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

3T3-L1 adipocytes represent an established physiological model for studying glucose uptake and storage. Overexpression of epidermal growth factor (EGF) receptors in these cells (200,000-250,000 receptors per cell) confers EGF-inducible GLUT4-mediated glucose uptake (17). We now report that EGF receptor (EGFR)-mediated signals can induce incorporation of glucose into glycogen and lipids in these cells. Incorporation into lipids was stimulated to similar levels by insulin or EGF in adipocytes expressing full-length (wild type) EGFR (2.05 +/- 0.26-fold for insulin vs. 2.28 +/- 0.15-fold for EGF). EGF induced incorporation into glycogen at roughly 60% of the level of insulin (4.53 +/- 0.57-fold for insulin vs. 2.76 +/- 0.25-fold for EGF); this corresponded with similarly lower levels of glycogen synthase activation by EGF relative to insulin stimulation. EGFR kinase activity was required for induced storage because a kinase-inactive (M721) EGFR failed to stimulate glucose incorporation into glycogen or lipids. EGFRs that lack all or part of the unique EGFR COOH-terminal tail induced glucose incorporation at levels similar to that stimulated by full-length (wild type) EGFR. Thus, domains in the COOH-terminal tail of the EGFR, which are necessary for stimulating glucose transport, are not required for signaling EGF-induced glucose storage. EGF-induced glucose storage did not require de novo protein synthesis, suggesting that EGFR signaling uses existing pathways in the adipocytes. These data demonstrate that signaling pathways for EGFR-mediated glucose storage and GLUT4-mediated glucose transport diverge at the receptor level. Thus, EGF-induced glucose storage can be achieved in the absence of induced GLUT4-mediated glucose transport.
Diabetes 1996 Nov
PMID:Epidermal growth factor induces glucose storage in transgenic 3T3-L1 adipocytes overexpressing epidermal growth factor receptors. 886 69

The pancreatic beta- and alpha-cells are developmentally related to each other but reveal diverse gene expression patterns. Among the two important transcription factors for insulin gene expression, IEF1 is present both in alpha- and beta-cells, but PDX-1/IPF1/STF-1/IDX-1, a homeodomain-containing transcription factor, is present in beta-cells but not in alpha-cells. To elucidate the function of PDX-1 in the expression of beta-cell-specific genes, we established stable alphaTC1 clone 6 (alphaTC1.6)-derived transfectants expressing PDX-1 and examined the changes in the gene expression patterns in them. The exogenous expression of PDX-1 in alphaTC1.6 cells alone could induce islet amyloid polypeptide (IAPP) mRNA expression in the cells but not the expression of insulin, glucokinase, or GLUT2 gene. However, when betacellulin was added to the medium, the PDX-1-expressing alphaTC1.6 cells, but not the control alphaTC1.6 cells, came to express insulin and glucokinase mRNAs. This did not occur with other growth factors such as epidermal growth factor, transforming growth factor alpha, and insulin-like growth factor I. GLUT2 mRNA remained undetectable in the PDX-1--expressing alphaTC1.6 cells. These observations demonstrate the potency of PDX-1 for the expression of the insulin, glucokinase, and IAPP genes and suggest that certain regulatory factors, which can partially be modified by betacellulin, also contribute to the beta-cell specificity of gene expression.
Diabetes 1996 Dec
PMID:PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin. 892 72

Thyroid epithelial cells are known to produce several growth factors and cytokines which influence thyroid cell growth and function in an autocrine and/or paracrine manner. It is already known that insulin-like growth factor I (IGF I) is overexpressed in toxic adenomas whereas epidermal growth factor (EGF) is found predominantly in thyroid neoplasia. We now investigated the expression of bFGF by immunohistochemistry in thyroid tissue of patients with toxic adenoma (n = 27), cold nodules (n = 27) and for comparison in Graves' disease (n = 5). In addition bcl-2-oncoprotein expression in these tissues were also detected by immunohistochemistry. Most of bFGF immunostaining was found in the connective tissue of all thyroid tissues with a predominance in adenomas and in Graves' diseases. The collagen surrounding the thyroid follicles close to their basal membrane were homogeneously and intensively stained. All the cytoplasm of fibroblast in the connective tissue were strongly positive. Within the cytoplasm of only 2-10% thyroid epithelial cells bFGF immunostaining was found without any difference between toxic adenomas or cold nodules. In the tissue of patients with Graves' disease, less than 2% of thyrocytes were stained. All thyroid epithelial cell showed clearly an immunostaining for bcl-2-oncoprotein in nodular goiter as well as Graves' disease.
Exp Clin Endocrinol Diabetes 1996
PMID:Role of basic fibroblast growth factor in the pathogenesis of nodular goiter. 898 Sep 98

Within the last decades multiple iodolipid-classes have been identified in thyroid tissue. For a long time they have been supposed to be involved in thyroid autoregulation, but for the time being no specific compounds could be isolated. A new approach was stimulated by the finding that thyroid cells were able to iodinate polyunsaturated fatty acids to form iodolactones and by the identification of alpha-iodohexadecanal (alpha-IHDA) as the major compound of an iodolipid fraction. alpha-IHDA exerts multiple inhibitory effects on adenylate cyclase, NADPH-oxidase and thyroid peroxidase. Therefore, it is speculated as a mediator of the Wolff-Chaikoff-effekt and to be involved in the autoregulation of specific thyroid functions mediated by the cyclic adenosine-3',5'-monophosphate (cAMP)-pathway. Meanwhile 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid delta-lactone (delta-iodolactone) has been identified in human thyroid tissue and it could be demonstrated that this iodoeicosanoid specifically inhibits signal transduction pathways induced by local growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Therefore, delta-iodol-actones seem to act as mediators of iodine, especially in the autoregulation of cAMP-independent thyroid cell proliferation. We will summarize these important new findings and discuss the role of these iodolipids on thyroid cell growth regulation.
Exp Clin Endocrinol Diabetes 1996
PMID:Iodolactones and iodoaldehydes--mediators of iodine in thyroid autoregulation. 898 Oct

We have studied the acute changes (up to 30 days) in the expression of epidermal growth factor (EGF) and its receptor (EGFr) in the kidneys of adult male Wistar rats made diabetic by a single intravenous injection of streptozotocin (55 mg/kg) using a combination of immunocytochemical staining and in situ hybridization histochemistry. In the absence of insulin treatment, diabetic rats displayed renal growth (hypertrophy and hyperplasia). It was accompanied by an increase in immunostainable EGF within the thick ascending limb (TAL) of the loops of Henle which was apparent within 24 h of the onset of diabetes, reached a peak by day 7 and persisted to the end of the experimental period (day 30). In situ hybridization histochemistry revealed that these changes were preceded by a rapid rise in EGF mRNA in the cells of the TAL, which was highest after 1 day but declined to control levels by day 7. Increased immunostainable EGFr was evident in both the proximal and TAL and in the cortical collecting ducts from day 1. Staining of the proximal tubules declined rapidly after day 1 but that of the TAL and collecting ducts persisted until day 7 and declined thereafter. These results are discussed in light of the role of EGF in the hypertrophy and repair of the diabetic kidney.
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PMID:Upregulation of epidermal growth factor and its receptor in the kidneys of rats with streptozotocin-induced diabetes. 900 88

Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. Overall PTPase activity in the cytosol fraction did not change with TNF-alpha treatment, and PTPase activity in the particulate fraction was decreased by 55-66%, demonstrating that increases in total cellular PTPase activity did not account for the observed alterations in receptor signalling. However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. These data suggest that at least part of the TNF-alpha effect on pathways of reversible tyrosine phosphorylation may be exerted through the dynamic modulation of the expression of specific PTPases. Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited.
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PMID:Effect of tumor necrosis factor-alpha on the phosphorylation of tyrosine kinase receptors is associated with dynamic alterations in specific protein-tyrosine phosphatases. 901 60

In autoradiographic studies in anesthetized rats, 125I-labeled amylin binding was associated with proximal convoluted tubules but not distal tubules, interstitium, or glomeruli in the renal cortex. Split-drop micropuncture experiments showed that perfusion of the peritubular capillaries with amylin (10(-9) M) stimulated proximal tubular fluid absorption by 28%. This effect was inhibited by luminal addition of ethylisopropylamiloride, indicating mediation by a brush-border Na+/H+ exchanger. Intravenous infusion of an amylin binding antagonist, AC-187, reduced proximal fluid reabsorption (22%) in anesthetized rats, indicating a role for endogenous amylin in salt homeostasis. In primary cultures of rat proximal tubule cells, amylin (10(-7) M) stimulated proliferation with a potency equal to epidermal growth factor. Peptide antagonists (AC-187, AC-413, and AC-512) of the amylin binding sites in the renal cortex blocked the mitogenic action of amylin. We conclude that amylin acts on renal proximal tubules to promote sodium and water reabsorption and cell proliferation. These novel actions may have implications for the development of hypertension for example in non-insulin-dependent diabetes mellitus and obesity in which hyperamylinemia has been observed.
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PMID:Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney. 903 44

Mitogen-activated protein (MAP) kinase plays crucial roles in cell growth and differentiation. It has recently been shown that the MAP kinase cascade in growth factor signaling diverges and cross-talks with other signaling pathways. In the present study, we examined the effects of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), on the activation of Ras, Raf-1 kinase, and MAP kinase by insulin and epidermal growth factor (EGF). The effect of LY294002, a structurally distinct PI3-kinase inhibitor, on the activation of Raf-1 kinase by both ligands was also examined. In 3T3-L1 adipocytes, 25 nmol/l wortmannin inhibited the insulin-induced activation of Raf-1 kinase to the basal level, whereas the same dose of wortmannin had little effect on the EGF-induced activation of Raf-1 kinase. One hundred micromol/l LY294002 blocked insulin-induced activation of Raf-1 kinase without affecting EGF-induced activation of this kinase. Twenty-five nmol/l wortmannin inhibited the insulin-induced activation of MAP kinase to the basal level with no effect on the EGF-induced activation of this kinase. But the same dose of wortmannin did not affect the formation of guanosine 5'-triphosphate (GTP)-bound Ras stimulated by either ligand. In KB cells, results similar to those in 3T3-L1 adipocytes were obtained. In contrast, in Chinese hamster ovary cells overexpressing the human insulin receptor (CHO-HIR cells), neither wortmannin nor LY294002 inhibited the insulin-induced activation of Raf-1 kinase, and wortmannin had little effect on the activation of MAP kinase by insulin. These results indicate that 1) PI3-kinase or wortmannin-sensitive molecules are involved in the interaction between activated Ras and Raf-1 kinase in the insulin signaling in 3T3-L1 adipocytes, 2) the involvement of PI3-kinase or wortmannin-sensitive molecules in the insulin-induced activation of MAP kinase appears to be cell-type specific, and 3) differential mechanisms to activate Raf-1 kinase and MAP kinase by insulin and EGF exist.
Diabetes 1997 May
PMID:Differential activation of mitogen-activated protein kinase by insulin and epidermal growth factor in 3T3-L1 adipocytes: a possible involvement of PI3-kinase in the activation of the MAP kinase by insulin. 913 38

Insulin resistance and hyperinsulinemia cluster with microalbuminuria in both diabetic and nondiabetic subjects, but the mechanism underlying this association is unknown. To test the hypothesis that insulin influences protein permeability, we measured the albumin transcapillary escape rate (TER) by the (131)I-labeled albumin technique in 12 healthy volunteers and 12 normoalbuminuric NIDDM patients (fasting plasma glucose, 10.9 +/- 1.3 mmol/l) during 4 h of isoglycemia with high (1.1 mU x min(-1) x kg(-1)) or, on a different day, low (0.1 mU x min(-1) x kg(-1)) insulin infusion. In both patients and control subjects, high insulin was associated with a 7% decrease in blood volume (P = 0.006) and a 6% decrease in diastolic blood pressure (P < 0.02), these two changes being related to one another (r = 0.56, P < 0.01). Basal albumin TER was similar in patients (8.4 +/- 0.5% x h(-1)) and control subjects (7.7 +/- 0.7% x h(-1)) and was not significantly changed by high insulin in either group (patients vs. control subjects, 7.3 +/- 0.9 vs. 6.2 +/- 0.4% x h(-1); NS vs. low insulin). In contrast, high insulin increased renal albumin excretion (from 3.6 +/- 0.8 to 5.4 +/- 1.1 microg/min, P < 0.01) and clearance rate (0.09 +/- 0.02 to 0.13 +/- 0.03 microl/min, P < 0.001) in patients but not in control subjects. To localize the effect of insulin along the nephron, we measured the urinary excretion of N-acetyl-beta-D-glucosaminidase (beta-NAG), released by the proximal tubule; retinol-binding protein (RBP), reabsorbed by the proximal tubule; and Tamm-Horsfall protein (THP) and epidermal growth factor (EGF), both secreted by the distal tubule. For both beta-NAG and RBP, but not EGF or THP, insulin enhanced urinary excretion (diabetics vs. controls: beta-NAG, 0.48 vs. -0.15 microU/min [P = 0.03]; RBP, 78 vs. -32 ng/min [P = 0.05]). In conclusion, physiological hyperinsulinemia does not affect systemic albumin permeability in healthy subjects or normoalbuminuric NIDDM patients. In contrast, in NIDDM patients, but not in healthy subjects, insulin increases the urinary excretion of albumin and protein markers of proximal tubular function. The significance of this finding for the pathogenesis of diabetic nephropathy remains to be established.
Diabetes 1997 May
PMID:Effect of insulin on systemic and renal handling of albumin in nondiabetic and NIDDM subjects. 913 57

Aldose reductase (AR) is known to be responsible for many side effects of diabetes. In the present work, we studied the effects of various extracellular signals on the regulation of the expression of AR in astrocytes in culture, by determining its enzymatic activity or its mRNA level. We found that basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), and hypertonic NaCl were able to increase the expression of AR in astrocytes. A superinduction was found when bFGF was combined with hypertonicity. We also observed that AR activity was independent of glucose concentration in the culture medium. However, when the concentration of glucose in the culture medium was under 1 g/l, bFGF did not increase the activity of AR. Thus, when glucose is depleted, the regulation of AR expression by bFGF does not operate. In addition, AR does not seem to be involved in control of astrocyte proliferation, in contrast to the effects reported on other cell types. These results indicate that AR is expressed in astrocytes and that its expression is upregulated by hypertonicity but also by FGFs and EGF. This suggests that in these cells, AR elicits some regulatory functions.
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PMID:Regulation of aldose reductase expression in rat astrocytes in culture. 917 98


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