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)

Angiogenesis, the process of new vessels sprouting from the existing vasculature, is a critical process during early development. However, angiogenesis rarely occurs in the adult, except in response to cyclic hormonal stimulation in the ovary and uterus, in response to injury, and in response to pathological conditions such as tumorigenesis and diabetes mellitus. Tie2 (also known as Tek) is a novel endothelium-specific receptor tyrosine kinase, which has been demonstrated to be essential for the development of the embryonic vasculature; Tie2 knockout mice die by embryonic day 10.5 with specific defects in the formation of microvessels. Tie2 is downregulated later in embryogenesis, and its function in the adult has been relatively unexplored. To gain insight into the potential functions of Tie2 in the adult vasculature, Tie2 expression was examined in adult tissues undergoing angiogenesis and in quiescent tissues. Tie2 expression was localized by immunohistochemistry to the endothelium of neovessels in rat tissues undergoing angiogenesis during hormonally stimulated follicular maturation and uterine development and in healing skin wounds. Immunoprecipitation and RNase protection assay demonstrated upregulation of Tie2 protein and mRNA in rat and mouse skin wounds, respectively. Moreover, Tie2 immunoprecipitated from skin wounds was tyrosine-phosphorylated, indicating active downstream signaling. Surprisingly, Tie2 was also expressed in the entire spectrum of the quiescent vasculature (arteries, veins, and capillaries) in a wide range of adult tissues, and Tie2 immunoprecipitated from quiescent adult tissues was also tyrosine-phosphorylated. Together, these results suggest a dual function for Tie2 in adult tissues involving both angiogenesis and vascular maintenance.
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PMID:Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. 931 38

Glucokinase plays an important role in regulating insulin secretion in response to changes in blood glucose levels. As a result, one form of maturity onset diabetes of the young (MODY) results from haploinsufficiency of glucokinase. In both liver and pancreatic islet, glucokinase is allosterically regulated by an inhibitory protein (glucokinase regulatory protein, GCKR). GCKR has therefore become an important gene for functional analysis in type 2 diabetes. To allow genetic assessment of any such role, we have determined the structure of the human GCKR gene. Characterization of P1 and YAC clones containing GCKR shows it to consist of 19 exons spanning 27 kb. RT-PCR, RACE, and RNase protection experiments defined a transcriptional start site for GCKR 66 bp upstream of the initiation codon, but provided no evidence for islet cell specific alternative splicing in the rat. By SSCP screening, a common polymorphic sequence variant has been defined within exon 15 of human GCKR, at nt 1400 of the cDNA. This alters amino acid residue 446 from proline, conserved in rat and Xenopus, to leucine.
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PMID:Organization of the human glucokinase regulator gene GCKR. 957 Sep 59

The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.
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PMID:The 2-5A system: modulation of viral and cellular processes through acceleration of RNA degradation. 962 81

Type 3 cyclic nucleotide phosphodiesterase (PDE-3) isoforms exhibit a high affinity ("low K(m)") for cAMP and are specifically inhibited by cGMP and a number of pharmacological agents, which increase myocardial contractility, inhibit platelet aggregation, and increase smooth muscle relaxation. The PDE-3 family consists of at least two isozymes, PDE-3A (cardiac type) and PDE-3B (adipocyte type), with distinct tissue-specific distributions. PDE-3A mRNA is highly expressed in the cardiovascular system, whereas PDE-3B mRNA is primarily expressed in adipocytes and hepatocytes. Toward understanding potential roles of PDE-3 in diabetes mellitus, we have established a specific and sensitive RNase protection assay (RPA) for quantitating PDE-3A and PDE-3B mRNA in rat diabetic models. In fatty Zucker diabetic (ZDF) rats, PDE-3A mRNA, but not PDE-3B mRNA, was expressed in heart, whereas liver and white and brown fat tissues predominantly expressed PDE-3B mRNA. Unexpectedly, PDE-3B mRNA expression was approximately 2.5 times higher than PDE-3A mRNA in aorta from both ZDF and Sprague-Dawley (SD) rats. In contrast, expression levels of PDE-3A mRNA in heart were similar in both species. With this RPA, we were thus able to compare PDE-3A and -3B mRNA levels in different tissues as well as in different rat species.
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PMID:Cyclic nucleotide PDE-3. Quantitation of PDE-3A and -3B mRNAs in rat tissues by RNase protection assay. 963 Dec 38

In rats with streptozotocin (STZ)-diabetes for 2 or 4 weeks, the atrial natriuretic peptide (ANP) concentrations in the atria decreased whilst that of ANP in the plasma and ventricles increased. ANP concentrations in the hypothalamus and in the brainstem did not change in either 2- or 4-week diabetic rats. Atrial ANP content was partly restored by insulin replacement in 4-week diabetic rats. Plasma ANP concentrations and ventricular ANP contents were reversed to normal by insulin treatment in both 2- and 4-week diabetic rats. Solution-hybridization-RNase protection assay showed a significant increase in the preproANP mRNA expression in the ventricles but not in the atria. These results indicated that the STZ-diabetes increased the synthesis of ANP in the ventricles and consequently its release from the ventricles. The synthesis of ANP in the atria did not change as judged from the preproANP mRNA expression but the release of ANP from the atria might also be increased for ANP content decreased in the atria. The reason for the difference in the response of atrial and ventricular preproANP concentrations to STZ-diabetes is not known.
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PMID:Streptozotocin-induced diabetes has differential effects on atrial natriuretic peptide synthesis in the rat atrium and ventricle: a study by solution-hybridization-RNase protection assay. 966 47

Glycation process in vivo results in two different products: early and advanced glycation endproducts (AGEs). The mechanism of early product formation has been well described, with HbA1c as the best-studied example. The finding that advanced glycation endproducts are also formed on haemoglobin suggests that HbA1c is a precursor for Hb-AGE formation. HbA1c has been well established as an important indicator for glycaemia monitoring, but the diagnostic role of Hb-AGE has not yet been clarified. A question is whether HbA1c and Hb-AGE are competitive or complementary parameters. In our study, Hb-AGE was quantified by the competitive ELISA technique using polyclonal anti-AGE-RNase antibodies to detect AGE immunoreactivities of proteins precipitated in red cell hemolysate. Results are expressed as AGE units/mg Hb. Hb-AGE was analysed in three groups of patients divided according to HbA1c values as follows: group I (n = 25) HbA1c < 7%, Hb-AGE = 6.93 (5.7-7.3) U/mg; group II (n = 25) HbA1c = 7-10%, Hb-AGE = 8.62 (7.7-10.2) U/mg; and group III (n = 25) HbA1c > 10%, Hb-AGE = 12.47 (10.8-13.9) U/mg (median (interquartile range)). A close relation between the amounts of red cell HbA1c and Hb-AGE was observed in all diabetic subjects (n = 75) r = 0.77, P < 0.001. Patients with HbA1c level > 8% were considered to be in poor glycaemic control and those with HbA1c < 8% in good control. In the well-controlled subgroup (n = 33), HbA1c and Hb-AGE were less tightly correlated (r = 0.37, P <0.001). However, in those patients with a higher level of HbA1c = 12.55 (8.9-13.3)% (n = 42), the related Hb-AGE was 11.5 (10.3-12.8) U/mg Hb, yielding a more significant correlation (r = 0.51, P < 0.001). The content of Hb-AGE did not correlate with age (r = 0.09), diabetes duration (r = 0.05) or severity of retinopathy and/or nephropathy. The observed difference may reflect a different kinetic rate of HbA1c production and subsequently the rate of Hb-AGE formation. The discrepancy in the correlation between HbA1c and Hb-AGE suggests that they are complementary rather than opposed parameters. The amount of haemoglobin-linked AGEs does not correlate with the presence or absence of retinopathy and/or nephropathy. It seems that Hb-AGE represents only the metabolic status, equally in the subjects with and without diabetic microangiopathy.
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PMID:Comparison of advanced glycation endproducts on haemoglobin (Hb-AGE) and haemoglobin A1c for the assessment of diabetic control. 985 99

In the past, endogenous retroviral sequences have been isolated from patients suffering from different kinds of autoimmune diseases. Recently, a full length retroviral genome, termed IDDMK(1,2)22, was isolated from patients with new-onset IDDM. This genome contains a major histocompatibility complex II-dependent superantigen within its envelope gene. The viral sequence was found in ten patients with new-onset IDDM, but not in age-matched control subjects (Conrad et al. [9]). We searched for the presence of this viral genome by nested reverse transcription-polymerase chain reaction (RT-PCR) in a cohort of six patients with new-onset IDDM and six control subjects of the same age. We found all samples to be positive without any differences between patients and control subjects. The same results were obtained with supernatants of activated peripheral blood mononuclear cells. We performed isopycnic ultracentrifugation in sucrose density gradients on all samples and were unable to detect particles of the new virus in any of our samples. However, positive signals were obtained from all pellet fractions. RNase, DNase treatment and nested PCRs without reverse transcription showed that the positive signals were probably derived from intracellular RNA and DNA. In summary, no correlation between a positive nested PCR signal for IDDMK(1,2)22 and diabetes was found indicating that the new sequence represents just an additional member of the human endogenous retrovirus (HERV) family with lack of an exogenous counterpart.
Diabetes 1999 Jan
PMID:No evidence for association between IDDMK(1,2)22, a novel isolated retrovirus, and IDDM. 989 46

The low precursor frequency of Ag-reactive CD4+ T cells has been a barrier to the study of CD4+ T cell responses to conventional Ags as well as CD4+ T cell responses to autoantigens recognized during the course of an autoimmune disease. We have recently reported that all "conventional Ag" reactive CD4+ T cells are contained within the subpopulation expressing high levels of the CD4 molecule, termed CD4high. We have identified a CD4high population in the islets of Langerhans of prediabetic nonobese diabetic (NOD) mice that is extremely potent in transferring disease. As few as 500 CD4high islet-infiltrating CD4+ T cells transferred insulin-dependent diabetes mellitus to CD8 reconstituted NOD-SCID mice within 30 days of transfer. In contrast, CD4high T cells isolated from either NOD spleen or salivary glands did not transfer insulin-dependent diabetes mellitus into similar CD8-reconstituted NOD-SCID recipients. These data indicate that the precursor frequency of NOD islet-reactive, pathogenic CD4+ T cells is much higher in the prediabetic NOD pancreas than in these other organs. The islet-infiltrating CD4high T cells displayed selected memory markers, by cell surface analysis, and displayed a Th 1 phenotype by RNase protection assay, but had a marked decrease in IL-4 mRNA determined by quantitative real time PCR when compared with the less pathogenic CD4normal islet-infiltrating T cells. Use of the CD4high marker to select Ag activated T cells represents a tool to isolate and study pathogenic CD4+ T cells from autoimmune lesions in which the Ag has not been previously defined.
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PMID:Isolation of self antigen-reactive cells from inflamed islets of nonobese diabetic mice using CD4high expression as a marker. 1055 2

Depletion of GLUT4, the primary glucose transporter protein in adipose tissue and skeletal muscle, is reported to contribute to insulin resistance in pregnancy or diabetes. To examine this phenomenon, the expression of GLUT4 protein was assessed by Western blotting in streptozotocin-induced diabetic pregnant rats. In adipose tissue, relative to control, it was decreased by 30% in the normal pregnant group (p<0.001), by 37% in the diabetic nonpregnant group (p<0.01) and by 65% in the diabetic pregnant group (p<0.001). On the other hand, no significant variation was evident among the groups in skeletal muscle. To assess the mechanisms responsible for depletion of GLUT4 protein in adipose tissue, we quantitated levels of GLUT4 mRNA with a RNase protection assay. It was decreased by 44% in the normal pregnant group (p<0.05) and by 55% in the diabetic pregnant group (p<0.05), but not altered in the diabetic nonpregnant group. These results suggest that the depletion of GLUT4 protein in adipose tissue is a factor contributing to insulin resistance in pregnancy or diabetes, especially when the two states exist in combination.
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PMID:Expression of GLUT4 glucose transporter protein in adipose tissue and skeletal muscle from streptozotocin-induced diabetic pregnant rats. 1056 52

To characterize the role of the kallikrein-kinin system in diabetic cardiopathy, we studied the effect of streptozotocin (STZ) on the regulation of the myocardial bradykinin (BK) receptors, the B1 and B2 type, and two tissue kallikrein genes, rat kallikrein 1 (rKLK1) and rKLK7, in severely hyperglycemic rats. Experiments were performed in STZ-induced diabetic male Wistar rats (n = 7) and compared to controls (n = 7). After extraction of myocardial total RNA, specific oligonucleotides were used to generate reverse transcription PCR (RT-PCR) products from myocardial rKLK1 and rKLK7 mRNA. Southern blot analyses of these RT-PCR products were hybridized with appropriate gene-specific oligonucleotide probes. Myocardial B1 and B2 receptor expression were analyzed by RNase protection assays using specific probes from the coding region of the receptor genes. Twelve weeks after diabetes induction, the rats were normotensive and hyperglycemic and polyuric. We observed an impairment of the main myocardial kinin-forming enzymes, indicated by a reduction of the expression of both, rKLK1 and rKLK7. At this time the myocardial expression of the B1 receptor was not detectable in either group. Thus, the B1 receptor does not play a regulatory role in either the healthy or in STZ-diabetic heart. In contrast, the B2-receptor expression was detectable but did not differ significantly in either group. The reduced synthesis of myocardial tissue KLK implies a reduced capacity to generate BK in diabetic rats. This reduction is not compensated by elevated BK receptor levels. We suggest that alterations of the KKS may contribute to myocardial dysfunction in diabetes mellitus.
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PMID:Myocardial expression of rat bradykinin receptors and two tissue kallikrein genes in experimental diabetes. 1060 22


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