nach oben

Reviews in Endocrine and Metabolic Disorders

Erschienen in:

01.03.2013

Role of insulin resistance in endothelial dysfunction

verfasst von: Ranganath Muniyappa, James R. Sowers

Erschienen in: Reviews in Endocrine and Metabolic Disorders | Ausgabe 1/2013

Einloggen, um Zugang zu erhalten

Abstract

Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.

DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14(3):173–94.PubMedCrossRef

Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(31):12587–94.PubMedCrossRef

Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113(6):898–918.PubMedCrossRef

Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev. 2007;28(5):463–91.PubMedCrossRef

Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, et al. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes. 2004;53(6):1418–23.PubMedCrossRef

Baron AD, Laakso M, Brechtel G, Edelman SV. Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J Clin Endocrinol Metab. 1991;73(3):637–43.PubMedCrossRef

Natali A, Taddei S, Quinones Galvan A, Camastra S, Baldi S, Frascerra S, et al. Insulin sensitivity, vascular reactivity, and clamp-induced vasodilatation in essential hypertension. Circulation. 1997;96(3):849–55.PubMedCrossRef

Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113(15):1888–904.PubMedCrossRef

Barac A, Campia U, Panza JA. Methods for evaluating endothelial function in humans. Hypertension. 2007;49(4):748–60.PubMedCrossRef

10.

Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest. 1996;98(4):894–8.PubMedCrossRef

11.

Dudzinski DM, Michel T. Life history of eNOS: partners and pathways. Cardiovasc Res. 2007;75(2):247–60.PubMedCrossRef

12.

Herman AG, Moncada S. Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis. Eur Heart J. 2005;26(19):1945–55.PubMedCrossRef

13.

Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23(2):168–75.PubMedCrossRef

14.

Muris DM, Houben AJ, Schram MT, Stehouwer CD. Microvascular dysfunction is associated with a higher incidence of type 2 diabetes mellitus–brief report: a systematic review and meta-analysis. Arterioscler Thromb Vasc Biol. 2012.

15.

Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008;117(19):2467–74.PubMedCrossRef

16.

Bonetti PO, Pumper GM, Higano ST, Holmes Jr DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004;44(11):2137–41.PubMedCrossRef

17.

Prior JO, Quinones MJ, Hernandez-Pampaloni M, Facta AD, Schindler TH, Sayre JW, et al. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation. 2005;111(18):2291–8.PubMedCrossRef

18.

Muniyappa R, Hall G, Kolodziej TL, Karne RJ, Crandon SK, Quon MJ. Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension. Am J Clin Nutr. 2008;88(6):1685–96.PubMedCrossRef

19.

Ketel IJ, Stehouwer CD, Serne EH, Korsen TJ, Hompes PG, Smulders YM, et al. Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance. J Clin Endocrinol Metab. 2008;93(9):3365–72.PubMedCrossRef

20.

Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest. 2009;119(2):315–22.PubMed

21.

Lteif A, Vaishnava P, Baron AD, Mather KJ. Endothelin limits insulin action in obese/insulin-resistant humans. Diabetes. 2007;56(3):728–34.PubMedCrossRef

22.

Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr Diab Rep. 2003;3(4):279–88.PubMedCrossRef

23.

Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol. 2005;289(2):H813–22.PubMedCrossRef

24.

Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, et al. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem. 2002;277(3):1794–9.PubMedCrossRef

25.

Mukai Y, Wang CY, Rikitake Y, Liao JK. Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells. Am J Physiol Heart Circ Physiol. 2007;292(4):H1937–42.PubMedCrossRef

26.

Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999;104(4):447–57.PubMedCrossRef

27.

Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, et al. The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest. 2003;111(9):1373–80.PubMed

28.

Duncan ER, Crossey PA, Walker S, Anilkumar N, Poston L, Douglas G, et al. Effect of endothelium-specific insulin resistance on endothelial function in vivo. Diabetes. 2008;57(12):3307–14.PubMedCrossRef

29.

Wheatcroft SB, Shah AM, Li JM, Duncan E, Noronha BT, Crossey PA, et al. Preserved glucoregulation but attenuation of the vascular actions of insulin in mice heterozygous for knockout of the insulin receptor. Diabetes. 2004;53(10):2645–52.PubMedCrossRef

30.

Kubota T, Kubota N, Moroi M, Terauchi Y, Kobayashi T, Kamata K, et al. Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury. Circulation. 2003;107(24):3073–80.PubMedCrossRef

31.

Fernandez-Hernando C, Ackah E, Yu J, Suarez Y, Murata T, Iwakiri Y, et al. Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Cell Metab. 2007;6(6):446–57.PubMedCrossRef

32.

Perticone F, Sciacqua A, Scozzafava A, Ventura G, Laratta E, Pujia A, et al. Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene. J Clin Endocrinol Metab. 2004;89(7):3606–9.PubMedCrossRef

33.

Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, et al. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004;109(3):399–405.PubMedCrossRef

34.

Okon EB, Chung AW, Rauniyar P, Padilla E, Tejerina T, McManus BM, et al. Compromised arterial function in human type 2 diabetic patients. Diabetes. 2005;54(8):2415–23.PubMedCrossRef

35.

Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett Jr JC. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991;325(14):997–1001.PubMedCrossRef

36.

Shemyakin A, Bohm F, Wagner H, Efendic S, Bavenholm P, Pernow J. Enhanced endothelium-dependent vasodilatation by dual endothelin receptor blockade in individuals with insulin resistance. J Cardiovasc Pharmacol. 2006;47(3):385–90.PubMed

37.

Mather KJ, Mirzamohammadi B, Lteif A, Steinberg HO, Baron AD. Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes. Diabetes. 2002;51(12):3517–23.PubMedCrossRef

38.

Cardillo C, Campia U, Kilcoyne CM, Bryant MB, Panza JA. Improved endothelium-dependent vasodilation after blockade of endothelin receptors in patients with essential hypertension. Circulation. 2002;105(4):452–6.PubMedCrossRef

39.

Cardillo C, Campia U, Iantorno M, Panza JA. Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension. 2004;43(1):36–40.PubMedCrossRef

40.

Cardillo C, Campia U, Bryant MB, Panza JA. Increased activity of endogenous endothelin in patients with type II diabetes mellitus. Circulation. 2002;106(14):1783–7.PubMedCrossRef

41.

Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, et al. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation. 1999;100(8):820–5.PubMedCrossRef

42.

Ahlborg G, Lindstrom J. Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans. J Appl Physiol. 2002;93(6):2112–21.PubMed

43.

Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97(11):2601–10.PubMedCrossRef

44.

Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, et al. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation. 2000;101(15):1780–4.PubMedCrossRef

45.

Han KA, Patel Y, Lteif AA, Chisholm R, Mather KJ. Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium-dependent vasodilation in humans. Diabetes Metab Res Rev. 2011;27(4):354–61.PubMedCrossRef

46.

Caballero AE, Arora S, Saouaf R, Lim SC, Smakowski P, Park JY, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes. 1999;48(9):1856–62.PubMedCrossRef

47.

Lteif AA, Han K, Mather KJ. Obesity, insulin resistance, and the metabolic syndrome: determinants of endothelial dysfunction in whites and blacks. Circulation. 2005;112(1):32–8.PubMedCrossRef

48.

Title LM, Lonn E, Charbonneau F, Fung M, Mather KJ, Verma S, et al. Relationship between brachial artery flow-mediated dilatation, hyperemic shear stress, and the metabolic syndrome. Vasc Med. 2008;13(4):263–70.PubMedCrossRef

49.

Lind L. Endothelium-dependent vasodilation, insulin resistance and the metabolic syndrome in an elderly cohort: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Atherosclerosis. 2008;196(2):795–802.PubMedCrossRef

50.

Wendelhag I, Fagerberg B, Hulthe J, Bokemark L, Wikstrand J. Endothelium-dependent flow-mediated vasodilatation, insulin resistance and the metabolic syndrome in 60-year-old men. J Intern Med. 2002;252(4):305–13.PubMedCrossRef

51.

Petrie JR, Ueda S, Webb DJ, Elliott HL, Connell JM. Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease. Circulation. 1996;93(7):1331–3.PubMedCrossRef

52.

Tack CJ, Ong MK, Lutterman JA, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia. 1998;41(5):569–76.PubMedCrossRef

53.

Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, Supiano MA. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab. 1998;83(6):1946–52.PubMedCrossRef

54.

Jaap AJ, Shore AC, Tooke JE. Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia. Diabetologia. 1997;40(2):238–43.PubMedCrossRef

55.

Watts GF, O’Brien SF, Silvester W, Millar JA. Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia. Clin Sci (Lond). 1996;91(5):567–73.

56.

Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996;27(3):567–74.PubMedCrossRef

57.

Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005;111(3):343–8.PubMedCrossRef

58.

Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic Biol Med. 2001;31(1):53–61.PubMedCrossRef

59.

Chen H, Karne RJ, Hall G, Campia U, Panza JA, Cannon 3rd RO, et al. High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol. 2006;290(1):H137–45.PubMedCrossRef

60.

Perticone F, Ceravolo R, Candigliota M, Ventura G, Iacopino S, Sinopoli F, et al. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C. Diabetes. 2001;50(1):159–65.PubMedCrossRef

61.

Lekakis JP, Anastasiou EA, Papamichael CM, Stamatelopoulos KS, Dagre AG, Alevizaki MC, et al. Short-term oral ascorbic acid improves endothelium-dependent vasodilatation in women with a history of gestational diabetes mellitus. Diabetes Care. 2000;23(9):1432–4.PubMedCrossRef

62.

Darko D, Dornhorst A, Kelly FJ, Ritter JM, Chowienczyk PJ. Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes. Clin Sci (Lond). 2002;103(4):339–44.

63.

Regensteiner JG, Popylisen S, Bauer TA, Lindenfeld J, Gill E, Smith S, et al. Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes. Vasc Med. 2003;8(3):169–75.PubMedCrossRef

64.

Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Keaney Jr JF, Creager MA. Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol. 2003;285(6):H2392–8.PubMed

65.

Pena AS, Wiltshire E, Gent R, Piotto L, Hirte C, Couper J. Folic acid does not improve endothelial function in obese children and adolescents. Diabetes Care. 2007;30(8):2122–7.PubMedCrossRef

66.

Title LM, Ur E, Giddens K, McQueen MJ, Nassar BA. Folic acid improves endothelial dysfunction in type 2 diabetes–an effect independent of homocysteine-lowering. Vasc Med. 2006;11(2):101–9.PubMedCrossRef

67.

Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Diabetologia. 2000;43(11):1435–8.PubMedCrossRef

68.

Nystrom T, Nygren A, Sjoholm A. Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease. Am J Physiol Endocrinol Metab. 2004;287(5):E919–25.PubMedCrossRef

69.

Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005;46(2):398–405.PubMedCrossRef

70.

Hamdy O, Ledbury S, Mullooly C, Jarema C, Porter S, Ovalle K, et al. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care. 2003;26(7):2119–25.PubMedCrossRef

71.

Maeda S, Jesmin S, Iemitsu M, Otsuki T, Matsuo T, Ohkawara K, et al. Weight loss reduces plasma endothelin-1 concentration in obese men. Exp Biol Med (Maywood). 2006;231(6):1044–7.

72.

Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20(6):1595–9.PubMedCrossRef

73.

Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003;107(25):3152–8.PubMedCrossRef

74.

Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55(2):496–505.PubMedCrossRef

75.

Diamanti-Kandarakis E, Alexandraki K, Protogerou A, Piperi C, Papamichael C, Aessopos A, et al. Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur J Endocrinol. 2005;152(5):749–56.PubMedCrossRef

76.

Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli A, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004;27(6):1349–57.PubMedCrossRef

77.

UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65.CrossRef

78.

Eddy D, Schlessinger L, Kahn R, Peskin B, Schiebinger R. Relationship of insulin resistance and related metabolic variables to coronary artery disease: a mathematical analysis. Diabetes Care. 2009;32(2):361–6.PubMedCrossRef

Titel: Role of insulin resistance in endothelial dysfunction
verfasst von: Ranganath Muniyappa
James R. Sowers
Publikationsdatum: 01.03.2013
Verlag: Springer US
Erschienen in: Reviews in Endocrine and Metabolic Disorders / Ausgabe 1/2013
Print ISSN: 1389-9155
Elektronische ISSN: 1573-2606
DOI: https://doi.org/10.1007/s11154-012-9229-1

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

26.04.2024 | Hüft-TEP | Nachrichten

Update Innere Medizin

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

Newsletter bestellen

Springer Medizin

Role of insulin resistance in endothelial dysfunction

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Update Innere Medizin

Springer Medizin

Abstract

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

Weitere Artikel der Ausgabe 1/2013

Lipotoxicity contributes to endothelial dysfunction: A focus on the contribution from ceramide

The microcirculation in adipose tissue inflammation

Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes

Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction

The vascular endothelium in diabetes—a therapeutic target?

Type 2 diabetes mellitus and exercise impairment

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Update Innere Medizin