nach oben

Diabetologia

Erschienen in:

01.12.2005 | Article

Insulin signalling downstream of protein kinase B is potentiated by 5′AMP-activated protein kinase in rat hearts in vivo

verfasst von: S. L. Longnus, C. Ségalen, J. Giudicelli, M. P. Sajan, R. V. Farese, E. Van Obberghen

Erschienen in: Diabetologia | Ausgabe 12/2005

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

5′AMP-activated protein kinase (AMPK) and insulin stimulate glucose transport in heart and muscle. AMPK acts in an additive manner with insulin to increase glucose uptake, thereby suggesting that AMPK activation may be a useful strategy for ameliorating glucose uptake, especially in cases of insulin resistance. In order to characterise interactions between the insulin- and AMPK-signalling pathways, we investigated the effects of AMPK activation on insulin signalling in the rat heart in vivo.

Methods

Male rats (350–400 g) were injected with 1 g/kg 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or 250 mg/kg metformin in order to activate AMPK. Rats were administered insulin 30 min later and after another 30 min their hearts were removed. The activities and phosphorylation levels of components of the insulin-signalling pathway were subsequently analysed in individual rat hearts.

Results

AICAR and metformin administration activated AMPK and enhanced insulin signalling downstream of protein kinase B in rat hearts in vivo. Insulin-induced phosphorylation of glycogen synthase kinase 3 (GSK3) β, p70 S6 kinase (p70^S6K)(Thr389) and IRS1(Ser636/639) were significantly increased following AMPK activation. To the best of our knowledge, this is the first report of heightened insulin responses of GSK3β and p70^S6K following AMPK activation. In addition, we found that AMPK inhibits insulin stimulation of IRS1-associated phosphatidylinositol 3-kinase activity, and that AMPK activates atypical protein kinase C and extracellular signal-regulated kinase in the heart.

Conclusions/interpretations

Our data are indicative of differential effects of AMPK on the activation of components in the cardiac insulin-signalling pathway. These intriguing observations are critical for characterisation of the crosstalk between AMPK and insulin signalling.

Hardie DG, Carling D, Carlson M (1998) The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem 67:821–855CrossRefPubMed

Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuck GD (1995) High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 270:17513–17520CrossRefPubMed

Russell RR 3rd, Bergeron R, Shulman GI, Young LH (1999) Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol 277:H643–H649PubMed

Marsin AS, Bertrand L, Rider MH et al (2000) Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 10:1247–1255CrossRefPubMed

Sambandam N, Lopaschuk GD (2003) AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog Lipid Res 42:238–256CrossRefPubMed

Russell RR 3rd, Li J, Coven DL et al (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503CrossRefPubMed

Xing Y, Musi N, Fujii N et al (2003) Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem 278:28372–28377CrossRefPubMed

Russell RR 3rd (2003) The role of AMP-activated protein kinase in fuel selection by the stressed heart. Curr Hypertens Rep 5:459–465PubMedCrossRef

Cohen P, Frame S (2001) The renaissance of GSK3. Nat Rev Mol Cell Biol 2:769–776CrossRefPubMed

10.

Merrill GF, Kurth EJ, Hardie DG, Winder WW (1997) AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 273:E1107–E1112PubMed

11.

Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ (1998) Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47:1369–1373PubMedCrossRef

12.

Bergeron R, Russell RR 3rd, Young LH et al (1999) Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol 276:E938–E944PubMed

13.

Chen HC, Bandyopadhyay G, Sajan MP et al (2002) Activation of the ERK pathway and atypical protein kinase C isoforms in exercise- and aminoimidazole-4-carboxamide-1-beta-d-riboside (AICAR)-stimulated glucose transport. J Biol Chem 277:23554–23562CrossRefPubMed

14.

Li J, Hu X, Selvakumar P et al (2004) Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol Endocrinol Metab 287:E834–E841CrossRefPubMed

15.

Fryer LG, Foufelle F, Barnes K, Baldwin SA, Woods A, Carling D (2002) Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells. Biochem J 363:167–174CrossRefPubMed

16.

Fisher JS, Gao J, Han DH, Holloszy JO, Nolte LA (2002) Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab 282:E18–E23PubMed

17.

Jessen N, Pold R, Buhl ES, Jensen LS, Schmitz O, Lund S (2003) Effects of AICAR and Exercise on Insulin-stimulated glucose uptake, insulin signaling and GLUT4 content in rat skeletal muscles. J Appl Physiol 94:1373–1379PubMed

18.

Jakobsen SN, Hardie DG, Morrice N, Tornqvist HE (2001) 5′-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. J Biol Chem 276:46912–46916CrossRefPubMed

19.

Borst SE, Snellen HG, Lai HL (2000) Metformin treatment enhances insulin-stimulated glucose transport in skeletal muscle of Sprague-Dawley rats. Life Sci 67:165–174CrossRefPubMed

20.

Kim YB, Ciaraldi TP, Kong A et al (2002) Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110beta protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes 51:443–448PubMedCrossRef

21.

Karlsson HK, Hallsten K, Bjornholm M et al (2005) Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. Diabetes 54:1459–1467PubMedCrossRef

22.

Galuska D, Nolte LA, Zierath JR, Wallberg-Henriksson H (1994) Effect of metformin on insulin-stimulated glucose transport in isolated skeletal muscle obtained from patients with NIDDM. Diabetologia 37:826–832PubMedCrossRef

23.

Shen Q, Cline GW, Shulman GI, Leibowitz MD, Davies PJ (2004) Effects of rexinoids on glucose transport and insulin-mediated signaling in skeletal muscles of diabetic (db/db) mice. J Biol Chem 279:19721–19731CrossRefPubMed

24.

Miyazaki Y, He H, Mandarino LJ, DeFronzo RA (2003) Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes 52:1943–1950PubMedCrossRef

25.

Jiang G, Dallas-Yang Q, Li Z et al (2002) Potentiation of insulin signaling in tissues of Zucker obese rats after acute and long-term treatment with PPARgamma agonists. Diabetes 51:2412–2419PubMedCrossRef

26.

Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590CrossRefPubMed

27.

Tee AR, Blenis J (2005) mTOR, translational control and human disease. Semin Cell Dev Biol 16:29–37CrossRefPubMed

28.

Gamble J, Lopaschuk GD, Makinde AO et al (1997) Insulin inhibition of 5' adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism 46:1270–1274CrossRefPubMed

29.

Beauloye C, Marsin AS, Bertrand L et al (2001) Insulin antagonizes AMP-activated protein kinase activation by ischemia or anoxia in rat hearts, without affecting total adenine nucleotides. FEBS Lett 505:348–352CrossRefPubMed

30.

Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR (2003) Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278:39422–39427CrossRefPubMed

31.

Zou MH, Kirkpatrick SS, Davies BJ et al (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem 279:43940–43951CrossRefPubMed

32.

Iglesias MA, Furler SM, Cooney GJ, Kraegen EW, Ye JM (2004) AMP-activated protein kinase activation by AICAR increases both muscle fatty acid and glucose uptake in white muscle of insulin-resistant rats in vivo. Diabetes 53:1649–1654PubMedCrossRef

33.

Buhl ES, Jessen N, Pold R et al (2002) Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 51:2199–2206PubMedCrossRef

34.

Halseth AE, Ensor NJ, White TA, Ross SA, Gulve EA (2002) Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. Biochem Biophys Res Commun 294:798–805CrossRefPubMed

35.

Giorgino F, Logoluso F, Davalli AM et al (1999) Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats. Diabetes 48:801–812PubMedCrossRef

36.

Fujitaki JM, Sandoval TM, Lembach LA, Dixon R (1994) Spectrophotometric determination of acadesine (AICA-riboside) in plasma using a diazotization coupling technique with N-(1-naphthyl)ethylenediamine. J Biochem Biophys Methods 29:143–148CrossRefPubMed

37.

Shioi T, McMullen JR, Kang PM et al (2002) Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 22:2799–2809CrossRefPubMed

38.

Wojtaszewski JF, Jorgensen SB, Hellsten Y, Hardie DG, Richter EA (2002) Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. Diabetes 51:284–292PubMedCrossRef

39.

Wojtaszewski JF, Nielsen P, Hansen BF, Richter EA, Kiens B (2000) Isoform-specific and exercise intensity-dependent activation of 5′-AMP-activated protein kinase in human skeletal muscle. J Physiol 528:221–226CrossRefPubMed

40.

Rocchi S, Tartare-Deckert S, Mothe I, Van Obberghen E (1995) Identification by mutation of the tyrosine residues in the insulin receptor substrate-1 affecting association with the tyrosine phosphatase 2C and phosphatidylinositol 3-kinase. Endocrinology 136:5291–5297PubMedCrossRef

41.

Miura A, Sajan MP, Standaert ML et al (2003) Cbl PYXXM motifs activate the P85 subunit of phosphatidylinositol 3-kinase, Crk, atypical protein kinase C, and glucose transport during thiazolidinedione action in 3T3/L1 and human adipocytes. Biochemistry 42:14335–14341CrossRefPubMed

42.

Bergeron R, Previs SF, Cline GW et al (2001) Effect of 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50:1076–1082PubMedCrossRef

43.

Carlson CL, Winder WW (1999) Liver AMP-activated protein kinase and acetyl-CoA carboxylase during and after exercise. J Appl Physiol 86:660–674

44.

McCrimmon RJ, Evans ML, Jacob RJ et al (2002) AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat. Am J Physiol Endocrinol Metab 283:E1076–E1083PubMed

45.

Shearer J, Fueger PT, Rottman JN, Bracy DP, Martin PH, Wasserman DH (2004) AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo. Am J Physiol Endocrinol Metab 287:E871–E877CrossRefPubMed

46.

Musi N, Hirshman MF, Nygren J et al (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51:2074–2081PubMedCrossRef

47.

Miles JM, Wooldridge D, Grellner WJ et al (2003) Nocturnal and postprandial free fatty acid kinetics in normal and type 2 diabetic subjects: effects of insulin sensitization therapy. Diabetes 52:675–681PubMedCrossRef

48.

Ye JM, Dzamko N, Cleasby ME et al (2004) Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 47:1306–1313CrossRefPubMed

49.

Vahl TP, Ulrich-Lai YM, Ostrander MM et al (2005) Comparative analysis of ACTH and corticosterone sampling methods in rats. Am J Physiol Endocrinol Metab 289:E823–E828CrossRefPubMed

50.

McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS (2004) Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53:1953–1958PubMedCrossRef

51.

Laviola L, Belsanti G, Davalli AM et al (2001) Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. Diabetes 50:2709–2720PubMedCrossRef

52.

Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95:1432–1437CrossRefPubMed

53.

Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K (1999) Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem 274:34493–34498CrossRefPubMed

54.

Soltys CL, Buchholz L, Gandhi M, Clanachan AS, Walsh K, Dyck JR (2002) Phosphorylation of cardiac protein kinase B is regulated by palmitate. Am J Physiol Heart Circ Physiol 283:H1056–H1064PubMed

55.

Wang L, Gout I, Proud CG (2001) Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes. J Biol Chem 276:32670–32677CrossRefPubMed

56.

Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22:6247–6260CrossRefPubMed

57.

Sarbassov DD, Guertin DA, Ali SM, Sabatina DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101CrossRefPubMed

58.

Alessi DR, Andjelkovic M, Caudwell B et al (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551PubMed

59.

Gao T, Furnari F, Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18:13–24CrossRefPubMed

60.

Nadler ST, Stoehr JP, Rabaglia ME, Schueler KL, Birnbaum MJ, Attie AD (2001) Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice. Am J Physiol Endocrinol Metab 281:E1249–E1254PubMed

61.

Lima MH, Ueno M, Thirone AC, Rocha EM, Carvalho CR, Saad MJ (2002) Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. Endocrine 18:1–12PubMedCrossRef

62.

Chan AY, Soltys CL, Young ME, Proud CG, Dyck JR (2004) Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J Biol Chem 279:32771–32779CrossRefPubMed

63.

Cheng SW, Fryer LG, Carling D, Shepherd PR (2004) Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. J Biol Chem 279:15719–15722CrossRefPubMed

64.

Horman S, Beauloye C, Vertommen D, Vanoverschelde JL, Hue L, Rider MH (2003) Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2. J Biol Chem 278:41970–41976CrossRefPubMed

65.

Kimura N, Tokunaga C, Dalal S et al (2003) A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8:65–79CrossRefPubMed

66.

Krause U, Bertrand L, Hue L (2002) Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. Eur J Biochem 269:3751–3759PubMedCrossRef

67.

Iijima Y, Laser M, Shiraishi H et al (2002) c-Raf/MEK/ERK pathway controls protein kinase C-mediated p70S6K activation in adult cardiac muscle cells. J Biol Chem 277:23065–23075CrossRefPubMed

68.

Wang L, Proud CG (2002) Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes. Circ Res 91:821–829CrossRefPubMed

69.

Akimoto K, Nakaya M, Yamanaka T et al (1998) Atypical protein kinase Clambda binds and regulates p70 S6 kinase. Biochem J 335:417–424PubMed

70.

Romanelli A, Martin KA, Toker A, Blenis J (1999) p70 S6 kinase is regulated by protein kinase Czeta and participates in a phosphoinositide 3-kinase-regulated signalling complex. Mol Cell Biol 19:2921–2928PubMed

71.

Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ, Avruch J (1998) Regulation of the p70 S6 kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J Biol Chem 273:16621–16629CrossRefPubMed

72.

Rolfe M, McLeod LE, Pratt PF, Proud CG (2005) Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). Biochem J 388:973–984CrossRefPubMed

73.

Bandyopadhyay G, Standaert ML, Sajan MP et al (1999) Dependence of insulin-stimulated glucose transporter 4 translocation on 3-phosphoinositide-dependent protein kinase-1 and its target threonine-410 in the activation loop of protein kinase C-zeta. Mol Endocrinol 13:1766–1772PubMedCrossRef

74.

Ravichandran LV, Esposito DL, Chen J, Quon MJ (2001) Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin. J Biol Chem 276:3543–3549CrossRefPubMed

75.

Liu YF, Paz K, Herschkovitz A et al (2001) Insulin stimulates PKCzeta-mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins. J Biol Chem 276:14459–14465PubMed

76.

De Fea K, Roth RA (1997) Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase. J Biol Chem 272:31400–31406CrossRefPubMed

77.

Qiao LY, Zhande R, Jetton TL, Zhou G, Sun XJ (2002) In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents. J Biol Chem 277:26530–26539CrossRefPubMed

78.

Ozes ON, Akca H, Mayo LD et al (2001) A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci USA 98:4640–4645CrossRefPubMed

Titel: Insulin signalling downstream of protein kinase B is potentiated by 5′AMP-activated protein kinase in rat hearts in vivo
verfasst von: S. L. Longnus
C. Ségalen
J. Giudicelli
M. P. Sajan
R. V. Farese
E. Van Obberghen
Publikationsdatum: 01.12.2005
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 12/2005
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-005-0016-3

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

19.04.2024 | Vorhofflimmern | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Insulin signalling downstream of protein kinase B is potentiated by 5′AMP-activated protein kinase in rat hearts in vivo

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretations

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Update Innere Medizin

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretations

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2005

Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS)

G.B. Morgagni Prizes 2006

High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NFκB

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Update Innere Medizin