/l) and fasting C-peptide (2.3 +/- 1.2 micrograms/l) were normal or slightly elevated in all but one patient. Mean C-peptide increased from 2.3 +/- 1.2 micrograms/l to 3.5 +/- 2.2 micrograms/l (152% over basal) 6 minutes after 1 mg i.v. glucagon. In 15 patients the C-peptide response was greater than 130% of basal. Islet cell cytoplasmic antibodies were detected in only two patients. The distribution of HLA types was not significantly different from a control population, with no increase in DR3 or DR4. Thus, absolute insulin deficiency is uncommon in non-insulin dependent diabetics with 'secondary failure' of oral hypoglycemic agents and such patients do not exhibit the immuno-genetic markers of insulin-dependent diabetes.
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PMID:Insulin secretion and immuno-genetic markers in diabetics with 'secondary failure' of oral hypoglycemic agents. 389 15

The frequency and significance of cytoplasmic pancreatic alpha cell autoantibodies (ACA) were investigated in 2102 healthy controls, 879 patients with insulin-dependent diabetes mellitus (IDDM) who were negative for islet cell autoantibodies (ICA), and 1567 relatives of IDDM patients. ACA were found in approximately 1 in 200 people of all ages and were not significantly associated with IDDM, the IDDM-associated HLA phenotypes DR3 and DR4, or thyrogastric or adrenal autoantibodies. Of 11 ACA-positive patients studied by arginine stimulation tests, none had frank glucagon deficiency. Thus, ACA do not appear to be associated with defective alpha cell function or with IDDM.
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PMID:Pancreatic alpha cell autoantibodies and glucagon response to arginine. 637 51

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.
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PMID:Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status. 940 79


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