RSS-Feed abonnieren
DOI: 10.1055/s-0028-1119378
© Georg Thieme Verlag KG Stuttgart · New York
Cardiovascular Effects of Disturbed Insulin Activity in Metabolic Syndrome and in Type 2 Diabetic Patients
Publikationsverlauf
received 22.09.2008
accepted 08.12.2008
Publikationsdatum:
12. Februar 2009 (online)
![](https://www.thieme-connect.de/media/hmr/200902/lookinside/thumbnails/10.1055-s-0028-1119378-1.jpg)
Abstract
The metabolic syndrome is associated with an excess of increase in cardiovascular complications. Disturbances in insulin efficacy and insulin secretion are major features of the metabolic syndrome and might precede the development of diabetes mellitus by decades. Recent investigations highlighted the link between disturbances in insulin physiology and subsequent mechanisms of atherosclerosis. Insulin resistance is an early feature of increasing visceral adipose tissue and is directly associated to the activation of a couple of atherogenic pathways, including inflammation and the activation of the mitogen-activated proteinkinase pathway accelerating the atherogenic process. In patients with normal beta-cell function, insulin resistance is compensated by increased insulin release from the beta cells to keep blood glucose levels compensated. In those patients, genetically predisposed to type 2 diabetes, beta-cell function deteriorates with the development of timely, qualitative and quantitative insulin secretion disorders, and the development of overt diabetes mellitus. The coexistence of insulin resistance with functional beta cell failure results in loss of blood glucose control especially after a meal and increases the cardiovascular risk of these patients far beyond the increased glucose levels.
Key words
diabetes mellitus type 2 - insulin resistance - insulin secretion
References
- 1 Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am. 2004; 33 283-303
- 2 Gaal LF Van, Mertens IL, Block CE De. Mechanisms linking obesity with cardiovascular disease. Nature. 2006; 444 875-880
- 3 Hara T, Fujiwara H, Shoji T, Mimura T, Nakao H, Fujimoto S. Decreased plasma adiponectin levels in young obese males. J Atheroscler Thromb. 2003; 10 234-238
- 4 Kern PA, Gregorio GB Di, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes. 2003; 52 1779-1785
- 5 Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000; 49 1751-1760
- 6 Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes. Diabetes. 2002; 51 ((Suppl. 1)) S109-S116
- 7 Gregg EW, Cheng YJ, Cadwell BL, Imperatore G, Williams DE, Flegal KM, Narayan KM, Williamson DF. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005; 293 1868-1874
- 8 Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Int J Obes Relat Metab Disord. 2003; 46 3-19
- 9 Ferrannini E, Mari A. Beta cell function and its relation to insulin action in humans: a critical appraisal. Int J Obes Relat Metab Disord. 2004; 47 943-956
- 10 Al Suwaidi J, Higano ST, Holmes Jr DR, Lennon R, Lerman A. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol. 2001; 37 1523-1528
- 11 Arcaro G, Zamboni M, Rossi L, Turcato E, Covi G, Armellini F, Bosello O, Lechi A. Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. Int J Obes Relat Metab Disord. 1999; 23 936-942
- 12 Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006; 113 1888-1904
- 13 Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414 799-806
- 14 Montagnani M, Quon MJ. Insulin action in vascular endothelium: potential mechanisms linking insulin resistance with hypertension. Diabetes Obes Metab. 2000; 2 285-292
- 15 Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation. 2000; 101 676-681
- 16 Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000; 101 1539-1545
- 17 Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol. 2002; 16 1931-1942
- 18 Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med. 2004; 117 109-117
- 19 Loscalzo J. Nitric oxide and vascular disease. N Engl J Med. 1995; 333 251-253
- 20 Loscalzo J. Antiplatelet and antithrombotic effects of organic nitrates. Am J Cardiol. 1992; 70 18B-22B
- 21 Scognamiglio R, Negut C, Kreutzenberg SV De, Tiengo A, Avogaro A. Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation. 2005; 112 179-184
- 22 Forst T, Kunt T, Pohlmann T, Goitom K, Löbig M, Engelbach M, Beyer J, Pfützner A. Microvascular skin blood flow following the ingestion of 75 g Glucose in healthy individuals. Exp Clin Endocrinol Diabetes. 1998; 106 453-458
- 23 Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006; 55 1436-1442
- 24 Wiggam MI, Hunter SJ, Ennis CN, Sheridan B, Atkinson AB, Bell PM. Insulin action and skeletal muscle blood flow in patients with Type 1 diabetes and microalbuminuria. Diabetes Res Clin Pract. 2001; 53 73-83
- 25 Pitkanen OP, Nuutila P, Raitakari OT, Ronnemaa T, Koskinen PJ, Iida H, Lehtimaki TJ, Laine HK, Takala T, Viikari JS, Knuuti J. Coronary flow reserve is reduced in young men with IDDM. Diabetes. 1998; 47 248-254
- 26 Sundell J, Knuuti J. Insulin and myocardial blood flow. Cardiovasc Res. 2003; 57 312-319
- 27 Gudbjornsdottir S, Sjostrand M, Strindberg L, Lonnroth P. Decreased muscle capillary permeability surface area in type 2 diabetic subjects. J Clin Endocrinol Metab. 2005; 90 1078-1082
- 28 Hermann TS, Li W, Dominguez H, Ihlemann N, Rask-Madsen C, Major-Pedersen A, Nielsen DB, Hansen KW, Hawkins M, Kober L, Torp-Pedersen C. Quinapril treatment increases insulin-stimulated endothelial function and adiponectin gene expression in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91 1001-1008
- 29 Rask-Madsen C, Ihlemann N, Krarup T, Christiansen E, Kober L, Nervil KC, Torp-Pedersen C. Insulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease. Diabetes. 2001; 50 2611-2618
- 30 Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, Baron AD. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation. 2001; 103 1410-1415
- 31 Verma S, Yao L, Stewart DJ, Dumont AS, Anderson TJ, MacNeill JH. Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension. 2001; 37 328-333
- 32 Eringa EC, Stehouwer CD, Nieuw Amerongen GP, Ouwehand L, Westerhof N, Sipkema P. Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol. 2004; 287 H2043-H2048
- 33 Prior JO, Quinones MJ, Hernandez-Pampaloni M, Facta AD, Schindler TH, Sayre JW, Hsueh WA, Schelbert HR. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation. 2005; 111 2291-2298
- 34 Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE. A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes. 2000; 49 2094-2101
- 35 Eringa EC, Stehouwer CD, Roos MH, Westerhof N, Sipkema P. Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab. 2007; 293 E1134-E1139
- 36 Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, Montagnani M. 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 H813-H822
- 37 Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, Johansen M, Kucik DF, Quon MJ, Draznin B. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem. 2002; 277 1794-1799
- 38 Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000; 105 311-320
- 39 Mather KJ, Lteif A, Steinberg HO, Baron AD. Interactions between endothelin and nitric oxide in the regulation of vascular tone in obesity and diabetes. Diabetes. 2004; 53 2060-2066
- 40 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 3517-3523
- 41 Rahmouni K, Morgan DA, Morgan GM, Liu X, Sigmund CD, Mark AL, Haynes WG. Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest. 2004; 114 652-658
- 42 Oh JY, Barrett-Connor E, Wedick NM. Sex differences in the association between proinsulin and intact insulin with coronary heart disease in nondiabetic older adults: the Rancho Bernardo Study. Circulation. 2002; 105 1311-1316
- 43 Roder ME, Porte Jr D, Schwartz RS, Kahn SE. Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1998; 83 604-608
- 44 Hostens K, Ling Z, Schravendijk C Van, Pipeleers D. Prolonged exposure of human beta-cells to high glucose increases their release of proinsulin during acute stimulation with glucose or arginine. J Clin Endocrinol Metab. 1999; 84 1386-1390
- 45 Seaquist ER, Kahn SE, Clark PM, Hales CN, Porte Jr D, Robertson RP. Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans. J Clin Invest. 1996; 97 455-460
- 46 Haffner SM, Mykkanen L, Stern MP, Valdez RA, Heisserman JA, Bowsher RR. Relationship of proinsulin and insulin to cardiovascular risk factors in nondiabetic subjects. Diabetes. 1993; 42 1297-1302
- 47 Pfützner A, Kunt T, Hohberg C, Mondok A, Pahler S, Konrad T, Lubben G, Forst T. Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes. Diabetes Care. 2004; 27 682-687
- 48 Langenfeld MR, Forst T, Standl E, Strotmann HJ, Lubben G, Pahler S, Kann P, Pfützner A. IRIS II Study: Sensitivity and specificity of intact proinsulin, adiponectin, and the proinsulin/adiponectin ratio as markers for insulin resistance. Diabetes Technol Ther. 2004; 6 836-843
- 49 Pfützner A, Standl E, Hohberg C, Konrad T, Strotmann HJ, Lubben G, Langenfeld MR, Schulze J, Forst T. IRIS II study: intact proinsulin is confirmed as a highly specific indicator for insulin resistance in a large cross-sectional study design. Diabetes Technol Ther. 2005; 7 478-486
- 50 Kirchhoff K, Machicao F, Haupt A, Schafer SA, Tschritter O, Staiger H, Stefan N, Haring HU, Fritsche A. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Int J Obes Relat Metab Disord. 2008; 51 597-601
- 51 Yudkin JS, May M, Elwood P, Yarnell JW, Greenwood R, Davey SG. Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study. Diabetologia. 2002; 45 327-336
- 52 Wohlin M, Sundstrom J, Arnlov J, Andren B, Zethelius B, Lind L. Impaired insulin sensitivity is an independent predictor of common carotid intima-media thickness in a population sample of elderly men. Atherosclerosis. 2003; 170 181-185
- 53 Lindahl B, Dinesen B, Eliasson M, Roder M, Hallmans G, Stegmayr B. High proinsulin levels precede first-ever stroke in a nondiabetic population. Stroke. 2000; 31 2936-2941
- 54 Alssema M, Dekker JM, Nijpels G, Stehouwer CD, Bouter LM, Heine RJ. Proinsulin concentration is an independent predictor of all-cause and cardiovascular mortality: an 11-year follow-up of the Hoorn Study. Diabetes Care. 2005; 28 860-865
- 55 Galloway JA, Hooper SA, Spradlin CT, Howey DC, Frank BH, Bowsher RR, Anderson JH. Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience. Diabetes Care. 1992; 15 666-692
- 56 Lindahl B, Dinesen B, Eliasson M, Roder M, Jansson JH, Huhtasaari F, Hallmans G. High proinsulin concentration precedes acute myocardial infarction in a nondiabetic population. Metabolism. 1999; 48 1197-1202
- 57 Forst T, Pfützner A, Lubben G, Weber M, Marx N, Karagiannis E, Koehler C, Baurecht W, Hohberg C, Hanefeld M. Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk–the PIOSTAT Study. Metabolism. 2007; 56 491-496
- 58 Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest. 2001; 108 1875-1881
- 59 Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002; 8 1288-1295
- 60 Mitsuhashi N, Onuma T, Kubo S, Takayanagi N, Honda M, Kawamori R. Coronary artery disease and carotid artery intima-media thickness in Japanese type 2 diabetic patients. Diabetes Care. 2002; 25 1308-1312
- 61 Haffner SM, D’Agostino R, Mykkanen L, Hales CN, Savage PJ, Bergman RN, O’Leary D, Rewers M, Selby J, Tracy R, Saad MF. Proinsulin and insulin concentrations in relation to carotid wall thickness: Insulin Resistance Atherosclerosis Study. Stroke. 1998; 29 1498-1503
- 62 Forst T, Hohberg C, Fuellert SD, Lubben G, Konrad T, Lobig M, Weber MM, Sachara C, Gottschall V, Pfützner A. Pharmacological PPARgamma stimulation in contrast to beta cell stimulation results in an improvement in adiponectin and proinsulin intact levels and reduces intima media thickness in patients with type 2 diabetes. Horm Metab Res. 2005; 37 521-527
- 63 Jia EZ, Yang ZJ, Zhu TB, Wang LS, Chen B, Cao KJ, Huang J, Ma WZ. Proinsulin Is an Independent Predictor of the Angiographical Characteristics of Coronary Atherosclerosis. Cardiology. 2007; 110 106-111
- 64 Nordt TK, Schneider DJ, Sobel BE. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease. Circulation. 1994; 89 321-330
- 65 Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation. 1995; 91 764-770
- 66 Nordt TK, Bode C, Sobel BE. Stimulation in vivo of expression of intra-abdominal adipose tissue plasminogen activator inhibitor Type I by proinsulin. Int J Obes Relat Metab Disord. 2001; 44 1121-1124
- 67 Lyon CJ, Hsueh WA. Effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease. Am J Med. 2003; 115 ((Suppl. 8A)) 62S-68S
- 68 Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, Galan BE de, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358 2560-2572
- 69 Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm Jr RH, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358 2545-2559
- 70 Jadhav S, Petrie J, Ferrell W, Cobbe S, Sattar N. Insulin resistance as a contributor to myocardial ischaemia independent of obstructive coronary atheroma: a role for insulin sensitisation?. Heart. 2004; 90 1379-1383
- 71 Verma S, Yao L, Dumont AS, MacNeill JH. Metformin treatment corrects vascular insulin resistance in hypertension. J Hypertens. 2000; 18 1445-1450
- 72 UKPDS Study Group. . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352 854-865
- 73 Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359 1577-1589
- 74 Satoh N, Ogawa Y, Usui T, Tagami T, Kono S, Uesugi H, Sugiyama H, Sugawara A, Yamada K, Shimatsu A, Kuzuya H, Nakao K. Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care. 2003; 26 2493-2499
- 75 Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S, Ferrannini E, Cusi K, Mandarino LJ, DeFronzo RA. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care. 2001; 24 710-719
- 76 Hanefeld M, Brunetti P, Schernthaner GH, Matthews DR, Charbonnel BH. QUARTET Study Group . One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004; 27 141-147
- 77 Pfützner A, Hohberg C, Lubben G, Pahler S, Pfützner AH, Kann P, Forst T. Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Horm Metab Res. 2005; 37 510-515
- 78 Forst T, Karagiannis E, Lubben G, Hohberg C, Schondorf T, Dikta G, Drexler M, Morcos M, Danschel W, Borchert M, Pfützner A. Pleiotrophic and anti-inflammatory effects of pioglitazone precede the metabolic activity in type 2 diabetic patients with coronary artery disease. Atherosclerosis. 2008; 197 311-317
- 79 Hanefeld M, Marx N, Pfützner A, Baurecht W, Lubben G, Karagiannis E, Stier U, Forst T. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J Am Coll Cardiol. 2007; 49 290-297
- 80 Pistrosch F, Passauer J, Fischer S, Fuecker K, Hanefeld M, Gross P. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control. Diabetes Care. 2004; 27 484-490
- 81 Vinik AI, Stansberry KB, Barlow PM. Rosiglitazone treatment increases nitric oxide production in human peripheral skin: a controlled clinical trial in patients with type 2 diabetes mellitus. J Diabetes Complications. 2003; 17 279-285
- 82 Forst T, Lubben G, Hohberg C, Kann P, Sachara C, Gottschall V, Friedrich C, Rosskopf R, Pfützner A. Influence of glucose control and improvement of insulin resistance on microvascular blood flow and endothelial function in patients with diabetes mellitus type 2. Microcirculation. 2005; 12 543-550
- 83 Potenza MA, Marasciulo FL, Tarquinio M, Quon MJ, Montagnani M. Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance. Diabetes. 2006; 55 3594-3603
- 84 Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998; 391 82-86
- 85 Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000; 101 235-238
- 86 O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999; 340 14-22
- 87 Touboul PJ, Elbaz A, Koller C, Lucas C, Adrai V, Chedru F, Amarenco P. Common carotid artery intima-media thickness and brain infarction: the Etude du Profil Genetique de l’Infarctus Cerebral (GENIC) case-control study. The GENIC Investigators. Circulation. 2000; 102 313-318
- 88 Nakamura T, Matsuda T, Kawagoe Y, Ogawa H, Takahashi Y, Sekizuka K, Koide H. Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients. Metabolism. 2004; 53 1382-1386
- 89 Langenfeld MR, Forst T, Hohberg C, Kann P, Lubben G, Konrad T, Fullert SD, Sachara C, Pfützner A. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation. 2005; 111 2525-2531
- 90 Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, Larochelliere R De, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008; 299 1561-1573
- 91 Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366 1279-1289
- 92 Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM. The effect of pioglitazone on recurrent myocardial infarction in 2 445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007; 49 1772-1780
- 93 Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med. 1998; 15 297-303
- 94 Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355 2427-2443
- 95 Aston-Mourney K, Proietto J, Morahan G, Andrikopoulos S. Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin. Int J Obes Relat Metab Disord. 2008; 51 540-545
- 96 Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY. Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab. 2005; 90 501-506
- 97 Alvarsson M, Sundkvist G, Lager I, Berntorp K, Fernqvist-Forbes E, Steen L, Orn T, Holberg MA, Kirksaether N, Grill V. Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up. Diabetes Obes Metab. 2008; 10 421-429
- 98 Takahashi A, Nagashima K, Hamasaki A, Kuwamura N, Kawasaki Y, Ikeda H, Yamada Y, Inagaki N, Seino Y. Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-cell death in the chronic phase. Diabetes Res Clin Pract. 2007; 77 343-350
- 99 Davies MJ, Metcalfe J, Day JL, Grenfell A, Hales CN, Gray IP. Effect of sulphonylurea therapy on plasma insulin, intact and 32/33 split proinsulin in subjects with type 2 diabetes mellitus. Diabet Med. 1994; 11 293-298
- 100 Margolis DJ, Hoffstad O, Strom BL. Association between serious ischemic cardiac outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf. 2008; 17 753-759
- 101 Rao AD, Kuhadiya N, Reynolds K, Fonseca VA. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies. Diabetes Care. 2008; 31 1672-1678
- 102 Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Int J Obes Relat Metab Disord. 2006; 49 930-936
- 103 Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002; 25 2244-2248
- 104 Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ. 2006; 174 169-174
- 105 UK Prospective Diabetes Study (UKPDS) Group. . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352 837-853
- 106 Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, Kohanovski M, Rotzak R, Schneider H, Behar S, Motro M. Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up. Clin Cardiol. 2001; 24 151-158
- 107 Stumvoll M, Fritsche A, Stefan N, Hardt E, Haring H. Evidence against a rate-limiting role of proinsulin processing for maximal insulin secretion in subjects with impaired glucose tolerance and beta-cell dysfunction. J Clin Endocrinol Metab. 2001; 86 1235-1239
- 108 Fritsche A, Madaus A, Stefan N, Tschritter O, Maerker E, Teigeler A, Haring H, Stumvoll M. Relationships among age, proinsulin conversion, and beta-cell function in nondiabetic humans. Diabetes. 2002; 51 ((Suppl. 1)) S234-S239
- 109 DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005; 28 1092-1100
- 110 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29 2638-2643
- 111 Stolar MW, Hoogwerf BJ, Gorshow SM, Boyle PJ, Wales DO. Managing type 2 diabetes: going beyond glycemic control. J Manag Care Pharm. 2008; 14 s2-s19
- 112 Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J. 2008; 29 166-176
- 113 Pfützner A, Lorra B, Abdollahnia MR, Kann PH, Mathieu D, Pehnert C, Oligschleger C, Kaiser M, Forst T. The switch from sulfonylurea to preprandial short- acting insulin analog substitution has an immediate and comprehensive beta-cell protective effect in patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2006; 8 375-384
- 114 Forst T, Pohlmann T, Kazda Ch, Welter K, Langer F, Forst S, Pfützner A. The impact of insulin lispro and regular insulin on postprandial endothelial function and microvascular blood flow in type 1 diabetic patients. Diabetes. 2003; 51 ((Suppl. 2)) A 292
- 115 Scognamiglio R, Negut C, Kreutzenberg SV De, Tiengo A, Avogaro A. Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients. Diabetes Care. 2006; 29 95-100
- 116 Hohberg C, Forst T, Larbig M, Safinowski M, Diessel S, Hehenwarter S, Weber MM, Schondorf T, Pfützner A. Effect of insulin glulisine on microvascular blood flow and endothelial function in the postprandial state. Diabetes Care. 2008; 31 1021-1025
- 117 Piatti PM, Monti LD, Conti M, Baruffaldi L, Galli L, Phan CV, Guazzini B, Pontiroli AE, Pozza G. Hypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans. Diabetes. 1996; 45 316-321
- 118 Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev. 2007; 28 463-491
- 119 Eurich DT, MacAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 2007; 335 497
- 120 Anselmino M, Ohrvik J, Malmberg K, Standl E, Ryden L. Glucose lowering treatment in patients with coronary artery disease is prognostically important not only in established but also in newly detected diabetes mellitus: a report from the Euro Heart Survey on Diabetes and the Heart. Eur Heart J. 2008; 29 177-184
- 121 Nagi DK, Knowler WC, Mohamed-Ali V, Bennett PH, Yudkin JS. Intact proinsulin, des 31,32 proinsulin, and specific insulin concentrations among nondiabetic and diabetic subjects in populations at varying risk of type 2 diabetes. Diabetes Care. 1998; 21 127-133
- 122 Mykkanen L, Zaccaro DJ, Hales CN, Festa A, Haffner SM. The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed type II diabetes: the Insulin Resistance Atherosclerosis Study. Diabetologia. 1999; 42 1060-1066
- 123 Pfützner A, Pfützner AH, Larbig M, Forst T. Role of intact proinsulin in diagnosis and treatment of type 2 diabetes mellitus. Diabetes Technol Ther. 2004; 6 405-412
Correspondence
T. ForstMD
Professor Internal Medicine
Institute for Clinical Research and Development
Parcusstraße 8
55116 Mainz
Germany
Telefon: +49/6131/576 36 13
Fax: +49/6131/576 36 11
eMail: thomasf@ikfe.de