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

The activation of protein kinase C (PKC) found in diabetic glomeruli and glomerular mesangial cells cultured under high glucose conditions has been proposed to contribute to the development of diabetic nephropathy. However, the abnormalities distal to PKC have not been fully elucidated yet. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) cascade, an important kinase cascade downstream to PKC and an activator of cytosolic phospholipase A2 (cPLA2) by direct phosphorylation, is activated in glomeruli isolated from streptozotocin-induced diabetic rats. MAPK cascade was also activated in glomerular mesangial cells cultured under high glucose (27.8 mmol/l) conditions for 5 days, and the activation of MAPK cascade was inhibited by treating the cells with calphostin C, an inhibitor of PKC. Furthermore, the activities of cPLA2 also increased in cells cultured under the same conditions and this activation was inhibited by both calphostin C and PD 098059, an inhibitor of MEK (MAPK or extracellular signal-regulated kinase [ERK] kinase). These results indicate that MAPK cascade is activated in glomeruli and mesangial cells under the diabetic state possibly through the activation of PKC. Activated MAPK, in turn, may induce various functional changes of mesangial cells at least through the activation of cPLA2 and contribute to the development of diabetic nephropathy.
Diabetes 1997 May
PMID:Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. 913 54

The betacyte is a genetically engineered insulin-secreting liver cell line that is glucose responsive. Whether this cell is affected by specific beta-cell toxins is unknown. To explore this possibility we exposed these cells and those from the NIT-1 beta-cell line (positive controls) to the toxins streptozotocin (STZ, 2.5-20 mM), alloxan (ALL, 2.5-20 mM), and pentamidine (PENT, 10(-6)-1 mM). STZ and ALL were added for 1 h and pentamidine for 24 h. Insulin secretion from betacytes during a period of 5 h after removal of the toxin was inhibited only by pentamidine; all agents were inhibitory to NIT-1 cells. Glucose metabolism, as determined by a colorimetric MTT reduction assay, was adversely affected in betacytes by ALL (20 mM) and PENT (1 mM), and in NIT-1 cells by STZ (20 mM) as well as by ALL (2.5 mM) and PENT (1 mM). The magnitude of inhibition was less for the betacytes-58 v. 99%. Confluence of cells in culture wells and cell viability as assessed by the fluorochromes propidium iodide and acridine orange was reduced to a lesser extent for the betacytes than for the NIT-1 cells. The metabolic and microscopic effects of the toxins were unchanged in the betacyte from those in the liver cell line, HEP G2, from which the betacyte was engineered. These results of general resistance of the betacyte to beta-cell toxins with differing modes of action offer hope that this cell, or cells created in a similar manner from primary hepatocytes, may be at least partly resistant to the adverse effect of beta-cell toxins involved in autoimmune destruction of the pancreas. This increases the potential of the use of these cells for reversal of diabetes.
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PMID:Effect of beta-cell toxins on genetically engineered insulin-secreting cells. 921 49

In order to design a feasible somatic cell gene delivery system for the treatment of type I diabetes, a suitable cell type needs to be determined. We have previously shown that the stable transfection of the full-length insulin cDNA into the human liver cell line, (HEP G2ins) resulted in synthesis, storage and acute regulated release of insulin to analogues of cAMP, but not to the physiological stimulus glucose. In attempting to explain the lack of glucose responsiveness of the HEP G2ins cells we have stably transfected these cells with the human islet glucose transporter GLUT 2 (HEP, G2ins/g cells). The HEP G2ins/g cell clones exhibit glucose-stimulated insulin secretion and glucose potentiation of the secretory response to nonglucose secretagogues. While glucose responsiveness commenced at a lower concentration than normal islets, a secretion curve approaching normal physiological conditions was generated. Immunoelectron microscopy revealed the presence of insulin-containing granules, similar in size and appearance to those of the normal beta cell. These results demonstrate that while it is most likely that the HEP G2ins/g cell line predominantly secretes insulin via the constitutive pathway, significant acute regulated release was seen in response to glucose, and thus represents significant progress in the creation of a genetically engineered 'artificial beta cell' from a human hepatocyte cell line.
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PMID:Gene therapy of diabetes: glucose-stimulated insulin secretion in a human hepatoma cell line (HEP G2ins/g). 942 44

Since the discovery that germ-line mutations in the RET protooncogene are responsible for the multiple endocrine neoplasia (MEN) syndromes types 2A and 2B, prophylactic thyroidectomy has been recommended for MEN patients to prevent medullary thyroid carcinoma (MTC). In this report, we present the medium-term follow up results on the earliest group of 18 patients having prophylactic thyroidectomy for MEN 2A. There were no operative complications. Microscopic or grossly evident MTC was present in 14 (78%) of the resected patients. None of the patients had metastasis of their MTC to regional lymph nodes. At three years' follow up, there is no evidence of residual or recurrent MTC, based on biochemical testing. We conclude that prophylactic thyroidectomy, based on direct DNA testing for RET gene mutations, is an effective and safe way to manage MTC in patients with MEN 2A.
Exp Clin Endocrinol Diabetes 1998
PMID:Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. 951 56

Fibroblast growth factor-2 (FGF-2) is a potent mitogen expressed widely during embryogenesis and in tissues of the human fetus. It is recognized as an endothelial cell mitogen and is angiogenic in vivo. Expression of FGF-2 mRNA has also been shown within the human term placenta, and FGF-2 isolated from placental tissue, suggesting a role in placental growth including angiogenesis. The purpose of this study was to quantify and localize the sites of expression of FGF-2 and its high-affinity receptor, FGFR1, within placentae from normal term human pregnancies (n=8, 39-42 weeks), and pregnancies complicated by pregestational, type 1 diabetes (n=8, 36-40 weeks). Tissues were collected immediately following delivery and were either snap-frozen for RNA isolation, or fixed for either in situ hybridization using a 35S-labelled cRNAs encoding human FGF-2 or FGFR1, or immunocytochemistry using antibodies against human FGF-2 or FGFR1. Northern blot hybridization showed a significantly increased abundance of mRNAs for both FGF-2 and FGFR1 in placentae from diabetic women compared to those from normal women. In normal term placenta FGF-2 mRNA was present at low abundance in fetal villous tissue, in the vascular endothelium of blood vessels, and in the syncytiotrophoblast. FGF-2 mRNA was considerably more abundant in the syncytiotrophoblast and villous tissue of placentae from diabetic patients. Messenger RNA for FGFR1 was similarly distributed to that encoding FGF-2. Immunocytochemistry revealed abundant FGF-2 and FGFR1 peptides in villous vascular endothelial cells, and associated with the cell membranes of stromal tissues in placentae from control pregnancies. Little immunoreactive FGF-2 was present in the syncytiotrophoblast at term. In pregnancies complicated by diabetes intense staining for immunoreactive FGF-2 and for FGFR1 additionally existed in syncytiotrophoblast. The results suggest that FGF-2 acting as an autocrine agent contributes to placental angiogenesis, but may be released from the syncytium into the maternal circulation. Expression is elevated in placentae from diabetic pregnancies, and is particularly associated with the syncytiotrophoblast. This suggests a placental source for the elevated circulating maternal FGF-2 previously described in diabetic pregnancy.
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PMID:Fibroblast growth factor-2 and fibroblast growth factor receptor-1 mRNA expression and peptide localization in placentae from normal and diabetic pregnancies. 954 79

Diabetes self-management is a challenging task due to its complexity and ever-present barriers to self-care. A key issue for patients, providers, and healthcare systems is how to deliver personalized behavioral support in ways that are affordable and can reach most patients. The Internet offers several advantages in this regard because it is available 24 hours a day, low cost, and capable of reaching thousands of patients. Although Internet sites for diabetes support are popular, they have not been evaluated. For this study, a Web site for diabetes self-management that emphasized personalized goal setting, feedback, and social support was developed. Over a 10-week period, 111 different persons logged onto D-NET for a total of 21,046 accesses. Users included persons across a broad age range (up to age 77 years) and duration of diabetes. The most popular areas of the site were the Social Support Conference and the Diabetes Information Pages. User ratings revealed high satisfaction with the service. The Internet has great potential for providing needed support and services for patients with diabetes and other chronic illnesses.
Diabetes Educ
PMID:Feasibility and use of an Internet support service for diabetes self-management. 955 56

Several investigators have postulated that soluble growth factors are involved in the early development of the pancreas. In many tissues in which soluble factors are implicated in development, these factors act on their target cells through tyrosine kinase receptors. Because we had some preliminary evidence that fibroblast growth factor receptors (FGFRs) were expressed in the early pancreas, we investigated the effect of fibroblast growth factors (FGFs) during embryonic pancreatic development. For that purpose, we first studied the distribution and the functionality of FGFRs during pancreatic organogenesis. FGFR1 and FGFR4 were shown to be expressed at a high level during early pancreatic development before embryonic day 16, their levels of expression decreasing thereafter. The functionality of FGFR was studied next. It was demonstrated in vitro that both FGF1 and FGF2 induce the expression of NGFI-A mRNA, a useful indicator of functional growth factor-signaling pathways. Finally, the effect of FGF2 on embryonic pancreatic epithelial cell proliferation was studied. It was shown that FGF2 induces the proliferation of pancreatic epithelial cells during embryonic life. Taken together, these data strongly suggest that FGFs are implicated in pancreatic development during embryonic life.
Diabetes 1998 Aug
PMID:Fibroblast growth factor 2 promotes pancreatic epithelial cell proliferation via functional fibroblast growth factor receptors during embryonic life. 970 23

Fetal growth demands a coordinated increase in size of the fetus and the placenta, and both are determined, in part, by locally produced peptide growth factors. The availability of growth factors to individual tissues may be due to local changes in gene expression, but it is also controlled by proteolytic release from extracellular matrix stores. Members of the fibroblast growth factor (FGF) family are stored within basement membranes, while insulin-like growth factors (IGFs) are stored in association with specific binding proteins (IGFBPs). Insulin is a major trophic hormone in utero, and pancreatic beta-cell mass is determined by locally produced IGF-II and members of the FGF family. The mitogenic effects of IGF-II on beta-cells are determined by IGFBPs, which are themselves expressed with a distinct ontogeny within the islets of Langerhans. Overexpression of IGF-II or IGFBP-I can result in nesidioblastosis. Shortly after birth in rodents, many pancreatic beta-cells are destroyed by a process of apoptosis but are simultaneously replaced as a result of beta-cell neogenesis. This process may enrich the pancreas in beta-cells suited to the metabolic demands of postnatal life. The wave of beta-cell apoptosis coincides with a dramatic decrease in the local expression of IGF-II. These events may be functionally linked, because exogenous IGF-II will protect isolated islets from cytokine-induced apoptosis. FGF-2 is also widely expressed within fetal tissues and may be an important regulator of placental angiogenesis. FGF-2 appears in the maternal circulation during pregnancy, with peak values late in the 2nd trimester. It is associated with a circulating binding protein derived from the extracellular domain of the FGFR1 receptor. Levels of FGF-2 in maternal serum correlate positively with fetal size both in the 2nd trimester and at term. The expression of FGF-2 in placenta and its presence in maternal blood are elevated in pregnancies complicated by diabetes and are greatest in diabetic pregnancies associated with retinopathy. Thus, maternal FGF-2 may be a useful indicator of both fetal development and the risk of maternal pathology in pregnancies complicated by diabetes.
Diabetes Care 1998 Aug
PMID:Growth factors and the regulation of fetal growth. 970 29

Proteins modified by advanced glycation endproducts (AGE) bind to cell surface receptors and other AGE binding proteins. AGE-binding receptors are: scavenger receptors types I and II, the receptor for advanced glycation endproducts (RAGE), oligosaccharyl transferase-48 (OST-48, AGE-R1), 80K-H phosphoprotein (AGE-R2) and galectin-3 (AGE-R3). AGE receptors are found in monocytes, macrophages, endothelial cells, pericytes, podocytes, astrocytes and microglia. AGE-modified proteins also bind to lysozyme and lactoferrin. A critical review of the evidence for receptors binding AGE-modified protein binding in vivo is presented. Scavenger receptors have only been shown to bind proteins modified by AGE to a much higher extent than found in vivo. 80K-H phosphoprotein is involved in FGFR3 signal transduction to MAP kinase, and may be involved in AGE-receptor signal transduction. Whether all of these proteins bind AGE-modified proteins in vivo is not yet clear. Cell activation in response to AGE-modified proteins is associated with increased expression of extracellular matrix proteins, vascular adhesion molecules, cytokines and growth factors. Depending on the cell type and concurrent signaling, this is associated with chemotaxis, angiogenesis, oxidative stress, cell proliferation or programmed cell death (PCD). Receptor recognition factors for agonism at the AGE receptor have been little studied but to date hydroimidazolones appear to be the most likely candidates. Pharmacologic inhibition of AGE receptor-mediated cell activation with specific antagonists may provide the basis for therapeutic intervention in diseases where AGE accumulation is a suspected etiological factor vascular complications of diabetes, macrovascular disease, renal insufficiency and Alzheimer's disease.
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PMID:Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. 984 83

We studied 68 Japanese NIDDM patients (38 men and 30 women), aged 56.9+/-1.2 years (range 33-75 years), with a BMI of 23.1+/-0.5 kg/m2 without hypertension, dyslipidemia, and diabetic macroangiopathy for evaluating the relationship between serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels and the severity of diabetic retinopathy. Fundus examination was performed by an ophthalmologist using an ophthalmoscope, and the findings were graded as: (1) no signs of diabetic retinopathy (NDR), (2) background diabetic retinopathy (BDR), or (3) proliferative diabetic retinopathy (PDR). Serum sVCAM-1 levels were measured in duplicate by enzyme-linked immunosorbent assay using the soluble VCAM-1 KIT (R&D Systems Ltd., Ablingdon, Oxfordshire, UK). There was no difference in serum sVCAM-1 levels between patients with BDR (n = 17) and patients with NDR (n = 40) (1035.3+/-104.4 and 978.8+/-48.9 ng/ml, respectively, P = 0.8), but patients with PDR (n = 11) showed a significant increase of serum sVCAM-1 levels compared with patients with NDR (1281.8+/-166.3 and 978.8+/-48.9 ng/ml, respectively, P = 0.02). Although serum sVCAM-1 levels were correlated, not only with age but also with the known diabetic duration (r = 0.39, P = 0.001, and r = 0.40, P = 0.0007, respectively), age-adjusted sVCAM-1 levels were still significantly higher in the PDR group than in the NDR group. In contrast. serum sVCAM-1 levels were not related to the presence of diabetic nephropathy or HbA1c levels. Our results suggest that sVCAM-1 might be implicated in the development of the diabetic retinopathy, and measurement of serum sVCAM-1 levels in NIDDM patients maybe clinically useful for assessing the severity and possibly the activity of diabetic retinopathy.
Diabetes Res Clin Pract 1998 Oct
PMID:Elevated serum levels of soluble vascular cell adhesion molecule-1 in NIDDM patients with proliferative diabetic retinopathy. 988 35


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