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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.
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PMID:Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. 993 Nov 33

By means of systematic abnormal Hb surveys of people living in eight districts (Okayama, Shimane, Kagawa, Hyogo, Osaka, Nara, Aichi, and Yamanashi Prefectures) using isoelectric focusing, the number of abnormal Hbs discovered and identified among 301,190 subjects was 128. The frequency was estimated to be about one per 2,350. Recently, however, abnormal Hb carriers have been found among individuals with high or low levels of Hb A1c or with an abnormal HPLC pattern. These carriers were found when glyco-HPLC was used to determine the HbA1c level for detection and diagnosis of diabetes mellitus in physical check-ups of inhabitants in each prefecture. To date, 1,227 cases of abnormal Hbs have been detected by isoelectric focusing and glyco-HPLC. These Hbs were analyzed by protein chemistry and DNA analytical methods. The most typical Hbs found in Japan have been Hb J-Cape Town (an alpha-chain variant) and Hb Riyadh (a beta-chain variant). Homozygotes for Hb J-Cape Town, Hb Ube-2, Hb Hamadan, Hb G-Szuhu and Hb Takamatsu have been discovered among abnormal Hb carriers. The carriers of Hb M-Hyde Park and Hb Koln, which cause hemolytic anemia due to their molecular instability, have been found in some parts of Japan, but by clinical examination rather than by Hb survey. On the other hand, alpha- and beta-thals have often been detected in blood samples with a high or low HbA2 level or in abnormal Hb such as Hb H, during systematic surveys for abnormal Hb. Peripheral blood examinations of these patients revealed typical data, a low MCV, MCH, and sometimes low Hb levels. The diagnosis was made by DNA analyses of the nucleotide sequencing of the beta-globin gene for beta-thals and of the alpha-globin gene arrangement for alpha-thals. beta-Thals found in Japanese mainly involve a point mutation, such as-31CapA-->G(in ATA box) and beta 90 codon GAG-->TAG(creation of a stop codon). The alpha-thals had genotypes of -alpha 3.7/alpha alpha for alpha-thal-2, -SEA/alpha alpha for alpha-thal-1 and -SEA/-alpha 3.7 for Hb H disease.
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PMID:[Hemoglobinopathy in Japan: detection and analysis]. 1022 86

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are angiogenic molecules whose combined mitogenic activity is potently synergistic. However, the molecular mechanism underlying this synergy is incompletely understood. We examined whether VEGF and bFGF affect expression of each other or alter expression of the VEGF receptor KDR in retinal capillary endothelial cells. In addition, we investigated the intracellular signaling mechanisms involved in this response. VEGF-induced [3H]thymidine uptake was tightly correlated with KDR mRNA and protein concentrations, suggesting that increased KDR expression might account for VEGF's synergistic activity in the presence of bFGF. bFGF (10 ng/ml) induced KDR mRNA expression within 4 h and attained a 4.0-fold increase after 24 h. KDR protein expression was increased 7.5-fold after 48 h. VEGF (= 50 ng/ml) did not alter bFGF, VEGF, or KDR mRNA expression under serum-deprived conditions. In contrast, VEGF increased KDR mRNA expression 87% under growth conditions and 2.9-fold under serum-deprived conditions in the presence of bFGF. The protein kinase C (PKC) agonist phorbol myristate acetate (PMA) induced KDR mRNA expression 5.1-fold at 100 nmol/l. bFGF increased p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation within 5 min, reaching a maximum within 15 min and remaining significantly elevated for >6 h. bFGF-induced MAPK phosphorylation and KDR mRNA expression were almost completely inhibited by 5 micromol/l GFX, a non-isoform-selective PKC inhibitor. MAPK inhibitor PD98059 reduced KDR mRNA expression 72% at concentrations that inhibited bFGF-induced MAPK phosphorylation 100%, suggesting that pathways in addition to MAPK might also be involved. Inhibitors of the beta isoform of PKC (LY333531), protein kinase A (PKA) (H89), and phosphotidylinositol (PI) 3 kinase (wortmannin) had no significant effect. These data suggest that bFGF stimulates KDR expression through a PKC and p44/p42 MAPK-dependent pathway not primarily involving the beta isoform of PKC, PKA, or PI-3 kinase. Since bFGF induces VEGF expression and since increased KDR expression potentiates VEGF action, resulting in additional KDR expression and marked mitogenic activity, these data provide a novel mechanistic explanation for the angiogenic synergy between VEGF and bFGF.
Diabetes 1999 May
PMID:Basic fibroblast growth factor induces expression of VEGF receptor KDR through a protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway. 1033 22

Results are presented of a double-blind, Australian multicentre study of the efficacy and safety of adjunctive repaglinide in patients with Type 2 diabetes who were controlled inadequately on metformin monotherapy. Patients had to have been on metformin for at least 6 months and to have glycated haemoglobin (HbA1c) levels of more than 7.1%. Patients were randomized to one of three treatment regimens: metformin plus placebo (MET, n = 27), repaglinide plus placebo (REP, n = 29) and metformin plus repaglinide (MET/REP, n = 27). The metformin dose remained unchanged from the prestudy dose, whereas repaglinide was titrated from 0.5 mg to 4.0 mg preprandially, depending on fasting capillary blood glucose concentration. Maintenance treatment was continued for 3 months. In the MET and REP groups, the HbA1c level decreased from 8.6% to 8.3% and from 8.6% to 8.2%, respectively; in the MET/REP group, HbA1c decreased from 8.3% to 6.9% (p < 0.001 vs. baseline; p < 0.05 vs. each monotherapy group). Overall, 59% of patients in the MET/REP group achieved a HbA1c level of less than 7.1% by the end of the study, compared with 20% and 22% in the MET and REP groups, respectively. No serious adverse events occurred that were considered to be related to study medication. Mild symptoms of hypoglycaemia were seen in the REP and MET/REP groups, in many cases during the titration phase. The combination of repaglinide with metformin was safe and well tolerated and produced a greater improvement in glycaemic control than that seen by the sum of the changes with the two agents alone.
Exp Clin Endocrinol Diabetes 1999
PMID:Repaglinide in combination therapy with metformin in Type 2 diabetes. 1052 39

Medullary thyroid carcinoma (MTC) occurs sporadically (sMTC) or as part of the inherited cancer syndrome, multiple endocrine neoplasia type 2 (MEN 2). While the occurence of the MEN 2 syndrome is associated with mutations in the RET protooncogene, the reason for carcinogenesis in sMTC still remains unclear. Ras is a frequently mutated oncogene in a broad spectrum of human tumors and has been found in about 50% of follicular, papillary or anaplastic thyroid carcinomas. The purpose of this study was to determine, whether mutations in the ras oncogene could play a possible role in the carcinogenesis of sMTC. In this study we analyzed 15 sMTC for mutations in the hotspots codon 12, 13 and 61 of the H- and K-ras oncogene. We used the direct sequencing technique. In none of the examined tumors we were able to detect a mutation in the codon 12, 13 and 61 of the H-ras and K-ras oncogene. Based upon these results, we conclude that H- and K-ras do not play an important role in the carcinogenesis of sMTC.
Exp Clin Endocrinol Diabetes 2000
PMID:Absence of H- and K-ras oncogene mutations in sporadic medullary thyroid carcinoma. 1076 32

Platelet-derived growth factor (PDGF) was found to contribute to the pathophysiological process in the development and progression of glomerulosclerosis characterized by mesangial cell proliferation and accumulation of extracellular matrix. To examine the role of PDGF in the development of diabetic nephropathy, we conducted immunohistochemical analysis for PDGF B-chain (PDGF-B) and PDGF beta-receptor (PDGFR-beta) in the glomeruli of streptozotocin-induced diabetic rats. At 2, 4, and 12 weeks after the onset of diabetes, the expression of PDGF-B in glomeruli of diabetic rats was increased significantly as compared to control or diabetic rats treated with insulin. Similar changes were observed on PDGFR-beta immunostaining. The immunostaining of mirror sections revealed the existence of PDGF-B or PDGFR-beta not only in mesangial cells but also in visceral epithelial cells. Glomerular volume was significantly increased in diabetes. This early glomerular abnormality was prevented by an inhibition of PDGF system with trapidil as well as by the treatment of insulin. Our results suggest that the activation of the PDGF system in glomerular cells might play an important role in the development of early glomerular lesion in diabetes.
Diabetes Res Clin Pract 2000 May
PMID:Immunohistochemical characterization of glomerular PDGF B-chain and PDGF beta-receptor expression in diabetic rats. 1080 45

To characterize the differentiation events that selectively target insulin-producing cells to interleukin (IL)-1beta-induced apoptosis, we studied IL-1beta signaling via mitogen-activated protein kinase (MAPK) and stress-activated protein kinase in 2 pancreatic endocrine cell lines. We studied the glucagon-secreting AN-glu cell line and the insulin and the islet amyloid polypeptide-producing beta-cell line (AN-ins cells), which is derived by stable transfection of AN-glu cells with the transcription factor pancreatic duodenal homeobox factor-1. AN-ins cells were more sensitive to the cytotoxic action of IL-1beta. This increased sensitivity was not associated with a more pronounced IL-l-induced nitric oxide production in AN-ins cells, but it correlated with a more marked activation of the 3 MAPKs extracellular signal-regulated kinases (ERKs)-1/2, c-Jun NH2-terminal kinase (JNK), and p38 MAPK (p38). This led to increased phosphorylation of the transcription factors c-Jun, Elk-1, and ATF2 and of heat shock protein 25. Inhibition of ERK-1/2 and p38 did not prevent but aggravated IL-1beta-induced cell death. In contrast, inhibition of JNK by transfection with the dominant negative inhibitor of the JNK-binding domain prevented apoptosis in both cell types. Cell death could be elicited by overexpressing the catalytic domain of MAPK kinase kinase 1, a specific activator of JNK and nuclear factor-kappaB, which does not recruit ERK-1/2 or p38. Coactivation of ERK-1/2 with JNK did not prevent apoptosis. In conclusion, increased MAPK signaling in response to IL-1beta may represent a novel molecular marker of beta-cell differentiation. JNK inhibition represents an effective means of preventing IL-1beta-activated beta-cell destruction.
Diabetes 2000 Sep
PMID:The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. 1096 30

Diabetes mellitus is commonly considered as a disease of a scant beta-cell mass that fails to respond adequately to the functional demand. Tyrosine kinases may play a role for beta-cell replication, differentiation (neoformation) and survival. Transfection of beta-cells with DNA constructs coding for tyrosine kinase receptors yields a ligand-dependent increase of DNA synthesis in beta-cells. A PCR-based technique was adopted to assess the repertoire of tyrosine kinases expressed in fetal islet-like structures, adult islets or RINm5F cells. Several tyrosine kinase receptors, such as the VEGFR-2 (vascular endothelial growth factor receptor 2) and c-Kit, were found to be present in pancreatic duct cells. Because ducts are thought to harbor beta-cell precursor cells, these receptors may play a role for the neoformation of beta-cells. The Src-like tyrosine kinase mouse Gtk (previously named Bsk/Iyk) is expressed in islet cells, and was found to inhibit cell proliferation. Furthermore, it conferred decreased viability in response to cytokine exposure. Shb is a Src homology 2 domain adaptor protein which participates in tyrosine kinase signaling. Transgenic mice overexpressing Shb in beta-cells exhibit an increase in the neonatal beta-cell mass, an improved glucose homeostasis, but also decreased survival in response to cytokines and streptozotocin. It is concluded that tyrosine kinase signaling may generate multiple responses in beta-cells, involving proliferation, survival and differentiation.
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PMID:Role of tyrosine kinase signaling for beta-cell replication and survival. 1109 2

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
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PMID:Attenuation of FGF signalling in mouse beta-cells leads to diabetes. 1113 Jul 26

Extensive angiogenesis and invasion of the maternal decidua by trophoblasts are essential for the development and function of the placenta. Vascular endothelial growth factors (VEGF), placenta growth factor (PlGF) and their receptors VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3/Flt4 have important roles in vasculogenesis and angiogenesis. We have studied the localization of these proteins by immunohistochemistry and Western blotting in the placenta and of PlGF in maternal serum, and their association with diabetes, pre-eclampsia, fetal growth restriction (FGR) and fetal alcohol syndrome (FAS). VEGFR-1 and VEGFR-3 were detected mainly in the syncytiotrophoblastic layer whereas VEGFR-2 was detected in the vascular endothelial cells of the placenta. VEGFR-1, but not the other receptors, showed increased expression in placental syncytiotrophoblasts from 50% of patients with severe pre-eclampsia and FGR when compared with normal placentas. PlGF was undetectable in 38 of 44 samples of amniotic fluid of mothers with normal and complicated pregnancies. However, maternal serum PlGF concentrations were significantly lower in pre-eclamptic patients and in those with FGR when compared to diabetic women or healthy controls. These results suggest that low maternal serum PlGF and increased placental expression of its receptor VEGFR-1 are associated with pre-eclampsia and FGR.
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PMID:Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. 1116 Aug 48


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