Obesity and type 2 diabetes mellitus (T2DM) are major drivers of cardiovascular disease (CVD). The link between environmental factors, obesity, and dysglycemia indicates that progression to diabetes with time occurs along a “continuum”, not necessarily linear, which involves different cellular mechanisms including alterations of insulin signaling, changes in glucose transport, pancreatic beta cell dysfunction, as well as the deregulation of key genes involved in oxidative stress and inflammation. The present review critically addresses key pathophysiological aspects including (i) hyperglycemia and insulin resistance as predictors of CV outcome, (ii) molecular mechanisms underpinning the progression of diabetic vascular complications despite intensive glycemic control, and (iii) stratification of CV risk, with particular emphasis on emerging biomarkers. Taken together, these important aspects may contribute to the development of promising diagnostic approaches as well as mechanism-based therapeutic strategies to reduce CVD burden in obese and diabetic subjects.
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Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world–a growing challenge. N Engl J Med. 2007;356:213–5.
Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab. 2011;96:1654–63.
Despres JP. Body fat distribution and risk of cardiovascular disease: an update. Circulation. 2012;126:1301–13.
Eckel RH. The complex metabolic mechanisms relating obesity to hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2011;31:1946–8.
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–6.
Arsenault BJ, Beaumont EP, Despres JP, Larose E. Mapping body fat distribution: a key step towards the identification of the vulnerable patient? Ann Med. 2012;44:758–72.
Despres JP. Intra-abdominal obesity: an untreated risk factor for Type 2 diabetes and cardiovascular disease. J Endocrinol Investig. 2006;29:77–82.
Ryden L, Mellbin L. Joint ESC/EASD guidelines on diabetes, where are we now and where should we go? Curr Vasc Pharmacol. 2012;10:690–2.
Paneni F. 2013 ESC/EASD guidelines on the management of diabetes and cardiovascular disease: established knowledge and evidence gaps. Diabetes Vasc Dis Res. 2014;11:5–10.
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.
Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291–7.
Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34:2436–43.
Beckman JA, Paneni F, Cosentino F, Creager MA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Eur Heart J. 2013;34:2444–52.
Anselmino M, Ryden L. Strategies to enhance cardiovascular disease prevention in patients with diabetes. Curr Opin Cardiol. 2009;24:461–7.
Authors/Task Force M, Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34:3035–87. The recent ESC/EASD Guidelines on the management of diabetes and CVD represent an important document providing a systematic approach to diagnose and treat the combination of DM and CVD. The evidence-based strategy promoted by the ESC/EASD Guidelines will be invaluable for a consistent improvement of CV outcome in DM subjects, thus strengthening the importance of appropriate diagnostic and therapeutic algorithms to achieve the best care for patients in an individualized setting.
Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall study. Lancet. 1980;1:1373–6.
Lenzen M, Ryden L, Ohrvik J, Bartnik M, Malmberg K, Scholte Op Reimer W, et al. Diabetes known or newly detected, but not impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro Heart Survey on diabetes and the heart. Eur Heart J. 2006;27:2969–74.
Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999;22:920–4.
The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet. 1999;354:617–21.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.
Emerging Risk Factors C, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–22.
Faerch K, Vaag A, Holst JJ, Hansen T, Jorgensen T, Borch-Johnsen K. Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glycemia and impaired glucose tolerance: the Inter99 study. Diabetes Care. 2009;32:439–44.
Kim SH, Reaven GM. Isolated impaired fasting glucose and peripheral insulin sensitivity: not a simple relationship. Diabetes Care. 2008;31:347–52.
Gast KB, Tjeerdema N, Stijnen T, Smit JW, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS ONE. 2012;7:e52036.
Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14:575–85.
Paneni F, Gregori M, Tocci G, Palano F, Ciavarella GM, Pignatelli G, et al. Do diabetes, metabolic syndrome or their association equally affect biventricular function? A tissue Doppler study. Hypertens Res. 2013;36:36–42.
Kumar R, Lee TT, Jeremias A, Ruisi CP, Sylvia B, Magallon J, et al. Comparison of outcomes using sirolimus-eluting stenting in diabetic versus nondiabetic patients with comparison of insulin versus non-insulin therapy in the diabetic patients. Am J Cardiol. 2007;100:1187–91.
Uetani T, Amano T, Harada K, Kitagawa K, Kunimura A, Shimbo Y, et al. Impact of insulin resistance on post-procedural myocardial injury and clinical outcomes in patients who underwent elective coronary interventions with drug-eluting stents. JACC Cardiovasc Interv. 2012;5:1159–67.
Kim SH, Reaven GM. Insulin resistance and hyperinsulinemia: you can't have one without the other. Diabetes Care. 2008;31:1433–8.
Bartnik M, Ryden L, Ferrari R, Malmberg K, Pyorala K, Simoons M, et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J. 2004;25:1880–90.
Control G, Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288–98.
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.
Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.
Cosentino F, Luscher TF. Tetrahydrobiopterin and endothelial nitric oxide synthase activity. Cardiovasc Res. 1999;43:274–8.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–70.
Tabit CE, Shenouda SM, Holbrook M, Fetterman JL, Kiani S, Frame AA, et al. Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation. 2013;127:86–95. This study, performed in primary human endothelial cells isolated from T2DM patients, is the first to provide clear evidence concerning the activation of PKC-related pathways in the diabetic endothelium. These findings have important implications for mechanism-based therapeutic approaches to prevent vascular disease burden in diabetic patients.
Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106:1319–31.
Cosentino F, Francia P, Camici GG, Pelicci PG, Luscher TF, Volpe M. Final common molecular pathways of aging and cardiovascular disease: role of the p66Shc protein. Arterioscler Thromb Vasc Biol. 2008;28:622–8.
Paneni F, Cosentino F, Marrara F, Palano F, Capretti G, Gregori M, et al. The clinical relevance of dysfunctional HDL in patients with coronary artery disease: a 3-year follow-up study. Int J Cardiol. 2012;158:158–60.
Migliaccio E, Giorgio M, Pelicci PG. Apoptosis and aging: role of p66Shc redox protein. Antioxid Redox Signal. 2006;8:600–8.
Trinei M, Migliaccio E, Bernardi P, Paolucci F, Pelicci P, Giorgio M. p66Shc, mitochondria, and the generation of reactive oxygen species. Methods Enzymol. 2013;528:99–110.
Camici GG, Schiavoni M, Francia P, Bachschmid M, Martin-Padura I, Hersberger M, et al. Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc Natl Acad Sci U S A. 2007;104:5217–22.
Pagnin E, Fadini G, de Toni R, Tiengo A, Calo L, Avogaro A. Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress. J Clin Endocrinol Metab. 2005;90:1130–6.
Paneni F, Mocharla P, Akhmedov A, Costantino S, Osto E, Volpe M, et al. Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes. Circ Res. 2012;111:278–89. Our recent work provides mechanistic insights for the persistent of vascular dysfunction despite optimal glycemic control with insulin. We demonstrated that epigenetic changes of p66(Shc) promoter, namely DNA hypomethylation and increased histone 3 acetylation, drive persistent oxidative stress and endothelial dysfunction during subsequent normoglycemia. These data suggest that chromatin alterations may contribute to an explanation of the residual vascular risk in diabetic patients.
Paneni F, Volpe M, Luscher TF, Cosentino F. SIRT1, p66(Shc), and Set7/9 in vascular hyperglycemic memory: bringing all the strands together. Diabetes. 2013;62:1800–7.
Ceriello A. The emerging challenge in diabetes: the “metabolic memory”. Vascu Pharmacol. 2012;57:133–8.
El-Osta A. Glycemic memory. Curr Opin Lipidol. 2012;23:24–9.
Cooper ME, El-Osta A. Epigenetics: mechanisms and implications for diabetic complications. Circ Res. 2010;107:1403–13.
Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011;123:2145–56.
Paneni F, Costantino S, Volpe M, Luscher TF, Cosentino F. Epigenetic signatures and vascular risk in type 2 diabetes: a clinical perspective. Atherosclerosis. 2013;230:191–7.
Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57:1349–54.
El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205:2409–17. El-Osta et al. demonstrate for the first time that transient spikes of hyperglycemia activate persistent epigenetic signatures in the human endothelium leading to NF-kB upregulation and subsequent inflammation. This work indicates that glycemic flucutations rather than costant high glucose is a detrimental process triggering vascular damage in diabetic patients.
Picconi F, Di Flaviani A, Malandrucco I, Giordani I, Frontoni S. Impact of glycemic variability on cardiovascular outcomes beyond glycated hemoglobin. Evidence and clinical perspectives. Nutr Metab Cardiovasc Dis. 2012;22:691–6.
Bazinet M, Hamdy S, Begin L, Aprikian A, Fair W, Wright G. Monoclonal-antibody pd-41 recognizes a prostate-cancer associated antigen whose expression increases in metastases and following hormonal-therapy. Int J Oncol. 1995;7:1421–5.
Bigornia SJ, Farb MG, Tiwari S, Karki S, Hamburg NM, Vita JA, et al. Insulin status and vascular responses to weight loss in obesity. J Am Coll Cardiol. 2013;62:2297–305.
Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113:1888–904.
Kim JK. Endothelial nuclear factor kappaB in obesity and aging: is endothelial nuclear factor kappaB a master regulator of inflammation and insulin resistance? Circulation. 2012;125:1081–3.
Hasegawa Y, Saito T, Ogihara T, Ishigaki Y, Yamada T, Imai J, et al. Blockade of the nuclear factor-kappaB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation. 2012;125:1122–33. The article shows that the transcription factor NF-kB is critically involved in endothelial IR. Suppression of NF-kB signaling in the endothelium results in improved insulin signaling in other organs as well as improved lifespan in mice. These novel findings suggest that NF-kB is a key molecular intermediate linking metabolic disease, inflammation, and aging.
Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, et al. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 2010;11:379–89.
Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest. 2006;116:1071–80.
Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011;13:294–307.
Li Q, Park K, Li C, Rask-Madsen C, Mima A, Qi W, et al. Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-beta isoform in the endothelium. Circ Res. 2013;113:418–27.
Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, Rosano GM. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med. 2005;258:250–6.
Naka KK, Papathanassiou K, Bechlioulis A, Pappas K, Kazakos N, Kanioglou C, et al. Rosiglitazone improves endothelial function in patients with type 2 diabetes treated with insulin. Diabetes Vasc Dis Res. 2011;8:195–201.
Avogaro A, de Kreutzenberg SV, Federici M, Fadini GP. The endothelium abridges insulin resistance to premature aging. J Am Heart Assoc. 2013;2:e000262.
Anand DV, Lim E, Hopkins D, Corder R, Shaw LJ, Sharp P, et al. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. Eur Heart J. 2006;27:713–21.
Roffi M, Angiolillo DJ, Kappetein AP. Current concepts on coronary revascularization in diabetic patients. Eur Heart J. 2011;32:2748–57.
Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, et al. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med. 2006;166:1368–73.
Tousoulis D, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Tentolouris K, et al. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches. J Am Coll Cardiol. 2013;62:667–76.
Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812–7.
Snell-Bergeon JK, West NA, Mayer-Davis EJ, Liese AD, Marcovina SM, D'Agostino Jr RB, et al. Inflammatory markers are increased in youth with type 1 diabetes: the SEARCH Case-Control study. J Clin Endocrinol Metab. 2010;95:2868–76.
Geisler T, Mueller K, Aichele S, Bigalke B, Stellos K, Htun P, et al. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after PCI: prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol. 2010;99:743–52.
Hohenstein B, Hugo CP, Hausknecht B, Boehmer KP, Riess RH, Schmieder RE. Analysis of NO-synthase expression and clinical risk factors in human diabetic nephropathy. Nephrol Dial Transplant. 2008;23:1346–54.
Meigs JB, Larson MG, Fox CS, Keaney Jr JF, Vasan RS, Benjamin EJ. Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study. Diabetes Care. 2007;30:2529–35.
Paneni F, Cosentino F. Advanced glycation endproducts and plaque instability: a link beyond diabetes. Eur Heart J. 2013. doi:10.1093/eurheartj/eht454.
Meerwaldt R, Graaff R, Oomen PH, Links TP, Jager JJ, Alderson NL, et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia. 2004;47:1324–30.
Shantikumar S, Caporali A, Emanueli C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc Res. 2012;93:583–93.
Zampetaki A, Mayr M. MicroRNAs in vascular and metabolic disease. Circ Res. 2012;110:508–22.
Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107:810–7. This comprehensive analysis shows an array of deregulated miRs in diabetic patients, thus shedding some light on potential biomarkers in this arena. Among other miRs, miR-126, an important pro-angiogenic precursor, was significantly downregulated in plasma samples from T2DM patients.
Mocharla P, Briand S, Giannotti G, Dorries C, Jakob P, Paneni F, et al. AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics. Blood. 2013;121:226–36.
Shantsila E, Kamphuisen PW, Lip GY. Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis. J Thromb Haemost. 2010;8:2358–68.
Tsimerman G, Roguin A, Bachar A, Melamed E, Brenner B, Aharon A. Involvement of microparticles in diabetic vascular complications. Thromb Haemost. 2011;106:310–21.
Chen Y, Feng B, Li X, Ni Y, Luo Y. Plasma endothelial microparticles and their correlation with the presence of hypertension and arterial stiffness in patients with type 2 diabetes. J Clin Hypertens (Greenwich). 2012;14:455–60.
Bernard S, Loffroy R, Serusclat A, Boussel L, Bonnefoy E, Thevenon C, et al. Increased levels of endothelial microparticles CD144 (VE-Cadherin) positives in type 2 diabetic patients with coronary noncalcified plaques evaluated by multidetector computed tomography (MDCT). Atherosclerosis. 2009;203:429–35.
Research discussed in this manuscript was supported by the Swiss Heart Foundation and the Italian Ministry of Education, University and Research, PRIN 2010-2011 (to F.C.). F.P was the recipient of a Ph.D. program in Experimental Medicine at the University of Rome “Sapienza”.
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Conflict of Interest
Francesco Paneni and Sarah Costantino declare that they have no conflicts of interest.
Francesco Cosentino reports grants from the Swiss Heart Foundation, the Italian Ministry of Education, University and Research, PRIN 2010-2011, personal fees from Roche, personal fees from Bristol Myers Squibb, personal fees from MSD, personal fees from Abbott, and personal fees from Astra Zeneca.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Cardiovascular Disease and Stroke
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Paneni, F., Costantino, S. & Cosentino, F. Insulin Resistance, Diabetes, and Cardiovascular Risk. Curr Atheroscler Rep 16, 419 (2014). https://doi.org/10.1007/s11883-014-0419-z
- Insulin resistance
- Cardiovascular disease