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)

This single-centre study investigated parameters that positively correlated with the success rate after islet allotransplantation in insulin-dependent diabetic (IDDM) patients. Twenty-one intrahepatic, fresh islet transplantations were performed in 20 IDDM patients (one patient had two transplants), after or simultaneous with kidney transplantation. The correlation between number and purity of transplanted islets and final outcome was investigated. One patient died of a cardiac arrest several hours after islet transplantation; this patient was not included in the follow-up analysis. Three patients (15%) experienced acute, irreversible, early failure of islet function, which was considered as a 'presumed rejection'. Nine patients (45%) achieved either complete insulin-independence (seven cases) or a reduction (> 50%) of exogenous insulin requirement (two cases), with sustained serum C-peptide secretion (0.89 +/- 0.04 nmol/l; duration: 21 +/- 7 months, range 2-58 months). Liver biopsy, performed 3 years after transplantation in one successful case, showed normal islets within the hepatic parenchyma. Eight cases (40%) did not show any metabolic effect of islet transplantation, with low serum C-peptide levels ('presumed function exhaustion'). Metabolic investigations performed in successful cases showed an early phase of insulin release after arginine, mild and reversible postprandial hyperglycaemia and normal HbA1c levels. Success of islet transplantation positively correlates with the number (p < 0.05) of the transplanted islets. Islet transplantation is a safe procedure, with 45% success rate, in terms of insulin-independence or relevant reductions of exogenous insulin requirement, although success can be transient.
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PMID:Islet transplantation in IDDM patients. 904 85

Endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disorders such as diabetic retinopathy. We hypothesized that either local endogenous nitric oxide (NO) synthesis or local reactivity to endogenous NO might be impaired in patients with IDDM and that this may contribute to the development of diabetic retinopathy. Ten otherwise healthy patients with long-standing IDDM and ten healthy control subjects were studied according to an open randomized two-way cross-over design. Subjects received intravenous infusions of either N(G)-monomethyl-L-arginine, an inhibitor of NO-synthase, or L-arginine, the precursor of NO synthesis, on two separate study days. Ocular hemodynamics were assessed by laser interferometric measurement of fundus pulsations and Doppler sonographic measurement of blood flow velocity in the ophthalmic artery. N(G)-monomethyl-L-arginine decreased fundus pulsations and blood flow velocity in the ophthalmic artery and increased blood pressure in healthy subjects. The responses to NO-synthase inhibition were significantly less in diabetic subjects. In contrast, L-arginine caused a comparable increase in fundus pulsations and decrease in blood pressure in both cohorts. These results indicate that systemic and ocular hemodynamic reactivity to NO-synthase inhibition is reduced in patients with long-standing IDDM, compared with healthy control subjects. Thus, this study indicates that either NO-synthase activity is increased or NO sensitivity is decreased in patients with IDDM and supports the concept of an involvement of the L-arginine-NO system in the pathophysiology of diabetic retinopathy.
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PMID:Nitric oxide and ocular blood flow in patients with IDDM. 907 7

HLA-DRB1, DQA1 and DQB1 alleles have been determined in 42 families with one IDDM proband and 64 healthy controls, by oligotyping (PCR-SSO) using primers and probes from the XI International Histocompatibility Workshop. A positive DRB1*03 and DRB1*04 association with the disease was observed, whereas DRB1*11 and DRB1*07 showed negative association but 19% of patients carried DRB1 alleles different to DRB1*03 or *04. When single alleles were considered, DQA1*03 showed the strongest association with susceptibility to the disease (RR = 8.2, Pc = 0.00001) but this association was outgrown by 2 and 3 allele combinations, with genotype DRB1*04-DQA1*03-DQB1*0302/DRB1*03- DQA1*0501- DQB1*0201 showing the strongest association (RR = 28, Pc = 0.002). Application of the relative predispositional effect (RPE) method to our data, revealed a further susceptibility risk provided by the DRB1*13-DQA1*0102-DQB1*0604 haplotype once DR3 and DR4 haplotypes were removed. When DQA1-DQB1 genotypes were analysed for presence of Arg 52 (DQ alpha) and absence of Asp 57 (DQ beta), genotypes SS/SS were found significantly increased in diabetics. Interestingly, one of the strongest associations with the disease was observed with the DQA1*03-DQB1*0201 combination encoded mainly by genes in trans (RR = 11.7 Pc = 0.00004). These observations and their comparison with DR-DQ haplotypes in more homogeneous ethnic groups support the stronger influence of the DQ molecule rather than the individual DR or DQ alleles in the susceptibility to IDDM. They also emphasize the need for detailed HLA haplotype studies in non-Caucasian and ethnically mixed populations to gain further insight into the nature of genetic and environmental factors contribution to autoimmunity.
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PMID:HLA-DQA1 and DQB1 allele and genotype contribution to IDDM susceptibility in an ethnically mixed population. 909 50

This article focuses on recent developments that have defined the autoimmune nature of this entity and its genetic basis, especially the crucial roles of aspartic acid at position 57 of the DQ beta chain and arginine at position 52 of the DQ alpha chain of the HLA complex on chromosome 6 in conferring susceptibility; other genetic markers on other genes are mentioned. These genetic markers help to explain the worldwide differences in prevalence and incidence of type 1 diabetes. Because the autoimmune process may be gradual, markers of beta pancreatic cell damage, such as islet cell antibodies, glutamic acid decarboxylase antibodies, and insulin autoantibodies, coupled with evidence of progressive failure of insulin secretion may be used to predict the future onset of disease. In turn, accurate prediction may permit preventive intervention. Two intervention trials are mentioned: (1) Diabetes Prevention Trial for Type 1, a multicenter trial in the United States using insulin; and (2) European Nicotinamide Diabetes Intervention Trial in Europe using nicotinamide as the preventive or delaying agent. These first steps reflect the remarkable progress and understanding of this major problem of childhood and the hopes for its future prevention.
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PMID:Aspects of the etiology, prediction, and prevention of insulin-dependent diabetes mellitus in childhood. 913 Sep 20

One form of maturity-onset diabetes of the young, MODY3, is characterized by a severe insulin secretory defect, compared with MODY2, a glucokinase-deficient diabetes. It has recently been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1 alpha cause MODY3. Because of the rapid progress to overt diabetes and the high prevalence of required insulin treatment in patients with MODY3, we screened the HNF-1 alpha gene for mutations in Japanese subjects with IDDM. Ten exons and flanking introns of the HNF-1 alpha gene in these subjects were amplified by polymerase chain reaction and direct sequencing of the products. Mutations were identified in three (5.5%) of the 55 unrelated subjects with IDDM. A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1 alpha was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age. A frameshift mutation of P291 fsinsC (insertion of a C in a polyC tract around codon 291 for Pro), which would generate a mutant truncated protein of 340 amino acids, was found in a subject who started insulin treatment when hyperglycemia and ketonuria were noticed at 13 years of age. A missense mutation of R583G (replacement of Arg by Gly in codon 583) in the transactivation domain of HNF-1 alpha was found in a subject with sudden-onset IDDM at 20 years of age. None of these mutations were present in 100 nondiabetic subjects (200 normal chromosomes). These results indicate that the HNF-1 alpha gene defects could lead to the development of not only early-onset NIDDM but also IDDM, implicating the importance of subclassification of HNF-1 alpha-deficient IDDM from a classical type of autoimmune-based IDDM in Japanese.
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PMID:Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM. 931 63

IDDM patients treated with conventional subcutaneous insulin have an abnormal increase in cholesteryl ester transfer (CET), the proatherogenic step in reverse-cholesterol transport that results in the enrichment of the apolipoprotein (apo) B-containing lipoproteins (VLDL, LDL) with cholesteryl ester (CE). This disturbance is closely linked to iatrogenic hyperinsulinemia and the nonphysiologic stimulation of lipoprotein lipase (LpL), a physiologic activator of CET, because lowering systemic insulin levels by administering insulin through the intraperitoneal insulin route normalizes LpL and CET. Hyperinsulinemia persists in IDDM patients who undergo successful pancreas-kidney transplantation (PKT) when their allografts are placed in the pelvis and drain into the iliac vein. Therefore, to determine whether hyperinsulinemia promotes CET in this setting, we studied CET, LpL, and insulin levels in 14 euglycemic normolipidemic IDDM PKT patients with near-normal kidney function (creatinine 1.5 +/- 0.4 mg/dl). Consistent with our prediction, the net mass of CE transferred from HDL to VLDL + LDL was significantly increased in the PKT group (P < 0.001) compared with nondiabetic renal transplant patients receiving the same immunosuppressive drugs and healthy control subjects. Both basal and arginine-stimulated insulin levels were increased above the kidney transplant group's levels and correlated with the mass of CE transferred at 2 h (r = 0.71, P < 0.05; r = 0.66, P < 0.05, respectively). Total basal LpL activities, LpL and hepatic triacylglycerol lipase activities, and LpL mass all tended to be higher than levels in healthy control subjects. Consistent with these changes in lipase activity, VLDL particle size was significantly reduced (P < 0.025) compared with that of control subjects. These findings indicate that PKT patients with systemically draining allografts have a persisting profile of potentially atherogenic disturbances in insulin levels, LpL, and CET that resemble IDDM patients treated with conventional subcutaneous insulin injections.
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PMID:Alterations in cholesteryl ester transfer, lipoprotein lipase, and lipoprotein composition after combined pancreas-kidney transplantation. 942 83

The WHO DiaMond Molecular IDDM Epidemiology Sub-Project is testing the hypothesis that population variation in the frequency of high-risk HLA-DQ alleles is a primary determinant of the global patterns of IDDM incidence. Data are currently available for 16 populations, and reveal significant variations in the frequencies of HLA-DQA1 and DQB1 alleles among the case and the control groups. However, DQA1 x Arg-(52) and DQB1 x non-Asp-57 (ND) were consistent and independent markers of IDDM susceptibility in all populations, except Japan. Individuals who carried only DQA1 x R and DQB1 x ND alleles had an IDDM risk similar to that observed for first degree relatives of affected individuals (3%-5%). Such information is essential for the development of clinical strategies or disease prevention approaches for the general population or individuals at high-risk. Thus, the DiaMond Molecular Epidemiology Sub-Project provides an excellent model that can be followed to assess the impact of new genetic discoveries on medicine and public health practice for diabetes and other chronic diseases.
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PMID:Molecular epidemiology of insulin-dependent diabetes mellitus: WHO DiaMond Project. WHO DiaMond Molecular Epidemiology Sub-Project Group. 950 18

Serum paraoxonase is a glycoprotein which binds to high-density lipoproteins (HDL) and may prevent oxidation of LDL by hydrolyzing lipid peroxides. Two polymorphisms identified in the paraoxonase gene (Met-Leu 54 and Gln-Arg 192) have been associated with cardiovascular disease. Oxidative low-density lipoprotein (LDL) is also toxic to retinal capillary endothelial cells and pericytes, so that mildly modified LDL may contribute to the development of diabetic retinopathy. To investigate the potential significance of these polymorphisms in the pathogenesis of diabetic retinopathy in IDDM, 80 patients with diabetic retinopathy and 119 controls without diabetic retinopathy were investigated in the current project. The allelic frequency of leucine 54 (L) was significantly higher in the group with retinopathy than without retinopathy (73% vs. 57%, p < 0.001). The genotype L/L was strongly associated with the development of diabetic retinopathy (p < 0.001), but a similar association was not found with Gln-Arg 192. Leucine 54 is a risk factor for diabetic retinopathy.
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PMID:A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. 966 50

Susceptibility and resistance to type 1 diabetes are associated with MHC class II alleles that carry non-Asp and Asp at residue 57 of their beta chain respectively. The effect of Asp or non-Aspbeta57 may relate to a differential ability of distinct class II molecules to bind specific immuno-pathogenic peptides. Recent studies in man and mouse have revealed that some type 1 diabetes-predisposing non-Aspbeta57 class II molecules (i.e. DQ8, DR4Dw15 and I-Ag7) preferentially bind peptides with a negatively charged anchor residue at P9. It has been suggested that this is a common feature of type 1 diabetes-predisposing class II molecules. The molecular explanation for such a phenomenon could be that class II beta chains with Aspbeta57 form a salt bridge between Aspbeta57 and a conserved Arg of the a chain, whereas in non-Aspbeta57 molecules the Arg is unopposed and free to interact with negatively charged P9 peptide anchor residues. We have investigated the specificity of the P9 pocket of the type 1 diabetes-associated DQ2 molecule and in particular examined for charge effects at this anchor position. Different approaches were undertaken. We analyzed binding of a high-affinity binding ligand and P9-substituted variants of this peptide, and we analyzed the binding of a set of synthetic random peptide libraries. The binding analyses were performed with wild-type DQ2 and a mutated DQ2 with Ala at beta57 substituted with Asp. Our results indicate that the wild-type DQ2 (non-Aspbeta57) prefers large hydrophobic residues at P9 and that there is no particular preference for binding peptides with negatively charged residues at this position. The specificity of the P9 pocket in the mutated DQ molecule is altered, indicating that the beta57 residue contributes to determining the specificity of the P9 pocket. Our data do not lend support to the hypothesis that all non-Asp beta57 class II molecules predispose to development of disease by binding peptides with negatively charged P9 anchor residues.
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PMID:The P9 pocket of HLA-DQ2 (non-Aspbeta57) has no particular preference for negatively charged anchor residues found in other type 1 diabetes-predisposing non-Aspbeta57 MHC class II molecules. 972 10

IDDM patients undergoing islet, segmental pancreas or whole pancreas allotransplantation were studied at regular intervals after surgery (3-6 months, 1, 2, 3 and 4 years) to evaluate glycometabolic control (24 h metabolic profile, OGTT) and serum free insulin response to insulinogenic stimuli (arginine, IVGTT). Patients received the same immunosuppressive therapy, based on cyclosporin, steroids and azathioprine. Islet transplanted patients showed: 1) an early peak of insulin secretion after arginine, that was maintained up to 4 years; 2) an early, but low peak of insulin secretion after IVGTT, which was lost at 3 years, despite evidence that islets were still functioning (insulin independence with normal HbAlc levels); 3) a diabetic-like response to OGTT at 3 months, which improved at 2 years (IGT response); 4) fasting euglycemia with mild and reversible post-prandial hyperglycemia during the 24 h metabolic profile, which was maintained for up to 2 years. Insulin secretory patterns of islet transplanted patients were similar to segmental pancreas transplanted patients, and lower than whole pancreas transplanted patients. The reduced beta cell mass transplanted and the functional denervation of the transplanted islets seem to be the major determinants of this behaviour.
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PMID:Insulin secretory patterns and blood glucose homeostasis after islet allotransplantation in IDDM patients: comparison with segmental- or whole-pancreas transplanted patients through a long term longitudinal study. 993 Sep 48


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