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)

To elucidate the mechanisms involved in the development of cutaneous fibrosis in scleredema adultorum, we studied a patient with long-standing scleredema who had no history of diabetes mellitus or preceding febrile illness. Histological examination of a biopsy specimen from involved forearm skin demonstrated marked thickening of the dermis and accumulation of mucin between collagen bundles. Increased levels of type I collagen mRNA, as evidenced by positive in situ hybridization signals with an alpha 1(I) procollagen cDNA were found in numerous fibroblasts throughout the dermis. The expression of several genes coding for proteins involved in the maintenance of connective tissue was examined by determining in vitro protein production and mRNA levels in fibroblasts from the affected skin. Total protein production, glucosamine incorporation and collagen synthesis, were elevated by 44-97% in scleredema fibroblasts, compared with fibroblasts from two healthy individuals. Levels of mRNAs for alpha 1(I) and alpha 1(III) procollagens and fibronectin were elevated in scleredema fibroblasts, whereas mRNA levels for the tissue inhibitor of metalloproteinase were unaltered compared with control cultures. The results suggest that fibroblasts from the involved skin in non-diabetic patients with scleredema may exhibit a biosynthetically activated phenotype, which persists for several years. These alterations are likely to be involved in the development of the cutaneous induration and thickening which is characteristic of this disease.
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PMID:Scleredema adultorum: case report and demonstration of abnormal expression of extracellular matrix genes in skin fibroblasts in vivo and in vitro. 766 81

Since vascular complications in diabetes mellitus are attributed in part to blood platelets, our study tested the hypothesis that adhesion of platelets to collagen is enhanced in diabetic subjects. Platelet adhesion kinetics to type I collagen in the presence of plasma were evaluated by a new continuous-flow, micro-adhesion assay combined with resistive-particle counting to detect the loss of single platelets between 0.3 and 2.3 sec. Adhesion was also studied in a magnesium-containing Krebs-Ringer buffer to help assess whether the platelets themselves might be abnormal. We did not observe any differences in adhesion kinetics to collagen between the insulin-dependent (type I), the non-insulin dependent (type II) diabetics and the control subjects for platelets suspended in plasma or in washed platelets (p > 0.05). These findings suggest that platelet adhesiveness to type I collagen is not enhanced in diabetic subjects and is unlikely to contribute to the development of vascular complications.
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PMID:Platelet adhesion to collagen under flow conditions in diabetes mellitus. 804 94

We investigated the relationship between papillary muscle function and the myosin isoenzyme pattern, collagen content, and the type of myocardial collagen in diabetic rats to elucidate the mechanism of short-term myocardial dysfunction in diabetes. Diabetes was induced in 9-week-old male Wistar rats with a single intravenous injection of streptozotocin. One-half of the diabetic rats were treated with insulin. Age-matched control rats were also studied. The time to peak tension (TPT) of isometric papillary muscle contraction, time to 1/2 relaxation, and time from the peak tension to the peak decrease in tension (TPN) were significantly prolonged in diabetic rats at 4, 8, and 12 weeks. The peak increase and decrease in tension were slower in the diabetic rats compared with control rats. The level of the myocardial myosin isoenzyme V3 was greater in diabetic rats than in control rats at each interval. Findings in insulin-treated rats were similar to those in controls. The collagen content and the ratio of type I collagen to type III collagen were similar in all groups. The V3 level was significantly correlated with mechanical parameters (TPT versus %V3: r = 0.81, p < 0.01; TPN versus % V3: r = 0.78, p < 0.01). Our findings suggest that short-term myocardial dysfunction in diabetic rats is related to changes in the myosin isoenzyme pattern.
J Diabetes Complications
PMID:Correlation between myocardial dysfunction and changes in myosin isoenzymes in diabetic rat hearts. 863 73

High glucose concentrations associated with diabetes have been shown to cause the nonenzymatic modification of proteins. Reducing sugars covalently bind to free amine groups, undergo Amadori rearrangements, and crosslink with other glucose-modified proteins. Crosslinking of type I collagen by incubation with different concentrations of glucose 6-phosphate for up to 5 days resulted in a nondeformable collagen lattice as assayed by physical compaction analysis. Nonglycated collagen was fully compactible. Fibroblasts cultured on nonglycated collagen lattices were able to contract the lattice over a 5-day period, while fibroblasts on collagen glycated with 50 mM or more glucose 6-phosphate were unable to do this. Cells on both nonglycated and glycated collagen lattices initially lacked organized bundles of actin microfilaments or stress fibers. Over time, the cells on glycated lattices formed stress fibers, suggesting that they were still exerting mechanical force on a nondeformable matrix. These results suggest that crosslinking of collagen fibrils by nonenzymatic glycation alters the physical properties of the extracellular matrix, resulting in changes in the organization of the intracellular actin cytoskeleton.
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PMID:Cellular contraction of collagen lattices is inhibited by nonenzymatic glycation. 889 80

Advanced glycation endproduct (AGE), whose formation is accelerated on long lived extracellular matrix proteins in diabetes, is implicated in diabetic complications in various tissues. Type I collagen is the predominant matrix protein of bone and plays an important role in bone cell-matrix interactions. We have previously reported the accelerated accumulation of AGE collagen in bone tissue in diabetes mellitus (DM), in which reduced bone mineral density was observed. In addition, when cultures of mature primary rat osteoblasts were plated onto an in vitro AGE-modified collagen substrate, they showed altered cell functions, in terms of alkaline phosphatase (ALP) activity, osteocalcin secretion, and nodule formation (J Bone Miner Res 11:931-937; 1996). To determine whether AGE collagen might also affect differentiation of preosteoblasts, we compared the effects of plating the preosteoblastic UMR 201-10B cell line onto AGE-modified collagen with plating onto unmodified collagen. The latter had been shown previously to promote differentiation of UMR 201 cells. We have also explored whether these effects might be partly mediated by the transforming growth factor beta (TGF-beta) receptor. Growth of UMR 201-10B cells on a type I collagen substrate significantly inhibited cell growth and retinoic acid (RA)-induced upregulation of ALP activity, compared to cells on plastic. These inhibitory effects were reduced by prior glycation of collagen, in a dose-dependent manner with respect to AGE content. Unmodified collagen stimulated production of osteopontin mRNA, which was reduced by AGE modification to levels attained in cells on plastic. Growth on control collagen inhibited TGF-beta type II receptor binding in 10B cells, while this inhibition was reduced by AGE modification. These data suggest that glycation of collagen interferes with specific interaction(s) between UMR 201-10B cells and collagen. Based on our previous results in UMR 201 cells, these results would be compatible with the notion that glycated collagen has reduced ability to promote differentiation of preosteoblasts to mature osteoblasts. These data further suggest that collagen-mediated events in these cells may be at least in part mediated by regulation of the TGF-beta receptor expression.
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PMID:Nonenzymatic glycation of type I collagen modifies interaction with UMR 201-10B preosteoblastic cells. 927 88

Little is known about the dynamics of bone formation and bone resorption in utero, particularly the normal changes that occur throughout gestation and in clinical situations that result in low bone mass at birth. The objectives of this study were to describe the effects of gestational age on markers of fetal bone turnover, and to investigate whether the reported low bone mass at birth in small-for-gestational-age (SGA) infants and infants of diabetic mothers (IDMs) was associated with biochemical markers of decreased bone formation or increased bone resorption in utero. Bone formation and resorption were assessed by measurement of carboxyterminal propeptide of type I procollagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP), respectively, in 201 amniotic fluid samples. These markers are by-products of type I collagen formation and degradation, respectively, and have been used in the assessment of bone metabolism ex utero. Both PICP and ICTP concentrations in amniotic fluid were inversely associated with gestational age (P < 0.0001). Amniotic fluid concentrations of PICP increased exponentially in relation to infant birthweight (P = 0.008), and SGA infants had lower amniotic fluid PICP concentrations than controls (P = 0.07). The presence of diabetes in the mother was not associated with alterations in amniotic fluid PICP or ICTP concentrations. Although maturational effects on clearance of bone markers from amniotic fluid cannot be excluded, these data are consistent with a high turnover of bone matrix early in fetal life, and a reduction in bone formation when fetal growth is compromised.
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PMID:Effects of gestational age, maternal diabetes, and intrauterine growth retardation on markers of fetal bone turnover in amniotic fluid. 950 52

With the increasing demand for clinically useful biomarkers of bone turnover, a number of assays for the measurement of bone resorption markers have been developed. In the present study, automated (ACS: 180 DPD, Chiron Diagnostics, USA) and manual (DPD-ELISA, Pyrilinks-D, Metra Biosystems, USA) immunoassays for free DPD, and a manual immunoassay for the aminoterminal telopeptide of type I collagen (NTX, Osteomark, Ostex International, USA) were compared to the automated HPLC method for free DPD. Urine samples from a total of 538 healthy and diseased subjects aged 20 to 80 years were analyzed. The age and sex stratified reference ranges were essentially identical for the HPLC, ACS: 180 and the DPD-ELISA, but differed from the NTX assay. Individual values for free DPD as generated by HPLC and immunoassay techniques were highly correlated with each other, whereas correlations between assays measuring free and peptide-bound crosslink components were less pronounced. Precision of the automated techniques (HPLC and ACS: 180) was superior to that of the manual immunoassays. Disease-specific changes in crosslink excretion were similar for all assays and most pronounced in metastatic osteopathy, primary hyperparathyroidism and untreated Paget's disease of bone. We conclude that the automated assays for free DPD in urine, i.e. the HPLC and the ACS: 180 assay, show better analytical performance than the manual immunoassays studied. All techniques used in the present study appear to provide similar or identical clinical information. Therefore, the decision which assay to use largely depends on the laboratory set-up, the number of samples to be analysed, the turn-around time required, and the application for which the test should be used.
Exp Clin Endocrinol Diabetes 1998
PMID:Automated and manual assays for urinary crosslinks of collagen: which assay to use? 962 47

Osteopenia has been ascribed to diabetics without residual insulin secretion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key regulator of bone cell function. To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassays in 52 adults with Type 1 (n=27) and Type 2 (n=25) diabetes mellitus and 100 age- and sex-matched healthy blood donors. In the diabetic patients, we further determined serum levels of proinsulin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and several biochemical bone markers, including osteocalcin (OSC), bone alkaline phosphatase (B-ALP), carboxy-terminal propeptide of type I procollagen (PICP), and type I collagen cross-linked carboxy-terminal telopeptide (ICTP). Urinary albumin excretion was ascertained as a marker of diabetic nephropathy. Bone mineral density (BMD) of hip and lumbar spine was determined by dual-energy X-ray absorptiometry. Data are presented as means+/-s.e.m. Differences between the experimental groups were determined by performing a one-way analysis of variance (ANOVA), followed by Newman-Keuls test. Correlations between variables were assessed using univariate linear regression analysis and partial correlation analysis. Type 1 diabetics showed significantly lower IGF-I (119+/-8 ng/ml) and IGFBP-3 (2590+/-104 ng/ml) but higher IGFBP-1 levels (38+/-10 ng/ml) compared with Type 2 patients (170+/-13, 2910+/-118, 11+/-3 respectively; P<0.05) or healthy controls (169+/-5, 4620+/-192, 3.5+/-0.4 respectively; P<0.01). IGFBP-5 levels were markedly lower in both diabetic groups (Type 1, 228+/-9; Type 2, 242+/-11 ng/ml) than in controls (460+/-7 ng/ml,P<0. 01), whereas IGFBP-4 levels were similar in diabetics and controls. IGF-I correlated positively with IGFBP-3 and IGFBP-5 and negatively with IGFBP-1 and IGFBP-4 in all subjects. Type 1 patients showed a lower BMD of hip (83+/-2 %, Z-score) and lumbar spine (93+/-2 %) than Type 2 diabetics (93+/-5 %, 101+/-5 % respectively), reaching significance in the female subgroups (P<0.05). In Type 1 patients, BMD of hip correlated negatively with IGFBP-1 (r=-0.34, P<0.05) and IGFBP-4 (r=-0.3, P<0.05) but positively with IGFBP-5 (r=0.37, P<0. 05), which was independent of age, diabetes duration, height, weight and body mass index, as assessed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) correlated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I, IGFBP-3 and IGFBP-5, while the opposite was observed with bone formation markers (PICP, B-ALP) and vitamin D3 metabolites. In 20 Type 2 patients in whom immunoreactive proinsulin could be detected, significant positive correlations were found between proinsulin and BMD of hip (r=0.63, P<0.005), IGF-I (r=0.59, P<0.01) as well as IGFBP-3 (r=0.49, P<0.05). Type 1 and Type 2 patients with macroalbuminuria showed a lower BMD of hip, lower IGFBP-5 but higher IGFBP-4 levels, suggesting that diabetic nephropathy may contribute to bone loss by a disturbed IGF system. In conclusion, the findings of this study support the hypothesis that the imbalance between individual IGF system components and the lack of endogenous proinsulin may contribute to the lower BMD in Type 1 diabetics.
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PMID:Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. 979 71

Biochemical modification of extracellular matrix (ECM) proteins can alter the function in overlying cells. We tested the hypothesis that metal-catalyzed oxidation of native ECM and individual matrix proteins modulates the activity of inducible nitric oxide synthase (iNOS) in cultured rat mesangial cells (RMC). Oxidized modification of native ECM resulted in a 32% increase in iNOS activity (P<0.01) without influencing the response to supplemental L-arginine or to the addition of the iNOS inhibitor, L-NAME. Immunoblot analysis indicated that enhanced iNOS activity was not associated with a parallel rise in the cytosolic content of iNOS. Synthesis of type IV collagen was unaffected by growth of RMC on oxidized native ECM. Oxidation of three normal constituents of the mesangial matrix - type IV collagen, laminin, and fibronectin - also stimulated iNOS activity in overlying RMC by 18-32% (P<0.05). Growth of RMC on oxidized type I collagen or Vitrogel had no effect on NO production. We conclude that oxidized modification of the mesangial matrix promotes increased iNOS activity and NO production by mesangial cells. Further work is required to determine whether this response limits glomerular injury or promotes damage to the mesangium in oxygen free radical-mediated diseases such as chronic renal failure, atherosclerosis and diabetes.
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PMID:Growth of rat mesangial cells on oxidized extracellular matrix increases inducible nitric oxide synthase activity. 1002 60

There is evidence that infants of insulin-dependent diabetics have increased intrauterine bone resorption and reduced bone mineral content at birth. The aim of this study was to determine if type I diabetes is associated with abnormal maternal bone metabolism. We measured the circulating levels of carboxyterminal propeptide of type I procollagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) in the third trimester of pregnancy in samples obtained from 19 pregnant women with type I diabetes and 19 pregnant controls, to monitor the rate of bone formation and degradation, respectively. Diabetic control was considered to be good as the mean hemoglobin A(1) level was less than 8.5%. The circulating levels of PICP were significantly higher in pregnant women with insulin-dependent diabetes than in controls with uncomplicated pregnancy (median IDDM 147 microgram/liter, control 115 microgram/liter, P = 0.0014), but there was no significant difference in the circulating levels of ICTP between the two groups (median IDDM 4.6 microgram/liter, control 4.6 microgram/liter, P = 0.907). Therefore, our findings suggest that there is an increase in bone formation in pregnant women with type I diabetes which may be related to the increased amount of insulin administered and the improvement in diabetic control associated with pregnancy.
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PMID:Increased maternal bone formation in type I diabetic pregnancies. 1044 52


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