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)

Insulin resistance characterizes type 1 diabetes in patients with albuminuria. A PC-1 glycoprotein amino acid variant, K121Q, is associated with insulin resistance. We examined the impact of the PC-1 K121Q variant on the rate of decline of the glomerular filtration rate (GFR) by creatinine clearance derived from the Cockroft-Gault formula in 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years (range 2.5-15). Patients carrying the Q allele (n = 22; 20 with KQ and 2 with QQ genotypes) had a faster GFR decline than those patients with the KK genotype (n = 55) (median 7.2 vs. 3.7 ml x min(-1) x year(-1); range 0.16 to 16.6 vs. -3.8 to 16.0 ml x min(-1) x year(-1); P < 0.001). Significantly more patients carrying the Q allele belonged to the highest tertile of GFR decline (odds ratio = 5.7, 95% CI 4.1-7.2, P = 0.02). Levels of blood pressure, HbA1c, and albuminuria were comparable in the two genotype groups. Albuminuria (P = 0.001), mean blood pressure (P = 0.046), and PC-1 genotype (P = 0.036) independently correlated with GFR decline. Because all patients were receiving antihypertensive treatment, the faster GFR decline in the patients carrying the Q allele could be the result of reduced sensitivity to the renoprotective effect of antihypertensive therapy. PC-1 genotyping identifies type 1 diabetic patients with a faster progression of diabetic nephropathy.
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PMID:A PC-1 amino acid variant (K121Q) is associated with faster progression of renal disease in patients with type 1 diabetes and albuminuria. 1086 79

The role of TNF-alpha in type 1 diabetes pathogenesis is controversial. Using double transgenic mice expressing (i) the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) as an islet self-antigen and (ii) TNF-alpha under control of a tetracycline-regulated promotor system (tTA) in the pancreatic beta cells, we could previously demonstrate a differential effect of TNF-alpha on the incidence of type 1 diabetes. Most interestingly, late expression of TNF-alpha resulted in a reversion of mice that were already diabetic to a nondiabetic state. Here we provide a model of how experienced autoaggressive CD8 lymphocytes are dying by apoptosis as a result of beta cell-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.
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PMID:Apoptosis of autoreactive CD8 lymphocytes as a potential mechanism for the abrogation of type 1 diabetes by islet-specific TNF-alpha expression at a time when the autoimmune process is already ongoing. 1202 Oct 99

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
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PMID:Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. 1256 31

The purpose of the case study was to define a degree of destructive changes in the connective tissue at different stages of diabetic nephropathy (DN) progression. One hundred and twenty eight DN patients with type 1 diabetes mellitus, disease duration-5 to 20 years (classification according C. Mogensen, 1983) were examined. Special biochemical tools were used to evaluate the connective-tissue condition. The parameters of metabolism of the connective-tissue biopolymers were investigated in blood, urea and saliva, i.e. general and sulphated glucosamine glycine (GAG), sialic acid (SA) and oxyproline fractions. The results showed an increasing value of total and sulphated GAG and SA with a worsening DN severity, which is indicative of a destruction degree of glycoprotein-complexes in the microvascular basal membranes. A high level of bound oxyproline fractions denotes the fibril-genesis processes, which start to activate yet at the preclinical DN stage. The changes detected previously in the parameters of metabolism of the connective-tissue biopolymers, as observed in DN patients, ensure a timely choice of a therapy and a proper monitoring of its efficiency.
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PMID:[Clinical significance of assessment of the metabolism of connective-tissue biopolymers in patients with type 1 diabetes mellitus and with diabetic nephropathy]. 1466 78

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease associated with the presence of different types of autoantibodies. The presence of these antibodies and the corresponding antigens in the circulation leads to the formation of circulating immune complexes (CIC). CIC are known to persist in the blood for long periods of time. Such CIC following deposition in the small blood vessels have the potential to lead to microangiopathy with debilitating clinical consequences. The aim of our pilot study was to investigate whether a correlation exists between CIC and the development of microvascular complications in diabetic children. Isolation of a new glycoprotein complement inhibition factor (CIF) from the parasitic plant Cuscuta europea seed, which appears to bind specifically to complement component C3 has provided an unique tool for the measurement of immune complexes by means of ELISA-type techniques (CIF-ELISA). We studied the levels of CIC (IgG, IgM and IgA) in 58 diabetic children (mean age 12.28 +/- 4.04 years, diabetes duration 5.3 +/- 3.7 years), 29 of them had vascular complications (group 1) and the other 29 were without vascular complications (group 2). As controls, we studied sera samples from 21 healthy children (mean age 13.54 +/- 4.03 years). Sera from the diabetic patients showed statistically significant higher levels of CIC IgG (p = 0.03) than sera from the control group. In sera from group 1 values of CIC IgG showed statistically significant higher levels than controls (0.720 +/- 0.31 vs. 0.46 +/- 0.045; p = 0.011) Sera from 59% of the patients were positive for CIC IgG, 36% for CIC IgM and 9% for CIC IgA. Among 26 patients with microalbuminuria, sera from 17/26 (65%) were positive for CIC IgG, 8/26 (31%) for CIC IgM and 2/26 (8%) for CIC IgA. CIC IgG correlated with HbAlc (r = 0.51; p = 0.005) and microalbuminuria (r = 0.42, p = 0.033). CIC IgA correlated with age (r = 0.44, p = 0.03). CIC IgM correlated with the duration of diabetes (r = 0.63, p = 0.02). These findings suggest that elevated levels of CIC IgG are associated with the development of early diabetic nephropathy.
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PMID:Circulating immune complexes among diabetic children. 1515 14

The antifreeze glycoprotein (AFGP), found in the blood of polar fish, is known to prevent ice crystal growth and to depress the freezing temperature, which may in turn protect tissues from freezing injury. The chemical synthesis of AFGP is an attractive alternative to its difficult isolation from natural sources, and this would permit quality control and mass production. In spite of recent success in islet transplantation for the treatment of type 1 diabetes mellitus, existing methods for the long-term preservation of islets are considered to be suboptimal and inadequate, which indicates the need for the development of improved methods. Rat islets were isolated from male Wistar rats, using intraductal collagenase distention, mechanical dissociation, and Ficoll-Conray gradient purification. Islets were cultured overnight and then cryopreserved in RPMI1640 in the presence of dimethyl sulfoxide (Me2SO) and 10% FCS with various concentrations of syAFGP, followed by slow cooling (0.3 degrees C/min) and rapid thawing (200 degrees C/min) as described by Rajotte. The freezing process was observed by cryomicroscopy. Islet recovery post-cryopreservation was 85.0 +/- 6.2% with syAFGP and 63.3 +/- 14.2% without syAFGP, both compared with the pre-cryopreservation counts (P < 0.05). The in vitro islet function measured by insulin release was equivalent to a static stimulation index of 3.86+/-0.43 for the islets that were frozen-and-thawed with syAFGP, compared to 2.98 +/- 0.22 without syAFGP (P < 0.05). At a concentration of around 500 microg/ml syAFGP, a strong attenuation of ice crystal growth and formation was observed by cryomicroscopy and these ice crystals did not cause cryoinjury. In conclusion, the attenuation of ice crystallization by syAFGP improves islet survival and function following cryopreservation and thawing.
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PMID:Effects of synthetic antifreeze glycoprotein analogue on islet cell survival and function during cryopreservation. 1632 94

Cellular prion protein (PrP(C)), an N-linked glycoprotein, is expressed in a variety of tissues, but its functions remain unclear. PrP(C) is abundantly expressed in the endocrine pancreas, which regulates blood glucose homeostasis. Therefore, we investigated whether the expression of PrP(C) was altered in islets of Langerhans in a model of spontaneous type 1 diabetes, the diabetes-prone BioBreeding (BBdp) rat and a model of beta-cell adaptation to hyperglycemia, the chronic glucose-infused Sprague Dawley rat. Pancreatic sections from animals aged 7-100 days were stained immunohistochemically and evaluated using light, fluorescence and confocal microscopy. PrP(C) was ubiquitously expressed in all four major endocrine cell types within islets. Surprisingly, cytosolic inclusions containing PrP(C) were identified exclusively in a subpopulation of insulin-producing beta-cells. The inclusions exhibited different molecular characteristics from the PrP aggregates previously described in vitro in neurons. The frequency of beta-cells with PrP(C) inclusions increased with age and was threefold greater in diabetes-prone rats than in controls at 100 days. Cytosolic PrP(C) expression in beta-cells was suppressed whereas the number and size of PrP(C) inclusions markedly increased in response to hyperglycemia during the first 2 days of continuous glucose infusion in Sprague Dawley rats. In summary, this is the first report describing in vivo cytosolic PrP(C) aggregation. These unique PrP(C) inclusions were beta-cell specific, more frequent in diabetes-prone animals, and responded to hyperglycemia in glucose-infused Sprague Dawley rats. These data suggest a potential dysfunction in beta-cells of diabetes-prone rats, and point to new avenues for the study of diabetes pathogenesis.
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PMID:Pronounced cytosolic aggregation of cellular prion protein in pancreatic beta-cells in response to hyperglycemia. 1714 48

We describe structural studies of the human leukocyte antigen DR52a, HLA-DRA/DRB3*0101, in complex with an N-terminal human platelet integrin alphaII(B)betaIII glycoprotein peptide which contains a Leu/Pro dimorphism. The 33:Leu dimorphism is the epitope for the T cell directed response in neonatal alloimmune thrombocytopenia and post-transfusion purpura in individuals with the alphaII(B)betaIII 33:Pro allele, and defines the unidirectional alloimmune response. This condition is always associated with DR52a. The crystallographic structure has been refined to 2.25 A. There are two alphabeta heterodimers to the asymmetric unit in space group P4(1)2(1)2. The molecule is characterized by two prominent hydrophobic pockets at either end of the peptide binding cleft and a deep, narrower and highly charged P4 opening underneath the beta 1 chain. Further, the peptide in the second molecule displays a sharp upward turn after pocket P9. The structure reveals the role of pockets and the distinctive basic P4 pocket, shared by DR52a and DR3, in selecting their respective binding peptide repertoire. We observe an interesting switch in a residue from the canonically assigned pocket 6 seen in prior class II structures to pocket 4. This occludes the P6 pocket helping to explain the distinctive "1-4-9" peptide binding motif. A beta57 Asp-->Val substitution abrogates the salt-bridge to alpha76 Arg and along with a hydrophobic beta37 is important in shaping the P9 pocket. DRB3*0101 and DRB1*0301 belong to an ancestral haplotype and are associated with many autoimmune diseases linked to antigen presentation, but whereas DR3 is susceptible to type 1 diabetes DR52a is not. This dichotomy is explored for clues to the disease.
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PMID:Crystallographic structure of the human leukocyte antigen DRA, DRB3*0101: models of a directional alloimmune response and autoimmunity. 1758 34

The nonobese diabetic (NOD) mouse is a useful model of autoimmune type 1 diabetes exhibiting many similarities to human type 1 diabetes patients including the presence of auto-reactive T cells and pancreas-specific autoantiboies. Multiple Idd loci control the development of diabetes in NOD mice. CD72, a B cell membrane-bound glycoprotein carrying a C-type lectin-like domain, is an inhibitory co-receptor of the B cell antigen receptor (BCR) that negatively regulates BCR signaling. Among four known haplotypes of mouse CD72, NOD mice carry the CD72(c) haplotype, whereas most of the other inbred strains of mice carry either CD72(a) or CD72(b). In this study, we generated congenic NOD.CD72(b) mice that carry C57BL/6 (B6) mouse-derived centromeric chromosome 4 interval (24-45cM) surrounding the CD72(b) locus. Unexpectedly, NOD.CD72(b) mice were not protected from diabetes, but rather exhibited accelerated development of both insulitis and diabetes. Our result defines novel locus or loci in the vicinity of CD72 gene that negatively control diabetes, indicating that NOD disease is under complex genetic controls of not only Idd genes but also disease-resistant genes.
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PMID:Centromeric interval of chromosome 4 derived from C57BL/6 mice accelerates type 1 diabetes in NOD.CD72b congenic mice. 1916 49

Diabetic nephropathy (DN) has an important impact on morbidity/mortality in diabetic patients. Genetic factors are probably involved in the development of this microvascular complication. Haptoglobin (Hp) is a genetically polymorphic glycoprotein that forms stable complexes with plasma-free hemoglobin (Hb) providing protection against heme-induced oxidative stress and kidney damage. The aim of the present study was to investigate the existence of association between the Hp genotypes and the presence of DN in Brazilian diabetic patients. The Hp genotypes of 265 patients, 95 type 1 diabetes mellitus (DM1) sufferers with at least 10 years of disease and 170 type 2 diabetes mellitus (DM2) sufferers with at least 5 years of disease were determined by allele-specific PCR; both groups included patients with and without DN. Hp allele and genotype frequencies were compared among the patient groups and between the patient groups and a control group of 142 healthy individuals. No association between Hp genotypes and DN could be demonstrated. Additionally, urinary albumin excretion values and the presence or absence of systemic arterial hypertension (SAH) were compared among the patient groups. Again, no significant correlations were found. The Hp polymorphism could not be associated with DN in the population studied here.
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PMID:Haptoglobin polymorphism and diabetic nephropathy in Brazilian diabetic patients. 1945 68


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