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

1. The effect of the biguanide metformin on hexose transport activity was studied in bovine cultured aortic endothelial (BEC) and smooth muscle cells (BSMC). 2. Metformin elevated the rate of hexose transport determined with 2-deoxyglucose (2DG) in a dose- and time-dependent manner in both cell types. Similar ED50 values (0.8-1.0 mM) were determined for the effect of metformin on 2DG uptake in both BEC and BSMC following 24 h exposure to increasing concentrations of metformin, with maximal stimulation at 2 mM. 3. In BEC, metformin increased the hexose transport rate 2-3 fold at all glucose concentrations tested (3.3-22.2 mM). In BSMC incubated with 22.2 mM glucose, metformin elevated the hexose transport approximately 2 fold. The drug was also effective at lower glucose levels, but did not exceed the maximal transport rate observed in glucose-deprived cells. 4. Similar results were obtained when the effect of metformin on hexose transport activity was assessed with the non-metabolizable hexose analogue, 3-O-methylglucose, suggesting that the drug affects primarily the rate of hexose transport rather than its subsequent phosphorylation. 5. The metformin-induced increase in hexose transport in BSMC treated for 24 h with the drug correlated with increased abundance of GLUT1 protein in the plasma membrane, as determined by Western blot analysis. 6. These data indicate that in addition to its known effects on hexose metabolism in insulin responsive tissues, metformin also affects the hexose transport system in vascular cells. This may contribute to its blood glucose lowering capacity in patients with Type 2, non-insulin-dependent diabetes mellitus.
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PMID:Regulation by metformin of the hexose transport system in vascular endothelial and smooth muscle cells. 888 31

The physiological regulation of nutrient catabolism in islet cells, its perturbation in non-insulin-dependent diabetes mellitus, and the tools available to compensate for such a perturbation are reviewed. In terms of physiology, emphasis is placed on the relevance of glucokinase to hexose-induced insulin release, protein-to-protein interaction and enzyme-to-enzyme channelling, and the preferential stimulation of mitochondrial oxidative events in glucose-stimulated B-cells. In terms of pathology, attention is drawn to the deficiency of FAD-linked mitochondrial glycerophosphate dehydrogenase. Last, as far as therapeutic aspects are concerned, the potential usefulness of hypoglycemic sulfonylureas and meglitinide analogs, adenosine analogs, non-glucidic nutrients, and GLP-1 is underlined.
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PMID:Regulation, perturbation, and correction of metabolic events in pancreatic islets. 890 21

The effect of insulin, thyroxine and alloxan induced diabetes has been studied on brush border membrane glycosylation in rat kidneys. Expressed on dry weight basis, the membrane protein was elevated in insulin, thyroxine and diabetic membranes compared to the control group. Sialic acid content of the membranes was significantly reduced in insulin and thyroxine injected animals whereas fucose level was unaffected under these conditions. Brush border fucose content was significantly reduced in diabetic animals but sialic acid content was unaffected. Membrane hexose and hexosamines levels were unaltered by hormone treatments, but in diabetic rats hexosamine level was significantly reduced. The binding of radiolabelled UEA, WGA, PNA to purified brush borders corroborated changes in membrane saccharides. These findings suggest the role of hormones in membrane glycosylation of rat kidney tubules.
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PMID:Changes in tubular membrane glycosylation in diabetic, insulin and thyroxin treated rat kidneys. 897 85

Why is it important to understand the mechanisms controlling intestinal adaptation? There are two major answers to this question. Firstly, in establishing the cellular and molecular events associated with intestinal adaptation, we will formulate a general framework that may be applied to the understanding of adaptation of other cell membranes. For example, alterations in the synthesis of glucose carriers and their subsequent insertion into membranes may alter sugar entry across the intestinal brush border membrane (BBM) using the sodium-dependent D-glucose transporter, SGLT1, or the BBM sodium-independent facultative fructose transporter, GLUT5, and may alter facilitated sugar exit across the basolateral membrane (BLM) using GLUT2. The precise role of transcriptional and translational processes in the up- or down-regulation of sugar transport requires further definition. Alterations in enterocyte microsomal lipid metabolic enzyme expression occurring during the course of intestinal adaptation will direct the synthesis of lipids destined for trafficking to the BBM and BLM domains of the enterocyte. This will subsequently alter the passive permeability properties of these membranes and ultimately influence lipid absorption. Therefore, establishing the physiological, cellular and molecular mechanisms of adaptation in the intestine will define principles that may be applied to other epithelia. Secondly, enterocyte membrane adaptation is subject to dietary modification, and these may be exploited as a means to enhance a beneficial or to reduce a detrimental aspect of the intestinal adaptive process in disease states. Alterations in membrane function occur in association with changes in dietary lipids, and these are observed in a variety of cells and tissues including lymphocytes, testes, liver, adipocytes, nerve tissue, nuclear envelope and mitochondria. Therefore, the elucidation of the mechanisms of intestinal adaptation and the manner whereby dietary manipulation modulates these processes affords the future possibility of dietary engineering aimed at using food as a therapeutic agent. It is hoped this approach will form the centerpiece for future investigation that would focus on disease prevention, as well as on the development of better therapeutic strategies to prevent the development or to treat the complications of conditions such as diabetes mellitus, obesity, hyperlipidemia and inflammatory bowel diseases. This review deals with the physiology of glucose transport with specific emphasis on transporters of the brush border membrane (BBM) and the basolateral membrane (BLM). On the BBM the sodium (Na)/glucose transporters (SGLT1 and SGLT2), the Na-independent transporter (GLUT5), and on the BLM the hexose transporter (GLUT2) are discussed. The molecular biology of these transporters is also reviewed.
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PMID:Adaptation of intestinal nutrient transport in health and disease. Part I. 907 26

The first part of this review dealt with the physiology of glucose transport with specific emphasis on transporters of the brush border membrane (BBM) and the basolateral membrane (BLM). On the BBM, the sodium (Na)/glucose transporters (SGLT1 and SGLT2), the Na-independent transporter (GLUT5) and on the BLM the hexose transporter (GLUT2) are discussed. The molecular biology of these transporters is also reviewed. In the second part of the review, we discuss the manner in which intestinal adaptation may be modified by alterations in the diet, especially the lipid constituents, and two important examples of intestinal adaptation will be given: diabetes mellitus and inflammatory bowel disease.
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PMID:Adaptation of intestinal nutrient transport in health and disease. Part II. 907 27

In the accompanying article, we describe the creation of novel cell lines derived from RIN 1046-38 rat insulinoma cells by stable transfection with combinations of genes encoding human insulin, GLUT2, and glucokinase. Herein we describe the regulation of insulin secretion and glucose metabolism in these new cell lines. A cell line (betaG I/17) expressing only the human proinsulin transgene exhibits a clear increase in basal insulin production (measured in the absence of secretagogues) relative to parental RIN 1046-38 cells. betaG I/17 cells engineered for high levels of GLUT2 expression and a twofold increase in glucokinase activity (betaG 49/206) or engineered for a 10-fold increase in glucokinase activity alone (betaG 40/110) exhibit a 66% and 80% suppression in basal insulin secretion relative to betaG I/17 cells, respectively. As a result, betaG 49/206 and betaG 40/110 cells exhibit potent insulin-secretory responses to glucose alone (6.1- and 7.6-fold, respectively) or to glucose plus isobutylmethylxanthine (10.8- and 15.1-fold, respectively) that are clearly larger than the corresponding responses of betaG I/17 or parental RIN 1046-38 cells. betaG 49/206 and betaG 40/110 cells also exhibit a rapid and sustained response to glucose plus isobutyl-methylxanthine in perifusion studies that is clearly larger in magnitude than that of the two control lines. Glucose dose-response studies show that both engineered and non-engineered lines respond maximally to submillimolar concentrations of glucose and that betaG 49/206 cells are the most sensitive to low concentrations of the hexose, consistent with their clearly elevated rate of [5-3H]glucose usage. Finally, 5-thioglucose, a potent inhibitor of low-K(m) hexokinases, most effectively normalizes glucose concentration dependence for insulin secretion in the cell line with highest glucokinase expression (betaG 40/110). We conclude that GLUT2 and/or glucokinase expression imposes tight regulation of basal insulin secretion in cell lines that overexpress human proinsulin, allowing a marked improvement in the range of secretagogue responsiveness in such cells.
Diabetes 1997 Jun
PMID:Regulation of insulin secretion from novel engineered insulinoma cell lines. 916 67

Post-receptor signalling molecules that convey the signal from the activated insulin receptor to the actual process of Glut4 translocation and hexose uptake are poorly understood. Various studies have suggested a requirement of the lipid kinase phosphatidylinositol-3 kinase (PI3-kinase) in this process. PI3kinase regulates the activation status of the small GTP-binding protein Rac which, in turn, is able to activate another G-protein Rho. Rac and Rho are known to regulate the structure of the membrane- and cytoplasmic actin-cytoskeleton. We have examined whether Rac and Rho transfer the signals generated by PI3kinase towards insulin-stimulated hexose uptake. For that purpose, we expressed in 3T3-L1 adipocytes the dominant-negative mutant of RacN17 using vaccinia virus-mediated gene transfer. The expression levels of the RacN17 protein were monitored by Western blotting. The abrogation of endogenous Rac signalling by expression of RacN17 was inferred from the observed loss of arachidonic acid release in response to insulin. Basal and insulin-stimulated hexose transport were not affected by expression of the RacN17 mutant. A possible contribution of Rho.GTP to stimulation of hexose uptake was examined by pre-incubation of adipocytes with lysophosphatidic acid (LPA). We observed a profound effect of LPA on the structure of the cytoskeleton and on the phosphorylation of Focal Adhesion Kinase (p125FAK), indicating that 3T3-L1 adipocytes respond to LPA and that Rho was activated by LPA. However, no effect was detected on the basal or on the insulin-stimulated hexose transport. We conclude that Rac and Rho are unlikely to be involved in insulin-stimulated hexose transport, suggesting a possible contribution of other signalling pathways, downstream of PI3kinase to this process.
Exp Clin Endocrinol Diabetes 1997
PMID:Changes in the signalling status of the small GTP-binding proteins Rac and Rho do not influence insulin-stimulated hexose transport. 935 53

The insulin-like effects of vanadate are independent of the insulin receptor and insulin receptor substrate 1 (IRS-1) phosphorylation. A cytosolic protein tyrosine kinase (CytPTK), sensitive to inhibition by nanomolar concentrations of staurosporine (concentration at which 50% inhibition occurs [IC50], 1-2 nmol/l), has been implicated in some (i.e., glucose oxidation, lipogenesis) but not all (i.e., hexose uptake, inhibition of lipolysis) of the insulin-like effects of vanadate. We report here the existence of another nonreceptor protein tyrosine kinase in rat adipocytes, located exclusively in the plasma membranes (MembPTK), which we suggest is associated with hexose uptake and the antilipolytic activity of vanadate. MembPTK is a nonglycoprotein with an estimated molecular weight of 55-60 kDa. In a cell-free experiment, vanadate activates MembPTK seven- to ninefold (median effective dose, 17 +/- 2 micromol/l). Vanadate-activated MembPTK is inhibited by staurosporine (IC50, 60 +/- 5 nmol/l). In intact adipocytes, staurosporine antagonized vanadate-induced hexose uptake (IC50, 6.0 +/- 0.3 micromol/l) and significantly reversed the antilipolytic effect of vanadate (IC50, 5.0 +/- 0.4 micromol/l). After vanadate treatment, a phosphorylated P55 protein is immunoprecipitated by antibodies to both phosphotyrosine and phosphatidylinositol (PI) 3-kinase. In conclusion, rat adipocytes contain an additional vanadate-activatable nonreceptor membranous protein tyrosine kinase that may participate in the effects of vanadate not carried out by CytPTK. We also suggest that after treatment with vanadate, MembPTK is activated by autophosphorylation and interacts with PI 3-kinase. This may explain how vanadate activates PI 3-kinase without involving receptor activation and IRS-1 phosphorylation.
Diabetes 1997 Nov
PMID:Vanadate activates membranous nonreceptor protein tyrosine kinase in rat adipocytes. 935 13

Insulin modulates the differentiation and synthetic activity of osteoblasts, but its mechanisms of action are not fully understood. Because ascorbate also influences osteoblast differentiation and is a cofactor for collagen synthesis, we examined the effects of insulin on the transport and metabolism of vitamin C in osteoblastic cells. UMR-106 rat osteoblast-like cells accumulated ascorbate intracellularly when incubated with dehydroascorbic acid (DHAA; oxidized vitamin C). Insulin increased the intracellular concentration of ascorbate derived from DHAA and also increased the initial rates of uptake of DHAA and 2-deoxyglucose, but not that of ascorbate. A half-maximal effect on DHAA uptake was observed with approximately 100 pM insulin, whereas insulin-like growth factor I (IGF-I) was less potent. Preincubation with insulin for 6-12 h was required for stimulation, similar to the period needed for increased expression of facilitative hexose transporters (GLUT). DHAA uptake was inhibited by the GLUT antagonist cytochalasin B as well as by the GLUT substrates D-glucose and 2-deoxyglucose, whereas L-glucose and fructose had no effect. We conclude that insulin and IGF-I stimulate osteoblastic uptake of DHAA through facilitative hexose transporters. The relative potency of insulin in stimulating DHAA uptake is consistent with mediation by insulin receptors. DHAA is reduced to ascorbate within osteoblasts, maintaining a high intracellular concentration of ascorbate available for collagen synthesis. Impaired uptake of DHAA may contribute to the osteopenia associated with type I diabetes. In addition, cytotoxic levels of DHAA may accumulate in the extracellular fluid due to decreased transport activity and competitive inhibition by elevated concentrations of glucose.
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PMID:Insulin stimulates vitamin C recycling and ascorbate accumulation in osteoblastic cells. 942 97

Succinic acid esters are currently under investigation as possible insulinotropic tools in the treatment of noninsulin-dependent diabetes mellitus. The present article introduces three novel nutrient esters and aims mainly to explore, in both normal and GK rats, the secretory response to such esters when tested alone or in combination. It documents that in pancreatic islets from normal rats, methyl acetate (10 mM), which fails to augment basal insulin output, potentiates the secretory response to succinate dimethyl ester (also 10 mM). It also reveals that alpha-D-glucose pentaacetate (alpha GPA) (1.7 mM) stimulates insulin release in the absence of any other exogenous nutrient and even more so in the presence of succinate methyl ester. Moreover, the methyl esters of succinic acid (10 mM), when used together with either methyl acetate or alpha GPA, provoked insulin secretion in islets from diabetic GK rats incubated in the absence of D-glucose, although no significant secretory response of such islets could be detected when each of these agents was tested separately. These findings thus draw attention to the insulinotropic potential in type 2 diabetes of selected combinations of nutrient esters, including a D-glucose ester presumably able to enter into islet cells without requiring the intervention of a hexose carrier.
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PMID:Synergistic insulinotropic action of succinate, acetate, and glucose esters in islets from normal and diabetic rats. 954 40


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