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Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
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2002 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 16, no 2, 249-251 p.Article in journal (Refereed) Published
Abstract [en]

Insulin-stimulated glucose uptake in muscle and adipose tissue is the result of translocation of insulin-regulated glucose transporters (GLUT4) from intracellular vesicles to the plasma membrane. Here we report that GLUT4 in the plasma membrane of 3T3-L1 adipocytes were located predominantly in caveolae invaginations: by immunogold electron microscopy of plasma membranes, 88% of GLUT4 were localized to caveolae structures and this distribution within the plasma membrane was not affected by insulin. By immunofluorescence microscopy, a major part of GLUT 4 was colocalized with caveolin. The total amount of GLUT4 in the plasma membrane increased 2.2-fold in response to insulin as determined by immunogold electron or immunofluorescence microscopy. GLUT4 were enriched in caveolae fractions isolated without detergents from plasma membranes of rat adipocytes. In these fractions, GLUT4 were largely confined to caveolin-containing membranes of the caveolae preparation isolated from insulin-stimulated cells, determined by electron microscopy. Insulin increased the amount of GLUT4 2.7-fold in this caveolae fraction. Caveolae were purified further by immunoisolation with antibodies against caveolin. The amount of GLUT4 increased to the same extent in the immunopurified caveolae as in the cruder caveolae fractions from insulin-stimulated cells. We conclude that insulin induces translocation of GLUT4 to caveolae.

Place, publisher, year, edition, pages
2002. Vol. 16, no 2, 249-251 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25037DOI: 10.1096/fj.01-0646fjeLocal ID: 9461OAI: oai:DiVA.org:liu-25037DiVA: diva2:245363
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-25Bibliographically approved
In thesis
1. Caveolae in insulin signalling in human and rat adipocytes
Open this publication in new window or tab >>Caveolae in insulin signalling in human and rat adipocytes
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pancreatic hormone insulin is a key hormone in maintenance of metabolic homeostasis but it also exerts control on gene expression and cell growth. This thesis presents results on fhe role of caveolae in insulin signalling in human and rat adipocytes. Caveolae are invaginations of the plasma membrane, characterised by the structural protein caveolin. Caveolae and caveolin have been implicated in a variety of functions, like uptake of molecular cargo into the cell, cholesterol transport and signal transduction. After isolation of caveolae and using electron microscopy on cell membranes, the insulin receptor was demonstrated to be localised in caveolae of human adipocytes. We also used biochemical and morphological methods to show that the glucose transporter GLUT4 was translocated to caveolae in response to insulin in rat adipocytes, indicating fhat the caveola is the locale for glucose uptake in adipocytes.

Adipocytes fhat were depleted of cholesterol using ß-cyclodextrin lacked caveolae invaginations. In cells fhus depleted of cholesterol and caveolae, fhe insulin receptor itself was not affected, but insulin signalling to metabolic control was inhibited. In rat adipocytes, insulin signalling to mitogenic control was not affected. In human fat cells, however, insulin's mitogenic signalling was dependent on caveolae/cholesterol. In contrast to other cells studied, including rat adipocytes, where the insulin receptor substrate (IRS-1) is mainly cytosolic, in human adipocytes IRS-1 was found in the plasma membrane and in caveolae. These results show the importance of choosing the relevant system to work with, since there are clear species differences.

We performed an analysis of the lipid composition of purified caveolae from rat adipocytes. As expected, cholesterol constitutes a major part of caveolae, but there is also an enrichment of sphingomyelin and the gangliosides GM1, GM3, GD3 and GD1a, while there is less protein, compared to the surrounding plasma membrane.

Taken together, caveolae appear as hnbs for insulin signalling. Caveolae seem necessary for fhe maintenance of metabolic signalling, like glucose uptake, and defects in caveolae may thus be the cause of insulin resistance.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 54 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 782
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25673 (URN)10049 (Local ID)91-7373-539-6 (ISBN)10049 (Archive number)10049 (OAI)
Public defence
2003-04-11, Berzeliussalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-09Bibliographically approved
2. Caveolae structure and importance in insulin action
Open this publication in new window or tab >>Caveolae structure and importance in insulin action
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type II diabetes is a disease characterized by chronic hyperglycaemia and abnormalities in lipid metabolism that affects approximately 5% of the population in the Western World. Caveolae are invaginations of the plasma membrane, described as 25-150 nm omega shaped structures, which are enriched in cholesterol, sphingolipids and the constituent protein caveolin. Caveolae have been shown to be involved in signal transduction, uptake over the plasma membrane and intracellular transport. By electron microscopy studies of cell membranes and biochemical analyses of isolated caveolae, we report that in rat adipocytes glucose transporter GLUT4 was translocated to caveolae in response to insulin. Insulin stimulation increased the amount of GLUT4 in the plasma membrane, but the ratio between GLUT4 in the planar and caveolae membrane remained constant. These findings indicate that caveolae are the locales for glucose uptake in the cell. We also report that the insulin receptor, independently of insulin stimulation, was localised in caveolae in human adipocytes. In these cells depletion of cholesterol destroyed the caveolae structure and the adipocytes became insulin resistant. Cholesterol depletion did not affect the insulinstimulated autophosphorylation of the insulin receptor nor the phosphorylation of the downstream IRS1. Further signalling to metabolic control or mitogenic control was inhibited, however. With transmission electron-, scanning electron- and fluorescence-microscopic techniques, we studied the ultrastructure and distribution of caveolae in the rat adipocyte. We found that caveolae can be divided into two subpopulations, small (<50 nm) and large (50-150 nm). The large caveolae are connected to the extracellular space via narrow necks and the orifices of caveolae were herein shown in primary adipocytes for the first time. Caveolin is located in the membrane proximal part of the small caveolae and to the neck in the large caveolae. The insulin receptor substrate IRS 1 was shown to be localized to caveolae in human adipocytes and to colocalize with the insulin receptor. In rat adipocytes, however, IRS1 was not localized to the plasma membrane in the absence of insulin stimulation. By transfection of rat adipocytes with human IRS1 we found that human IRS1 bound to the plasma membrane in the rat adipocyte, whereas the endogenous rat IRS1 did not. Taken together, caveolae seem to be closely involved in regulation of insulin action in the adipocyte.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 53 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 875
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24065 (URN)3624 (Local ID)91-7373-851-4 (ISBN)3624 (Archive number)3624 (OAI)
Public defence
2004-12-10, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-25Bibliographically approved

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Karlsson, MargaretaThorn, HansStrålfors, PeterGustavsson, Johanna

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