Skip to main content
Top

04-18-2018 | Cardiovascular disorders | Review | Article

Diabetes, cardiovascular disease and the microcirculation

Journal: Cardiovascular Diabetology

Authors: W. David Strain, P. M. Paldánius

Publisher: BioMed Central

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM), yet a significant proportion of the disease burden cannot be accounted for by conventional cardiovascular risk factors. Hypertension occurs in majority of people with T2DM, which is substantially more frequent than would be anticipated based on general population samples. The impact of hypertension is considerably higher in people with diabetes than it is in the general population, suggesting either an increased sensitivity to its effect or a confounding underlying aetiopathogenic mechanism of hypertension associated with CVD within diabetes. In this contribution, we aim to review the changes observed in the vascular tree in people with T2DM compared to the general population, the effects of established anti-diabetes drugs on microvascular outcomes, and explore the hypotheses to account for common causalities of the increased prevalence of CVD and hypertension in people with T2DM.
Literature
2.
Struijker-Boudier AHJ. The burden of vascular disease in diabetes and hypertension: from micro- to macrovascular disease—the “bad loop”. Medicographia. 2009;31:251–6.
3.
Chantler PD, Frisbee JC. Arterial function in cardio-metabolic diseases: from the microcirculation to the large conduits. Prog Cardiovasc Dis. 2015;57:489–96. PubMedCrossRef
4.
Niiranen TJ, Kalesan B, Hamburg NM, Benjamin EJ, Mitchell GF, Vasan RS. Relative contributions of arterial stiffness and hypertension to cardiovascular disease: the Framingham Heart Study. J Am Heart Assoc. 2016;5:e004271. PubMedPubMedCentralCrossRef
5.
Bastos JM, Bertoquini S, Polónia J. Prognostic significance of ambulatory arterial stiffness index in hypertensives followed for 8.2 years: its relation with new events and cardiovascular risk estimation. Rev Port Cardiol. 2010;29:1287–303. PubMed
6.
Cardoso CR, Ferreira MT, Leite NC, Salles GF. Prognostic impact of aortic stiffness in high-risk type 2 diabetic patients: the Rio deJaneiro type 2 diabetes cohort study. Diabetes Care. 2013;36:3772–8. PubMedPubMedCentralCrossRef
7.
Smulyan H, Lieber A, Safar ME. Hypertension, diabetes type II, and their association: role of arterial stiffness. Am J Hypertens. 2016;29:5–13. PubMedCrossRef
8.
Natali A, Toschi E, Baldeweg S, Ciociaro D, Favilla S, Saccà L, et al. Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. Diabetes. 2006;55:1133–40. PubMedCrossRef
9.
Strain WD, Chaturvedi N, Dockery F, Shiff R, Shore AC, Bulpitt CJ, et al. Increased arterial stiffness in Europeans and African Caribbeans with type 2 diabetes cannot be accounted for by conventional cardiovascular risk factors. Am J Hypertens. 2006;19:889–96. PubMedCrossRef
10.
Park CM, Tillin T, March K, Jones S, Whincup PH, Mayet J, et al. Adverse effect of diabetes and hyperglycaemia on arterial stiffness in Europeans, South Asians, and African Caribbeans in the SABRE study. J Hypertens. 2016;34:282–9. PubMedPubMedCentralCrossRef
11.
Madonna R, Balistreri CR, Geng YJ, De Caterina R. Diabetic microangiopathy: pathogenetic insights and novel therapeutic approaches. Vasc Pharmacol. 2017;90:1–7. CrossRef
12.
Stehouwer CD, Ferreira I. Diabetes, lipids and other cardiovascular risk factors. In: Safar M, O’Rourke M, editors. Handbook of hypertension. Arterial stiffness hypertension, vol. 23. Edinburgh: Elsevier; 2006. p. 427–56.
13.
Urbina EM, Khoury PR, McCoy C, Daniels SR, Kimball TR, Dolan LM. Cardiac and vascular consequences of pre-hypertension in youth. J Clin Hypertens. 2011;13:332–42. CrossRef
14.
Tropeano AI, Boutouyrie P, Katsahian S, Laloux B, Laurent S. Glucose level is a major determinant of carotid intima-media thickness in patients with hypertension and hyperglycemia. J Hypertens. 2004;22:2153–60. PubMedCrossRef
15.
Rubin J, Nambi V, Chambless LE, Steffes MW, Juraschek SP, Coresh J, et al. Hyperglycemia and arterial stiffness: the atherosclerosis risk in the communities study. Atherosclerosis. 2012;225:246–51. PubMedPubMedCentralCrossRef
16.
Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: clinical effects and molecular mechanisms. Mol Metab. 2013;3:94–108. PubMedPubMedCentralCrossRef
17.
Brohall G, Odén A, Fagerberg B. Carotid artery intima-media thickness in patients with type 2 diabetes mellitus and impaired glucose tolerance: a systematic review. Diabet Med. 2006;23:609–16. PubMedCrossRef
18.
Madonna R, Caterina RD. Cellular and molecular mechanisms of vascular injury in diabetes–part I: pathways of vascular disease in diabetes. Vasc Pharmacol. 2011;54:68–74. CrossRef
19.
Madonna R, Caterina RD. Cellular and molecular mechanisms of vascular injury in diabetes–part II: cellular mechanisms and therapeutic targets. Vasc Pharmacol. 2011;54:75–9. CrossRef
20.
Park SW, Jun HO, Kwon E, Yun JW, Kim JH, Park YJ, et al. Antiangiogenic effect of betaine on pathologic retinal neovascularization via suppression of reactive oxygen species mediated vascular endothelial growth factor signalling. Vasc Pharmacol. 2017;90:19–26. CrossRef
21.
Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7. PubMedCrossRef
22.
Zinman B, Marso SP, Poulter NR, Emerson SS, Pieber TR, Pratley RE, et al. Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2). Diabetologia. 2018;61:48–57. PubMedCrossRef
23.
Su G, Mi SH, Tao H, Li Z, Yang HX, Zheng H, et al. Impact of admission glycemic variability, glucose, and glycosylated hemoglobin on major adverse cardiac events after acute myocardial infarction. Diabetes Care. 2013;36:1026–32. PubMedPubMedCentralCrossRef
24.
Rizzo MR, Barbieri M, Marfella R, Paolisso G. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care. 2012;35:2076–82. PubMedPubMedCentralCrossRef
25.
Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, et al. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227:349–54. PubMedCrossRef
26.
Frisbee JC, Butcher JT, Frisbee SJ, Olfert IM, Chantler PD, Tabone LE, et al. Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol. 2016;310(4):H488–504. PubMedCrossRef
27.
de Boer RA, Doehner W, van der Horst IC, Anker SD, Babalis D, Roughton M, et al. Influence of diabetes mellitus and hyperglycemia on prognosis in patients > or = 70 years old with heart failure and effects of nebivolol (data from the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure [SENIORS]). Am J Cardiol. 2010;106:78–86. PubMedCrossRef
28.
Sarma S, Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, et al. Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial. Eur J Heart Fail. 2013;15:194–202. PubMedCrossRef
29.
Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27:699–703. PubMedCrossRef
30.
Cavallo Perin P, Pacini G, Giunti S, Comune M, Conte MR, Cassader M, et al. Microvascular angina (cardiological syndrome X) per se is not associated with hyperinsulinemia or insulin resistance. Eur J Clin Invest. 2000;30:481–6. PubMedCrossRef
31.
Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol. 2018;250:16–20. PubMedCrossRef
32.
Valenzuela-Garcia LF, Matsuzawa Y, Sara JD, Kwon TG, Lennon RJ, Lerman LO, et al. Lack of correlation between the optimal glycaemic control and coronary micro vascular dysfunction in patients with diabetes mellitus: a cross sectional study. Cardiovasc Diabetol. 2015;14:106. PubMedPubMedCentralCrossRef
33.
Smits MM, Tonneijck L, Muskiet MH, Hoekstra T, Kramer MH, Diamant M, et al. GLP-1-based therapies have no microvascular effects in type 2 diabetes mellitus: an acute and 12-week randomized, double-blind placebo-controlled trial. Arterioscler Thromb Vasc Biol. 2016;36:2125–32. PubMedCrossRef
34.
Rizzoni D, Agabiti Rosei E. Small artery remodeling in hypertension and diabetes. Curr Hypertens Rep. 2006;8:90–5. PubMedCrossRef
35.
Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015;116:1007–21. PubMedCrossRef
36.
Gliemann L, Buess R, Nyberg M, Hoppeler H, Odriozola A, Thaning P, et al. Capillary growth, ultrastructure remodelling and exercise training in skeletal muscle of essential hypertensive patients. Acta Physiol. 2015;214:210–20. CrossRef
37.
Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, et al. Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus. Circulation. 2001;103:1238–44. PubMedCrossRef
38.
Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation. 2002;106:3037–43. PubMedCrossRef
39.
Scalia R, Gong Y. Berzins Bc. Hyperglycemia is a major determinant of albumin permeability in diabetic microcirculation: the role of mu-calpain. Diabetes. 2007;56:1842–9. PubMedCrossRef
40.
Akerstrom T, Laub L, Vedel K, Brand CL, Pedersen BK, Lindqvist AK, et al. Increased skeletal muscle capillarization enhances insulin sensitivity. Am J Physiol Endocrinol Metab. 2014;307:E1105–16. PubMedCrossRef
41.
Strain WD, Chaturvedi N, Hughes A, Nihoyannopoulos P, Bulpitt CJ, Rajkumar C, et al. Associations between cardiac target organ damage and microvascular dysfunction: the role of blood pressure. J Hypertens. 2010;28:952–8. PubMedCrossRef
42.
Strain WD, Chaturvedi N, Bulpitt CJ, Rajkumar C, Shore AC. Albumin excretion rate and cardiovascular risk: could the association be explained by early microvascular dysfunction? Diabetes. 2005;54:1816–22. PubMedCrossRef
43.
Jumar A, Ott C, Kistner I, Friedrich S, Michelson G, Harazny JM, et al. Early signs of end-organ damage in retinal arterioles in patients with type 2 diabetes compared to hypertensive patients. Microcirculation. 2016;23:447–55. PubMedCrossRef
44.
Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, et al. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation. 2008;118:968–76. PubMedCrossRef
45.
Buus NH, Bottcher M, Jorgensen CG, Christensen KL, Thygesen K, Nielsen TT, et al. Myocardial perfusion during long-term angiotensin-converting enzyme inhibition or β-blockade in patients with essential hypertension. Hypertension. 2004;44:465–70. PubMedCrossRef
46.
von Scholten BJ, Rosendahl A, Hasbak P, Bergholdt R, Kjaer A, Rossing P, et al. Impaired coronary microcirculation in type 2 diabetic patients is associated with elevated circulating regulatory T cells and reduced number of IL-21R + T cells. Cardiovasc Diabetol. 2016;15:67. CrossRef
47.
Strain WD, Hughes AD, Mayet J, Wright AR, Kooner J, Chaturvedi N, et al. Attenuated systemic microvascular function in men with coronary artery disease is associated with angina but not explained by atherosclerosis. Microcirculation. 2013;20:670–7. PubMedCrossRef
48.
Yip W, Sabanayagam C, Ong PG, Patel UD, Chow KY, Tai ES, Ling LH, Wong TY, Cheung CY. Joint effect of early microvascular damage in the eye & kidney on risk of cardiovascular events. Sci Rep. 2016;6:27442. PubMedPubMedCentralCrossRef
49.
Mathur R, Bhaskaran K, Edwards E, Lee H, Chaturvedi N, Smeeth L, et al. Population trends in the 10-year incidence and prevalence of diabetic retinopathy in the UK: a cohort study in the Clinical Practice Research Datalink 2004–2014. BMJ Open. 2017;7:e014444. PubMedPubMedCentralCrossRef
50.
Guo VY, Cao B, Wu X, Lee JJ, Zee BC. Prospective association between diabetic retinopathy and cardiovascular disease—a systematic review and meta-analysis of cohort studies. J Stroke Cerebrovasc Dis. 2016;25:1688–95. PubMedCrossRef
51.
Wong TY, Klein R, Sharrett AR, Schmidt MI, Pankow JS, Couper DJ, et al. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA. 2002;287:2528–33. PubMedCrossRef
52.
Wong TY, Rosamond W, Chang PP, Couper DJ, Sharrett AR, Hubbard LD, et al. Retinopathy and risk of congestive heart failure. JAMA. 2005;293:63–9. PubMedCrossRef
53.
Hafner J, Ginner L, Karst S, Leitgeb R, Unterluggauer M, Sacu S, et al. Regional patterns of retinal oxygen saturation and microvascular hemodynamic parameters preceding retinopathy in patients with type II diabetes. Invest Ophthalmol Vis Sci. 2017;58:5541–7. PubMedCrossRef
54.
Liew G, Wong TY, Mitchell P, Cheung N, Wang JJ. Retinopathy predicts coronary heart disease mortality. Heart. 2009;95:391–4. PubMedCrossRef
55.
Forst T, Michelson G, Ratter F, Weber MM, Anders S, Mitry M, et al. Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med. 2012;29:1115–8. PubMedCrossRef
56.
Ott C, Raff U, Schmidt S, Kistner I, Friedrich S, Bramlage P, et al. Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes. Cardiovasc Diabetol. 2014;13:19. PubMedPubMedCentralCrossRef
57.
Berndt-Zipfel C, Michelson G, Dworak M, Mitry M, Löffler A, Pfützner A, et al. Vildagliptin in addition to metformin improves retinal blood flow and erythrocyte deformability in patients with type 2 diabetes mellitus—results from an exploratory study. Cardiovasc Diabetol. 2013;12:59. PubMedPubMedCentralCrossRef
58.
Faber R, Zander M, Pena A, Michelsen MM, Mygind ND, Prescott E. Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes—a randomized, single-blinded, cross-over pilot study. Cardiovasc Diabetol. 2015;14:41. PubMedPubMedCentralCrossRef
59.
Jax T, Stirban A, Terjung A, Esmaeili H, Berk A, Thiemann S, et al. A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes. Cardiovasc Diabetol. 2017;16:13. PubMedPubMedCentralCrossRef
60.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22. PubMedPubMedCentralCrossRef
61.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New Engl J Med. 2007;356:2457–71. PubMedCrossRef
62.
Food and Drug Association. Guidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. http://​www.​fda.​gov/​ucm/​groups/​fdagov-public/​@fdagov-drugs-gen/​documents/​document/​ucm071627.​pdf. Accessed 19 May 2017.
63.
European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012. http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Scientific_​guideline/​2012/​06/​WC500129256.​pdf. Accessed 12 July 2017.
64.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44. PubMedCrossRef
65.
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57. PubMedCrossRef
66.
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2017;377:1228–39. PubMedCrossRef
67.
Ban K, Kim KH, Cho CK, Sauvé M, Diamandis EP, Backx PH, et al. Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by Exendin (9-39) yet does not require the known GLP-1 receptor. Endocrinology. 2010;151:1520–31. PubMedCrossRef
68.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28. PubMedCrossRef
69.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34. PubMedCrossRef
70.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57. PubMedCrossRef
71.
Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017;16:26. PubMedPubMedCentralCrossRef
72.
Kim KM, Jung KY, Yun HM, Lee SY, Oh TJ, Jang HC, et al. Effect of rosuvastatin on fasting and postprandial endothelial biomarker levels and microvascular reactivity in patients with type 2 diabetes and dyslipidemia: a preliminary report. Cardiovasc Diabetol. 2017;16:146. PubMedPubMedCentralCrossRef
73.
Iacobellis G, Cipriani R, Gabriele A, Di Mario U, Morano S. High circulating vascular endothelial growth factor (VEGF) is related to a better systolic function in diabetic hypertensive patients. Cytokine. 2004;27:25–30. PubMedCrossRef
74.
Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19:927–34. PubMedCrossRef
75.
Fukami M, Iwase T, Yamamoto K, Kaneko H, Yasuda S, Terasaki H. Changes in retinal microcirculation after intravitreal ranibizumab injection in eyes with macular edema secondary to branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 2017;58:1246–55. PubMedCrossRef
76.
Svensson MK, Cederholm J, Eliasson B, Zethelius B, Gudbjörnsdottir S. Albuminuria and renal function as predictors of cardiovascular events and mortality in a general population of patients with type 2 diabetes: a nationwide observational study from the Swedish National Diabetes Register. Diab Vasc Dis Res. 2013;10:520–9. PubMedCrossRef
77.
Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med. 2003;139:901–6. PubMedCrossRef
78.
Xia F, Liu G, Shi Y, Zhang Y. Impact of microalbuminuria on incident coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis of prospective studies. Int J Clin Exp Med. 2015;8:1–9. PubMedPubMedCentral
79.
Klausen KP, Scharling H, Jensen JS. Very low level of microalbuminuria is associated with increased risk of death in subjects with cardiovascular or cerebrovascular diseases. J Intern Med. 2006;260:231–7. PubMedCrossRef
80.
Strain WD, Shore AC, Melzer D. Albumin:creatinine ratio predicts mortality after stroke: analysis of the NHANES III. J Am Geriatr Soc. 2010;58:2434–5. PubMedCrossRef
81.
Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dørup I, Nielsen TT, et al. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation. 2001;103:1109–14. PubMedCrossRef
82.
Solini A, Penno G, Bonora E, Fondelli C, Orsi E, Arosio M, et al. Diverging association of reduced glomerular filtration rate and albuminuria with coronary and non-coronary events in patients with type 2 diabetes: the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study. Diabetes Care. 2012;35:143–9. PubMedCrossRef
83.
Naidoo DP. The link between microalbuminuria, endothelial dysfunction and cardiovascular disease in diabetes. Cardiovasc J S Afr. 2002;13:194–9. PubMed
84.
Collaboration Emerging Risk Factors, 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. CrossRef
85.
Haffner SM, Lehto S, Rönnemaa T, Pyörälä 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. PubMedCrossRef
86.
Sezer M, Kocaaga M, Aslanger E, Atici A, Demirkiran A, Bugra Z, et al. Bimodal pattern of coronary microvascular involvement in diabetes mellitus. J Am Heart Assoc. 2016;5(11):e003995. PubMedPubMedCentralCrossRef
87.
El-Asrar MA, Andrawes NG, Ismail EA, Salem SM. Kallistatin as a marker of microvascular complications in children and adolescents with type 1 diabetes mellitus: relation to carotid intima media thickness. Vasc Med. 2015;20:509–17. PubMedCrossRef
88.
Hannemann MM, Liddell WG, Shore AC, Clark PM, Tooke JE. Vascular function in women with previous gestational diabetes mellitus. J Vasc Res. 2002;39:311–9. PubMedCrossRef
89.
Jaap AJ, Hammersley MS, Shore AC, Tooke JE. Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1994;37:214–6. PubMedCrossRef
90.
Hsu PC, Liao PY, Chang HH, Chiang JY, Huang YC, Lo LC. Nailfold capillary abnormalities are associated with type 2 diabetes progression and correlated with peripheral neuropathy. Medicine. 2016;95:e5714. PubMedPubMedCentralCrossRef
91.
Jaap AJ, Pym CA, Seamark C, Shore AC, Tooke JE. Microvascular function in type 2 (non-insulin-dependent) diabetes: improved vasodilation after one year of good glycaemic control. Diabet Med. 1995;12:1086–91. PubMedCrossRef
92.
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;48:1856–62. PubMedCrossRef
93.
Jonasson H, Bergstrand S, Nystrom FH, Länne T, Östgren CJ, Bjarnegård N, et al. Skin microvascular endothelial dysfunction is associated with type 2 diabetes independently of microalbuminuria and arterial stiffness. Diab Vasc Dis Res. 2017;14:363–71. PubMedCrossRef
94.
Casanova F, Adingupu DD, Adams F, Gooding KM, Looker HC, Aizawa K, et al. The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control Cardiovasc Diabetol. 2017;16:114. PubMed
95.
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;17:279–85. PubMedCrossRef
96.
Ijzerman RG, de Jongh RT, Beijk MA, van Weissenbruch MM, Delemarre-van de Waal HA, Serné EH, et al. Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin. Eur J Clin Invest. 2003;33:536–42. PubMedCrossRef
97.
Strain WD, Hughes AD, Mayet J, Wright AR, Kooner J, Chaturvedi N, et al. Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent. BMC Cardiovasc Disord. 2010;10:3. PubMedPubMedCentralCrossRef
98.
Östlund Papadogeorgos N, Jörneskog G, Bengtsson M, Kahan T, Kalani M. Severely impaired microvascular reactivity in diabetic patients with an acute coronary syndrome. Cardiovasc Diabetol. 2016;15:66. PubMedPubMedCentralCrossRef
99.
Rathsman B, Jensen-Urstad K, Nyström T. Intensified insulin treatment is associated with improvement in skin microcirculation and ischaemic foot ulcer in patients with type 1 diabetes mellitus: a long-term follow-up study. Diabetologia. 2014;57:1703–10. PubMedCrossRef
100.
Chaturvedi N, Jarrett J, Morrish N, Keen H, Fuller JH. Differences in mortality and morbidity in African Caribbean and European people with non-insulin dependent diabetes mellitus: results of 20 year follow up of a London cohort of a multinational study. BMJ. 1996;313:848–52. PubMedPubMedCentralCrossRef
101.
Strain WD, Chaturvedi N, Leggetter S, Nihoyannopoulos P, Bulpitt CJ, Rajkumar C, et al. Ethnic differences in skin microvascular function and their relation to cardiac target-organ damage. J Hypertens. 2005;23:133–40. PubMedCrossRef
102.
Strain WD, Chaturvedi N, Nihoyannopoulos P, Bulpitt CJ, Rajkumar C, Shore AC. Differences in the association between type 2 diabetes and impaired microvascular function among Europeans and African Caribbeans. Diabetologia. 2005;48:2269–77. PubMedCrossRef
103.
Lucas J, Schiller J, Benson V. Summary health statistics for US adults: National Health Interview Survey, 2001. National Center for Health Statistics. Vital Health Stat. 2004;2004(10):1–134.
104.
Harris MI, Klein R, Cowie CC, Rowland M, Byrd-Holt DD. Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites with type 2 diabetes? A US population study. Diabetes Care. 1998;21:1230–5. PubMedCrossRef
105.
Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, et al. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA. 2002;288:67–74. PubMedCrossRef
106.
Fuchs D, Dupon PP, Schaap LA, Draijer R. The association between diabetes and dermal microvascular dysfunction non-invasively assessed by laser Doppler with local thermal hyperemia: a systematic review with meta-analysis. Cardiovasc Diabetol. 2017;16:11. PubMedPubMedCentralCrossRef
107.
Clough GF, Kuliga KZ, Chipperfield AJ. Flow motion dynamics of microvascular blood flow and oxygenation: Evidence of adaptive changes in obesity and type 2 diabetes mellitus/insulin resistance. Microcirculation. 2017. https://​doi.​org/​10.​1111/​micc.​12331. CrossRefPubMed
108.
de Jong PE, Hillege HL, Pinto-Sietsma SJ, de Zeeuw D. Screening for microalbuminuria in the general population: a tool to detect subjects at risk for progressive renal failure in an early phase? Nephrol Dial Transplant. 2003;18:10–3. PubMedCrossRef