Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defective glucose counterregulation commonly seen in intensively treated insulin-dependent diabetes (IDDM) is mediated in part by a failure of compensatory stimulation of hepatic glucose production. Since the response of the liver to insulin-induced hypoglycemia normally involves activation of gluconeogenesis, we measured [14C]alanine conversion to [14C]glucose (a qualitative index of gluconeogenesis) and glucose production (using [3-3H]glucose) in seven intensively treated type I diabetic subjects (hemoglobin-A1, 7.1 +/- 0.4%) during low dose infusion of insulin (0.3 mU/kg.min for 210 min). IDDM patients received insulin overnight to maintain euglycemia before study. Although insulin levels rose to a similar extent as those in normal control subjects (n = 6), the fall in plasma glucose was markedly greater in IDDM (2.5 +/- 0.2 vs. 3.64 +/- 0.2 mM in controls; P < 0.01). The glucagon response was totally lost in IDDM, and epinephrine release was delayed and slightly reduced compared to that in control subjects. In contrast to that in normal subjects, hepatic glucose production in the IDDM subjects remained persistently suppressed by about 60% throughout the study. The conversion of alanine and lactate to glucose remained virtually unchanged in the IDDM, whereas in controls it increased 2-fold above baseline during the last hour of the study. Our data suggest that the failure of gluconeogenesis to increase during hypoglycemia is an important factor contributing to the defective hepatic response observed in the intensively treated type I diabetic subjects.
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PMID:Impaired stimulation of gluconeogenesis during prolonged hypoglycemia in intensively treated insulin-dependent diabetic subjects. 140 Aug 74

Genetic susceptibility alleles have been identified at the DQ HLA region. The aim of the present study was to confirm the value of these markers, and to evaluate the respective weight in the risk of the different alleles at the DQA1 and DQB1 levels, identified by restriction mapping after polymerase chain reaction on exon 2. A significant enrichment in DQB1 alleles encoding for an aminoacid different from Aspartic acid at position 57 (NA) was observed in diabetic (n = 213) in comparison to control (n = 93) children (94% vs 52%; p < 10(-8)). Not all the given NA/NA allelic combinations were equally and positively associated to the disease. Homozygous "Ala/Ala" combinations carried the highest relative risk (OR = 12.3; p < 10(-8)), and among them, the *0201/*0302 genotype was more positively associated to type 1 diabetes (OR = 66; p < 10(-8)). A significant enrichment in DQA1 alleles encoding for Arginine at position 52 in diabetic children was also observed (82% vs 40%; p < 10(-8)). The *0301/*0501 (Arg/Arg) genotype was significantly associated to Type 1 diabetes (OR = 16.2; p < 10(-4)). The highest risk was carried by the whole genotype, a result which could be expected from the known linkage desequilibrium between HLA-DQA1 and DQB1, DRB1 loci. The frequency of Ala DQB1 alleles was low in the background non-at-risk population, although the incidence of the disease is low in our country.
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PMID:[Respective weight of genotypes DQA1 and DQB1 associated with insulin-dependent diabetes in French children]. 145 18

Patients with type 1 diabetes are usually given insulin subcutaneously, but this does not mimic the physiological route of pancreatic insulin release, which may be better achieved with intraperitoneal insulin. Five C-peptide negative type 1 diabetic patients were studied on two occasions, once with intravenous (IV) and once with intraperitoneal (IP) insulin. Normoglycaemia was maintained from 1700 h with variable insulin infusion, and glucose turnover and recycling assessed from 0600 to 0800 h. A 4-h hyperinsulinaemic (25 mU kg-1 h-1) euglycaemic clamp was then performed, with IP or IV insulin delivery. During the night similar insulin infusion rates were needed to achieve equal blood glucose concentrations. Glucose turnover was identical (IV: 2.4 +/- 0.2 vs IP: 2.3 +/- 0.1 mg kg-1 min-1) (+/- SE) with glucose/carbon recycling 8.8 +/- 4.7 and 12.8 +/- 2.9% (NS). Blood lactate, pyruvate and alanine concentrations were significantly higher with IP than IV insulin (P less than 0.05). During the clamp, insulin concentration was 28 +/- 3 mU/l with IV insulin and 15 +/- 1 mU/l with IP insulin (P less than 0.05) and glucose requirement 2.0 +/- 0.5 and 0.8 +/- 0.3 mg kg-1 min-1, respectively (P less than 0.05). Glucose carbon recycling was higher with IP insulin (P less than 0.05). We conclude that: (1) in type 1 (insulin-dependent) diabetic patients hepatic glucose production could be normalized with both routes of insulin administration, and (2) at the same insulin infusion rate, the relative peripheral hypoinsulinaemia with IP route is sufficient to increase the rate of release of gluconeogenic precursors, or decrease their hepatic uptake.
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PMID:The effect of intraperitoneal insulin delivery on carbohydrate metabolism in type 1 (insulin-dependent) diabetic patients. 157 23

1. In no ethnic group is the overall association between systemic sclerosis and the MHC strong enough for direct clinical use. MHC associations do support the classification of the disease into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis. 2. Indications are that associations between specific subsets of patients with systemic sclerosis and genetic markers will assume greater importance both diagnostically and prognostically. The group with lung fibrosis look prime candidates, for example. 3. Genetic markers are useful means of relating chemically induced systemic sclerosis like disorders with the classical disease. Vinyl chloride disease provides an example. 4. Evidence is emerging of strong associations between certain genetic markers and autoantibody production; a similar story has emerged in systemic lupus erythematosus. We believe that, eventually, genetic tests will be used to influence treatment in at least a subset of patients with systemic sclerosis but that a dramatic breakthrough will not be made until we know how the genetics of the disease relate to the primary biochemical disease characteristic--that is, the overproduction of collagen. In this respect it has been suggested that the 5' flanking DNA of dermal collagen genes is particularly susceptible to the action of Scl-70 (topoisomerase I). A problem is how to tie this and the other observations discussed above together. The association of autoantibodies with topoisomerase I provides a tentative link between the MHC and collagen gene expression. Although the role and reason for anti-Scl-70 in systemic sclerosis is unknown, humoral autoimmunity, at least in systemic lupus erythematosus, seems to be strongly dependent on specific HLA genes. With an understanding of the function of MHC products at the molecular level, HLA and disease associations can now be analysed on a mechanistic level. For insulin dependent diabetes mellitus it has been shown that the MHC determined susceptibility to the disease is conferred by neutral residues (Val, Ser, Ala), at position 57 of the DQ beta chain, while Asp at this position correlates with resistance. A similar phenomenon has been described in rheumatoid arthritis. Although DR4 in general is associated with rheumatoid arthritis, it is heterogeneous, but a subtype of DR4 which is characterised by positively charged residues at positions 70 and 71 of the beta chains is not found in patients with rheumatoid arthritis (Wordsworth B P et al, unpublished data). A similar approach applied to the study of systemic sclerosis is likely to be similarly rewarding. The precise subtyping of the class II genes and the characterisation of their associated haplotypes is therefore required for a complete understanding of the contribution of the MHC to the disease. Additional genes linked to the MHC must not be overlooked, and are relevant to associations of haplotypes with the disease. Of particular interest are the recent reports of a new class of proteins, which are determined by genes in the MHC and which are considered to play a part in the assembly of the antigen peptide/MHC molecule complex.
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PMID:Major histocompatibility complex class II genes and systemic sclerosis. 175 Jul 98

Renal metabolism of amino acids (AAs) was evaluated in 5 patients with early IDDM, and in 7 controls (C) in the basal state for 80 minutes after the ingestion of an AA mixture simulating an animal protein meal. Insulin was withdrawn 20 hours before the study. Renal metabolism of AAs was evaluated by the arterial-venous difference technique. In the basal state in IDDM, as in C, the kidney takes up large amounts of a few nonessential AAs (NEAAs): it releases many NEAAs and a few essential AAs (EAAs). After AA ingestion in C, renal extraction of most EAAs, mainly BCAAs, Lys, and Thr, occurs; Pro extraction also increases and a significant uptake of Gly, Glu, Asp, Orn, and Tyr takes place. EAA extraction accounts for 30-40% of total AA uptake. In IDDM, after AA ingestion, a) renal uptake of total AAs is significantly lower, owing mainly to a markedly lower uptake of BCAAs, Lys, and also of Pro, Orn, and Ala; b) renal EAA uptake accounts for less than 20% of total AA extraction. These results indicate that in IDDM postprandial renal N repletion is impaired and unbalanced.
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PMID:Renal metabolism of amino acids in early insulin-dependent diabetes mellitus. 177 10

We have previously reported a decrease in gluconeogenesis from alanine in normal pregnant women at term gestation as compared with nonpregnant women. In the present study, the effect of diabetes on alanine metabolism was examined in five gestationally diabetic (GDM) women and seven women with type I (insulin-dependent) diabetes (IDDM) during the third trimester of pregnancy. The hemoglobin A1c (HbA1c) concentrations in all subjects were within normal range, indicating good metabolic control. After an overnight fast, each subject was infused simultaneously with L-[2,3, 13C2]alanine and D-[6,6,2H2]glucose tracers as prime constant rate infusion. Plasma alanine and glucose isotopic enrichments were measured by gas chromatography-mass spectrometry. Alanine and glucose turnover rates were quantified by tracer dilution. In five subjects, the contribution of alanine carbon to CO2 was quantified by respiratory calorimetry and by measurement of 13C enrichment of expired CO2. Data from 15 previously reported normal pregnant subjects were used for comparison. The rate of alanine turnover was similar in the GDM and IDDM subjects and was not different from the normal subjects (GDM, 4.6 +/- 1.9; IDDM, 5.4 +/- 2.5; normals, 4.4 +/- 0.8 mumol/kg.min, mean +/- SD). The rate of glucose turnover was significantly reduced (P less than .05) in IDDM as compared with GDM and normal subjects (IDDM, 8.1 +/- 0.8; GDM, 11.5 +/- 3.5; normals, 12.2 +/- 2.2 mumol/kg.min). The contribution of alanine C to glucose C and expired CO2 was similar in the three groups. These data demonstrate that rigorous metabolic control results in normal glucose and alanine metabolism in diabetic pregnancy during fasting.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose-alanine relationship in diabetes in human pregnancy. 190 12

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is closely associated with the HLA-DQ gene, especially the residue 57 of the DQ beta chain. Aspartic acid at this position provides protection against IDDM, and substitution of this residue by alanine, valine or serine increases susceptibility to IDDM. To determine whether this is a common feature of IDDM in different ethnic groups, we studied DQB1 DNA in Japanese patients with IDDM by polymerase chain reaction and non-radioactive restriction site analysis. In contrast to Caucasian patients with IDDM, most Japanese patients with IDDM possessed at least one aspartic acid at position 57 of DQ beta. This finding strongly suggests that aspartic acid at position 57 of DQ beta does not protect the Japanese from IDDM.
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PMID:Aspartic acid at position 57 of the HLA-DQ beta chain is not protective against insulin-dependent diabetes mellitus in Japanese people. 197 Nov 72

The DQw3.2 specificity has previously been recognized using genomic RFLP analysis and certain combinations of monoclonal antibodies. Here we report three CD4+ T lymphocyte clones (TLCs) generated from a DR3,4; DQw2,w3.1 responder stimulated with cells from a DR3,4; DQw2,w3.2 donor, and using a modified cloning procedure involving enrichment of IL-2 receptor-positive T cell during priming. The resulting TLCs were strongly inhibited by some monoclonal anti-DQ, but not anti-DR or -DP antibodies. In panel studies using HLA homozygous stimulating cells, it was found that the TLCs recognize an HLA epitope encoded by a DQ gene carried only by DR4,DQw3.2 haplotypes. By comparison with published DQ chain amino acid sequences of some stimulating cells able or not to induce a response in these clones, evidence was obtained that Ala at position 57 on the DQ beta chain is most probably involved in the epitope. The epitope is present on cells from 12 out of 12 DR4,DQw3 insulin dependent diabetes mellitus (IDDM) patients, but on cells only from 6 out of 12 healthy DR4,DQw3 controls. Thus, a DQ-encoded epitope involving residue 57 on the DQ beta chain, and which is strongly associated to IDDM, may be recognized by T cells.
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PMID:T lymphocyte clones recognizing an HLA-DQw3.2-associated epitope involving residue 57 on the DQ beta chain. 245 88

The effects of insulin in vitro on perfused liver from streptozotocin-diabetic rats and their untreated littermates during gluconeogenesis from either [3-13C]alanine + ethanol or [2-13C]pyruvate + NH4Cl + ethanol were studied by 13C NMR. A 13C NMR determination of the rate of pyruvate kinase flux under steady-state conditions of active gluconeogenesis was developed; this assay includes a check on the reuse of recycled pyruvate. The preparations studied provided gradations of pyruvate kinase flux within the confines of the assay's requirement of active gluconeogenesis. By this determination, the rate of pyruvate kinase flux was 0.74 +/- 0.04 of the gluconeogenic rate in liver from 24-h-fasted controls; in liver from 12-h-fasted controls, relative pyruvate kinase flux increased to 1.0 +/- 0.2. In diabetic liver, this flux was undetectable by our NMR method. Insulin's hepatic influence in vitro was greatest in the streptozotocin model of type 1 diabetes: upon treatment of diabetic liver with 7 nM insulin in vitro, a partial reversal of many of the differences noted between diabetic and control liver was demonstrated by 13C NMR. A major effect of insulin in vitro upon diabetic liver was the induction of a large increase in the rate of pyruvate kinase flux, bringing relative and absolute fluxes up to the levels measured in 24-h-fasted controls. By way of comparison, the effects of ischemia on diabetic liver were studied by 13C NMR to test whether changes in allosteric effectors under these conditions could also increase pyruvate kinase flux. A large increase in this activity was demonstrated in ischemic diabetic liver.
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PMID:Effects of insulin on perfused liver from streptozotocin-diabetic and untreated rats: 13C NMR assay of pyruvate kinase flux. 303 Apr 12

Metabolic effects of muscular exercise were studied in eleven subjects with type I diabetes mellitus during poor metabolic control, and again during good metabolic control, and in ten healthy control subjects. All the subjects were submitted to a submaximal gradual triangular test on an electrically braked bicycle ergometer; glucose, FFA, alanine and lactate were measured at rest, and after exercise. In poorly controlled patients, glucose and FFA were unchanged after exercise, whereas blood alanine and lactate increased by a percentage similar to that of the controls, and well-controlled diabetic patients. Baseline alanine concentrations were lower and lactate concentrations higher than in the controls and well-controlled patients. After adequate metabolic control was achieved, in the well-controlled diabetic patients a normalization of pre-exercise alanine and lactate levels and a decrease in blood glucose and FFA after exercise was observed.
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PMID:The effects of muscular exercise on glucose, free fatty acids, alanine and lactate in type I diabetic subjects in relation to metabolic control. 322 91


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