Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of tissue advanced glycation end products (AGEs) that result from nonenzymatic reactions of glucose and proteins are high in both diabetic and aging people. Irreversible AGE formation is based on increases in AGE-derived protein-to-protein cross-linking and is considered to be a factor contributing to the complications of diabetes. A novel inhibitor of advanced glycation, OPB-9195, belongs to a group of thiazolidine derivatives, known as hypoglycemic drugs; however, they do not lower blood glucose levels. We did studies to determine if OPB-9195 would prevent the progression of nephropathy in spontaneous diabetic rats. In vitro inhibitory effects of OPB-9195 on AGE formation and AGE-derived cross-linking were examined by enzyme-linked immunosorbent assay (ELISA) and SDS-PAGE, respectively. Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of NIDDM, were used to evaluate the therapeutic effect of OPB-9195. Light microscopic findings by periodic acid-Schiff (PAS) staining, the extent of AGE accumulation detected by immunohistochemical staining in the kidneys, the levels of serum AGEs by AGE-specific ELISA, and urinary albumin excretion were examined. OPB-9195 effectively inhibited both AGE-derived cross-linking and the formation of AGEs, in a dose-dependent manner in vitro. In addition, the administration of OPB-9195 prevented the progression of glomerular sclerosis and AGE deposition in glomeruli. Elevation of circulating AGE levels and urinary albumin excretion were dramatically prevented in rats, even at 56 weeks of age and with persistent hyperglycemia. We concluded that a novel thiazolidine derivative, OPB-9195, prevented the progression of diabetic glomerular sclerosis in OLETF rats by lowering serum levels of AGEs and attenuating AGE deposition in the glomeruli.
Diabetes 1997 May
PMID:Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. 913 61

In an attempt to shed more light on the relation between the glycation process and structural protein alterations, we followed the formation of glycated products in the lenses of hyperglycaemic Wistar rats during a period of 5 months following alloxan diabetes inducement. The study groups included non-diabetic (control), untreated diabetic rats (D), and diabetic rats receiving insulin alone or in combination with phlorizin, an inhibitor of renal tubular glucose transport. Lenses were removed at 4 and 20 weeks, and advanced glycation products in alkalisoluble lens proteins were determined by their characteristic spectrofluorescence (emission at 385 nm with excitation of 335 nm). In 20-week untreated diabetic rats as compared to control rats, a significant increase was observed in the fluorescence level (3.25 +/- 1.02 vs 1.61 +/- 0.17 FU/mg, p < 0.001), while in 4-week animals the increase was from 1.26 +/- 0.11 FU/mg in controls to 1.80 +/- 0.25 FU/mg in diabetics (P < 0.001). Daily treatment of 20-week diabetic rats with insulin alone (2.46 +/- 0.48 FU/mg) or in combination with phlorizin (2.30 +/- 0.26 FU/mg) did not significantly influence lens fluorescence level. The amount of glucosebound ketoamine linkage was estimated after acid hydrolysis as released 5-hydroxymethylfurfural (HMF). In 20-week controls, it was slightly higher than in 4-week controls (0.57 +/- 0.31 vs 0.41 +/- 0.20 nmol HMF/mg, respectively). The diabetic group showed a significant increase, however. In 4-week diabetics, a level of 1.07 +/- 0.36 nmol HMF/mg was found, while in 20-week animals the glycated protein amount rose to 2.46 +/- 0.79 nmol HMF/mg. In addition to the increases in glycated content with continuing diabetic hyperglycaemia, significant changes in protein composition of alkali-soluble lenses developed. The SDS-PAGE pattern showed an appearance of protein polymers of heterogeneous size (C 4 weeks 3.0 +/- 1.1% vs C 20 weeks 17.9 +/- 2.9%, D 4 weeks 7.3 +/- 2.1% vs D 20 weeks 19.8 +/- 3.6%) and the proteins of high molecular weight (HMW) failed to penetrate into the gel. Only a small amount of these HMW proteins was present in controls (C 20 weeks 2.5 +/- 1.2%) and short-term diabetes (D 4 weeks 0.8 +/- 0.2%), whereas in long-term untreated diabetes there was a dramatic increase (D 20 weeks 30.5 +/- 3.2%) with a corresponding decrease in other peaks. All diabetic animals from this group had macroscopically detectable cataractous lenses. Treatment with insulin or insulin/phlorizin followed the HMW protein level of the untreated animals (28.2 +/- 4.0% or 27.08 +/- 3.3% vs 30.52 +/- 3.32%).
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PMID:Temporal association between lens protein glycation and cataract development in diabetic rats. 913 59

Sequential chromatography of human follicular fluid (hFF) on Sephadex G-50, Q-Sepharose and finally Cibracon Blue yielded a protein molecule which biologically had a stimulating effect on steroid secretion (SSF) by ovarian granulosa cells in vitro. SDS-gel electrophoresis followed by blotting on PVDF membrane of the biologically active fraction revealed 3 bands of ca. 28, 27 and 24 kDa. The N-terminal sequence of the 3 bands corresponded completely with that of apolipoprotein A-I. In view of this, it was of interest to examine whether human ovary expresses apo A-I. Using specific primers for apo A-I and apo A-I-like protein (ALP; Richardson et al., 1996), we could demonstrate the presence of mRNA for apo A-I as well as ALP in the granulosa cells. The expression of ALP was found to be much higher than that of apo A-I. Like hFF-protein, purified apo A-I could also stimulate steroid secretion by human granulosa cells incubated in the presence of cholesterol. The functional role of ovarian apo A-I/ALP may be speculated as a transport molecule for steroid precursors.
Exp Clin Endocrinol Diabetes 1997
PMID:Expression of mRNA for ovarian steroid-stimulating factor (apolipoprotein A-I and apolipoprotein A-I-like protein) in human granulosa cells. 913 45

Antibody titres (IgA and IgG) for Helicobacter pylori were assayed in 69 insulin-dependent diabetes mellitus patients (42 males, age 1-20 years) and 310 healthy controls (171 males, age 1-20 years). A positive antibody titre for Helicobacter pylori was found in 18/69 diabetic subjects compared to 17/310 controls (p < 0.001). There was no difference between Helicobacter pylori positive and negative diabetic subjects as regards age, sex, duration of diabetes, diabetic control, insulin dose and SDS for weight and height. Gastroduodenoscopy revealed presence of Helicobacter pylori and evidence of gastric inflammation in 7/8 symptomatic diabetic children. There was a significant association in the diabetic subjects between positivity for anti-cow's milk protein and anti-Helicobacter antibodies, compared to the control group. Seven of the 17 diabetics studied within 3 months of the onset of diabetes had positive antibody titres for Helicobacter. Of these seven patients, five were positive for anti-cow's milk protein antibodies. In our study the prevalence of Helicobacter pylori infection was significantly higher in diabetic subjects than in controls, but the infection was asymptomatic and there was no correlation with diabetes control. In diabetic subjects Helicobacter pylori infection was associated with a humoral response to cow's milk proteins and was often present from the onset of diabetes.
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PMID:High risk of Helicobacter pylori infection associated with cow's milk antibodies in young diabetics. 924 Aug 76

The human HLA-DQ8 (A1*0301/B1*0302) allelic product manifests a strong association with insulin-dependent diabetes mellitus (IDDM). Previous biochemical studies of the major histocompatibility complex (MHC) class II I-A(g)7 protein of IDDM-prone non-obese diabetic mice produced controversial results. To better define the biochemical properties of IDDM-associated MHC class II molecules, we analyzed DQ8 proteins, in comparison to other DQ allelic products, by partially denaturing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). We now report that DQ8 proteins have a normal peptide occupancy and lifespan in cells. Similar to I-A(g)7, DQ8 proteins formed only a minor fraction of SDS-stable complexes with peptides. Although this phenotype was not unique to DQ8, some DQ allelic products such as IDDM-protective DQ6 proteins were SDS resistant. The DQ9 allelic product, differing from DQ8 only at position (P) beta 57, was SDS stable, suggesting that non-Asp residues at beta 57 might decrease the SDS stability of DQ proteins. We identified a single peptide which specifically induced an SDS-stable conformation in DQ8 as well as in I-A(g)7 molecules. The residues at anchor P1 in this peptide were found to influence the SDS stability of both molecules. Together with our previous observation of similar binding motifs of I-A(g)7 and DQ8, these results demonstrate an overall biochemical similarity of mouse and human diabetes-associated MHC class II molecules. This similarity might contribute to a common immunological mechanism of IDDM in both species.
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PMID:Biochemical characterization of the human diabetes-associated HLA-DQ8 allelic product: similarity to the major histocompatibility complex class II I-A(g)7 protein of non-obese diabetic mice. 936 99

Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-4alpha gene give rise to maturity-onset diabetes of the young, type 1 (MODY1). HNF-4, an orphan member of the nuclear receptor superfamily, contains a DNA-binding domain (DBD) and a putative ligand-binding domain (LBD) that can act independently of each other. The first MODY1 mutation identified creates a stop codon at amino acid 268 in the LBD of HNF-4 (Q268X) that leaves the DBD intact, suggesting that the mutant protein may retain some of the properties of the wild-type protein. To determine the functional properties of this mutant, we constructed HNF4.Q268X and tested it in vitro and in vivo for DNA binding, protein dimerization, and transactivation activity. Results of an electrophoretic mobility shift assay showed that HNF4.Q268X neither binds DNA alone nor binds it as a dimer with wild-type HNF-4 (HNF4.wt). In contrast, a co-immunoprecipitation assay showed that HNF4.Q268X is capable of dimerizing in solution with HNF4.wt. Transient transfection assays, however, indicated that HNF4.Q268X does not affect transactivation by HNF4.wt in vivo, supporting the argument against a dominant negative effect. Additional results suggest that the lack of a dominant negative effect could be due to a striking differential subcellular localization of the HNF4.Q268X protein: HNF4.Q268X could be extracted from transfected cells only when treated with SDS. Taken together, our results suggest that the MODY1 phenotype is due to a loss of functional HNF-4 protein that is aggravated in tissues that express relatively low amounts of HNF-4, such as pancreas.
Diabetes 1998 Jun
PMID:MODY1 mutation Q268X in hepatocyte nuclear factor 4alpha allows for dimerization in solution but causes abnormal subcellular localization. 960 81

The aim of this study was to investigate growth and final height in young adults after therapy for malignant diseases. Final height and weight was studied in 50 long-term survivors (LTS) of childhood cancer (aged 17-31 years; 30 men, 20 women) 3-18 years after treatment for malignant diseases (7 acute lymphoblastic leukemia, 20 lymphoma, 8 sarcoma, 15 malignant central nervous system [CNS] tumours). None of the LTS had been treated with growth hormone (GH). A decrease in final height SDS (Standard deviation score) occurred in both LTS of malignant CNS tumours (median height SDS at diagnosis, 0.3; range, -0.9 to 2.2; median final height SDS, -1.3; range, -3.9 to 1.9; p < 0.01) and LTS of lymphoma (p < 0.05) or leukemia (p < 0.05). However, only LTS who received cranial (p < 0.05) or craniospinal (p < 0.001) irradiation (XRT) exhibited reduced final heights. LTS who had received XRT not involving the CNS or had received no XRT at all presented no reduction in final height. LTS of CNS tumours treated with high craniospinal XRT doses (24 to 56 Gy) reached lower (p < 0.01) final heights when compared with LTS of leukemia who received lower cranial XRT doses (18 to 24 Gy). Final height SDS correlated with chronological age at initiation of therapy (p < 0.05). No correlation was found between the cumulative doses of applied chemotherapeutic agents and the final height of LTS. During follow-up LTS developed an increase in weight for height index (WFH) which occurred independent of XRT. In conclusion, cranial and craniospinal XRT especially in young children with malignancies resulted in a decrease in final height SDS. As 6 of 15 LTS of malignant CNS tumours exhibited a final height SDS below -2 SD, analysis of pituitary function and substitution of GH after diagnosis of GH deficiency should be considered for these patients at a young age. Others factors not directly related to XRT are responsible for the increased risk for obesity in LTS of childhood cancer.
Exp Clin Endocrinol Diabetes 1998
PMID:Final height and weight of long-term survivors of childhood malignancies. 962 45

Overweight in insulin-dependent diabetes mellitus (IDDM) has been repeatedly reported, especially in girls during adolescence. Potential pathophysiologic factors include tight metabolic control, insulin dose, treatment regimen, puberty and genetics. A standardized data-base from all IDDM patients treated at our institution was evaluated. IDDM patients with hypothyroidism or celiac's disease as well as all records from the first year of diabetes were excluded, resulting in a total of 427 patients (2454 patient-years) available for analysis. BMI and SD-score for BMI based on the Zurich longitudinal growth study were evaluated. Standardized BMI was higher in pubertal children ( + 1.07+/-0.06) compared to prepubertal children (+ 0.68+/-0.07; p < 0.002). This increase was present both for boys and girls. Increasing overweight during puberty was found irrespective of the age at diagnosis of diabetes (prepubertal or pubertal). The daily dose of insulin and the long-term metabolic control had only a minor impact on the development of overweight. In contrast, in pubertal children, SDS-BMI was significantly higher in patients on intensified insulin regimens (3 or 4 daily injections) compared to patients with 2 injections (p < 0.05). These data demonstrate that both boys as well as girls with IDDM develop overweight during puberty. Multiple injection therapy, not daily dose of insulin or the level of metabolic control achieved, was the main predictor of weight gain. This finding may be explained by increased caloric intake due to the flexibility allowed by intensified treatment.
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PMID:Contributions of age, gender and insulin administration to weight gain in subjects with IDDM. 962 71

RT6 is a rat lymphocyte glycosylphosphatidylinositol (GPI)-anchored alloantigen with nicotinamide adenine dinucleotide (NAD) glycohydrolase (NADase) and auto-ADP-ribosyltransferase activities. RT6 may have immunoregulatory properties based in part on the observation that injection of diabetes-resistant (DR)-BB rats with depleting doses of anti-RT6.1 mAb induced autoimmune diabetes and thyroiditis. We now report that injection of DR-BB rats with anti-RT6.1 mAb increased plasma NADase activity, which localized, by fluid phase liquid chromatography fractionation, to the high density lipoprotein (HDL) fraction. Following ultracentrifugation in high salt, however, RT6 was found in the nonlipoprotein fraction, where it existed, under nondenaturing conditions, as a 200-kDa complex and, by SDS-PAGE, as a 30- to 36-kDa species. Thy-1, another GPI-linked protein, and proteins that reacted with anti-GPI-oligosaccharide Abs also translocated from HDL to the nonlipoprotein fraction under similar conditions. Injection of anti-RT6.1 mAb into thymectomized DR and diabetes-prone-BB rats increased soluble RT6 to levels comparable to those observed in euthymic DR-BB rats, suggesting that HDL-bound RT6 is not derived from peripheral lymphocytes. In agreement, NADase activity in the plasma of eviscerated DR-BB rats did not increase following injection of anti-RT6 mAb. These data suggest that HDL is a carrier of plasma RT6 and other GPI-linked proteins, with equilibrium between the lipoprotein and nonlipoprotein fractions being salt dependent. Since GPI-linked proteins in HDL can transfer to cells in a functionally active form, the presence of RT6 in HDL is consistent with it having a role in signaling in nonlymphoid cells.
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PMID:Characterization of high density lipoprotein-bound and soluble RT6 released following administration of anti-RT6.1 monoclonal antibody. 968 81

Glycation of basement membrane collagen IV has been implicated as a major pathogenetic process leading to diabetic microvascular complications. To evaluate the relevance of carbohydrate-induced modifications on collagen IV in diabetic nephropathy, we isolated the cross-linking domains 7S and NC1 from the glomerular basement membrane (GBM) of patients with diabetes mellitus. Modifications characteristic for glycated proteins were identified when the domains from diabetic kidney were compared with the same domains from human placenta as an unmodified control. In both domains a marked formation of inter-and intramolecular cross links could be demonstrated by SDS-PAGE. Furthermore circular dichroism studies showed a decrease in helicity of the 7S domain from human diabetic kidneys of 13%, indicating denaturation already at room temperature. Thermal transition profiles, showing a shift of the denaturation temperature towards a lower temperature, with loss of a distinct second melting point, confirmed this observation. Our data provide further evidence for a possible role of protein-modification by glycoxidative reactions in the onset of diabetic nephropathy in vivo.
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PMID:Biochemical and biophysical alterations of the 7S and NC1 domain of collagen IV from human diabetic kidneys. 975 26


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