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| 2. |
- Gustavsson, Johanna, 1956-
(författare)
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Insulin control of glucose transport in caveolae microdomains of the plasma membrane
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Caveolae are invaginated, dynamic microdomains in the plasma membrane and believed to be involved in receptor-mediated uptake of small molecules (potocytosis) and in signal transduction. A phosphatidylinositol glycan, a precursor of potential insulin second messengers, has been found to be enriched in the caveolae-fraction of adipocyte plasma membranes (Parpal et al., 1995, J Cell Biol 131:125-135). We now demonstrate that the insulin receptor is localized to caveolae microdomains. This was investigated in i) 3T3-Ll adipocyte plasma membranes by a morphological method (double immunofluorescence labeling and contbcal microscopy) and in ii) caveolae isolated by a biochemical, detergent-free method. The insulin receptor was enriched in caveolae and, in response to insulin, phosphorylated on tyrosine which indicated that the insulin receptor was active.Insulin stimulates the translocation of glUcose transporter protcins from intracellular stores to the plasma membrane which leads to an increased glucose uptake. Long-chain 1 ,2-diacylgiycerol, one of two potential second messengers for insulin, has been found to stimulate glucose uptake in rat adipocytes (Stn\1fors, 1988, Nature, 335:554-556). Here, we report that long-chain 1,2-diacylglycerol, emulsified in taurodeoxycholate, stimulates the translocation of GLUT4 to the plasma membrane. Moreover, physiological long-chain 1,2~diacylglycerols are taken up by different cell types in amounts sufficient to have biological eftects, equally well in the absence or presence of taurodeoxycholate.We also report that a rapid translocation of GLUT4 to the plasma membrane was followed by a slower transition of GLUT4 into caveolae. Accumulation of GLUT4 in caveolae coincided with the insulin-stimulated increase in glucose uptake. This offers a mechanistic explanation for the observed discrepancy between the appearance of GLUT4 in the plasma membrane and the delayed increase in glucose uptake.Non-hydrolyzable GTP-analogs stimulate the translocation of GLUT4 and increase glucose uptake in permeabilized cells. The small GTP·binding protein RaM is suggested to be involved in these processes since Rab4 has been localized to GLUT4-containing vesicles and is redistributed in response to insulin. We found that Rab4 is enriched in caveolae and that the amount of Rab4 increased in caveolae, in the same extent a<> GLUT4 did, in re!.J)Onse to insulin.Caveolae are characterized by high levels of sphingolipids and cholesterol. Depletion of cholesterol, which disrupts the integrity of caveolae, abolished insulin-stimulated glucose uptake reversibly. Insulin's control of protein pho.<:phorylation was also abolished while j3-adrenergic signaling was unaffected.The results suggest that caveolae are crucial Jor insulin-signuling in adipocytes and a disruption of these structures may have consequences for the development of insulin re.~istance and diabetes mellitus.
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- Hellerström, Claes, et al.
(författare)
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Diabetes
- 2002
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Bok (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Henriksson, Jan, et al.
(författare)
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Per-Olof Åstrand : Nekrolog
- 2015
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Annan publikation (populärvet., debatt m.m.)abstract
- Nekrolog över Per-Olof ÅstrandProfessor emeritus Per-Olof Åstrand har avlidit i en ålder av 92 år. Hans närmaste anhöriga är makan Irma och barnen Elin och Per med familjer.Per-Olof Åstrand föddes i Bredaryd i Småland den 21 oktober 1922, och avled den 2 januari 2015 i Näsby Park norr om Stockholm. Efter värnplikt och beredskapstjänstgöring i pansartrupperna under andra världskriget kom han 1944 till Kungl. Gymnastiska Centralinstitutet (GCI/GIH) för studier till gymnastiklärare. Vid sluttentamen i fysiologi var hans svar så avancerade att den ansvarige läraren bad professorn, Erik Hohwü Christensen, att rätta dem. Kort därefter fick GCI:s fysiologiska institution en ny amanuens.Efter gymnastikdirektörsexamen 1946 följde läkarstudier, och parallellt med dessa inleddes avhandlingsarbetet ”Experimental studies of physical working capacity in relation to sex and age”, som försvarades 1952. Genom detta utvecklades en metodik för att mäta maximal syreupptagning. Det blev en avgörande variabel att relatera till i hans senare forskning om den cirkulatoriska och respiratoriska anpassningen till fysiskt arbete och träning. Det submaximala konditionstest som P.-O., och hans blivande hustru Irma Ryhming, publicerade år 1954 bidrog till att göra GCI känt över världen. Det finns fog att benämna honom som ”den vetenskapligt baserade konditionsträningens fader”. 1970 blev han professor i kroppsövningarnas fysiologi vid GIH.P.-O. visade tidigt ett stort intresse för undervisning, och många mötte honom i populärvetenskapliga skrifter såsom ”Kondition och hälsa” och ”Bättre kondition”, men det var genom den omfattande läroboken ”Textbook of Work Physiology: Physiological Bases for Exercise”, skriven tillsammans med Kaare Rodahl, som han blev det riktigt stora namnet inom internationell arbetsfysiologi. Där framträdde holisten Åstrand med en bredd och ett djup som ingen förr hade fångat och skrivit fram. Denna bok, P.-O:s pedagogiska förmåga och engagemang har haft avgörande betydelse för många studenter och kolleger.Hans gärningar gjorde honom till ledamot i många lärda sällskap och hedersdoktor vid ett antal universitet ute i världen. Därtill var han en hedersman, med en personlighet präglad av en stor omtanke, slagkraftig humor och generös spiritualitet, ofta med inslag av en särpräglad musikalisk förmåga. För oss som studenter och lärare vid GIH kom samvaron med P.-O. ofta att formas till högtidsstunder. En legendar har nu lämnat oss i djupaste sorg, men också i tacksamhet över allt han bidrog med i våra liv.Jan HenrikssonHans RosdahlPeter SchantzHarriet Wallberg
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| 5. |
- Krämer, David Kitz, et al.
(författare)
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Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor delta
- 2005
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Ingår i: Diabetes. - Alexandria, USA : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:4, s. 1157-1163
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Tidskriftsartikel (refereegranskat)abstract
- Activators of peroxisome proliferator-activated receptor (PPAR)gamma have been studied intensively for their insulin-sensitizing properties and antidiabetic effects. Recently, a specific PPARdelta activator (GW501516) was reported to attenuate plasma glucose and insulin levels when administered to genetically obese ob/ob mice. This study was performed to determine whether specific activation of PPARdelta has direct effects on insulin action in skeletal muscle. Specific activation of PPARdelta using two pharmacological agonists (GW501516 and GW0742) increased glucose uptake independently of insulin in differentiated C2C12 myotubes. In cultured primary human skeletal myotubes, GW501516 increased glucose uptake independently of insulin and enhanced subsequent insulin stimulation. PPARdelta agonists increased the respective phosphorylation and expression of AMP-activated protein kinase 1.9-fold (P < 0.05) and 1.8-fold (P < 0.05), of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) 2.2-fold (P < 0.05) and 1.7-fold (P < 0.05), and of p38 MAPK 1.2-fold (P < 0.05) and 1.4-fold (P < 0.05). Basal and insulin-stimulated protein kinase B/Akt was unaltered in cells preexposed to PPARdelta agonists. Preincubation of myotubes with the p38 MAPK inhibitor SB203580 reduced insulin- and PPARdelta-mediated increase in glucose uptake, whereas the mitogen-activated protein kinase kinase inhibitor PD98059 was without effect. PPARdelta agonists reduced mRNA expression of PPARdelta, sterol regulatory element binding protein (SREBP)-1a, and SREBP-1c (P < 0.05). In contrast, mRNA expression of PPARgamma, PPARgamma coactivator 1, GLUT1, and GLUT4 was unaltered. Our results provide evidence to suggest that PPARdelta agonists increase glucose metabolism and promote gene regulatory responses in cultured human skeletal muscle. Moreover, we provide biological validation of PPARdelta as a potential target for antidiabetic therapy.
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| 6. |
- Pillon, Nicolas J., et al.
(författare)
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Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes
- 2022
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Ingår i: Science Advances. - : NLM (Medline). - 2375-2548. ; 8:36
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Tidskriftsartikel (refereegranskat)abstract
- Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines (exerkines) on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells. These exercise effects were potentiated in type 2 diabetes. In response to contraction or hypoxia, cytokines were mainly produced by endothelial cells and macrophages. The chemokine CXCL12 was induced by hypoxia in endothelial cells, as well as by conditioned medium from contracted myotubes in macrophages. We found that CXCL12 was associated with skeletal muscle remodeling after exercise and differentiation of cultured muscle. Collectively, acute aerobic exercise mounts a noncanonical inflammatory response, with an atypical production of exerkines, which is potentiated in type 2 diabetes.
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| 7. |
- Tsuchida, Hiroki, et al.
(författare)
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Gene expression of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in skeletal muscle from type 2 diabetic subjects.
- 2002
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Ingår i: Pflügers Archiv. - : Springer Science and Business Media LLC. - 0031-6768 .- 1432-2013. ; 445:1, s. 25-31
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Tidskriftsartikel (refereegranskat)abstract
- The gene of the p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase gives rise to several splice variants. We hypothesized that the expression of p85alpha splice variants may be altered in skeletal muscle from subjects with type 2 diabetes mellitus. Skeletal muscle biopsies were obtained from nine type 2 diabetic and eight healthy men, matched for age, body mass index (BMI) and physical fitness. PI 3-kinase activity in skeletal muscle following in vitro insulin stimulation was reduced in subjects with type 2 diabetes. p85alpha mRNA was elevated fourfold in type 2 diabetic as compared to healthy control subjects ( P<0.05). p85alpha mRNA abundance was positively correlated with plasma insulin concentration ( P<0.01) and serum glucose concentration ( P<0.01). Despite this, protein levels of p85alpha, p55alpha, and the novel human p50alpha were not altered in type 2 diabetic subjects. Thus, although gene expression of full-length p85alpha is increased in skeletal muscle from type 2 diabetics, this is not reflected by increased protein levels. Therefore, defects in PI 3-kinase activity are likely due to impaired activation of the enzyme rather than changes in protein expression of the isoforms of the regulatory subunit.
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