Acute Hyperglycemia Rapidly Suppresses Endothelium-dependent Arterial Dilation in First-degree Relatives of Type 2 Diabetic Patients

Abstract

Objective: Previous studies showed that endothelium-dependent arterial dilation is impaired in first-degree relatives of type 2 diabetes in the fasting state. In the present study, we examined whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading in this cohort.

Patients and Methods: This study included 32 normal glucose tolerant subjects. Of them, 17 with a family history (FH) of type 2 diabetic parents (FH+) and 15 with no first-degree relative with diabetes or coronary artery disease (FH-). The examination of vascular function was performed in fasting state and repeated 1 and 2 hours after a 75-g oral glucose loading by high resolution ultrasound.

Results: Endothelium- dependent arterial dilation in FH+ group were significantly lower than those in FH- before and after oral glucose loading (5.12±0.61% vs 6.03±0.56%, fasting; 4.0±0.65% vs 5.70±0.42%, 1 h; 4.43±0.61% vs 5.82±0.67% 2 h, p<0.05 each). In FH+ group, endothelium-dependent arterial dilation decreased significantly at 60 min (4.0±0.65% vs 5.12±0.61%, p<0.01) and increased markedly from 60 min at 120 min (4.43±0.61% vs 4.0±0.65%, p<0.05), which was still significantly lower than baseline (4.43±0.61% vs 5.12±0.61%, p<0.01) . In FH- group, however, the arterial dilation did not differ significantly among the three time points (p 0.05). In multiple regression analysis, endothelium-dependent arterial dilation was significantly correlated to FH+(r=-0.302, p<0.01). In addition, endothelium-dependent arterial dilation showed a correlation with plasma glucose (r=-0.460, p<0.01) and TBARS (r=-0.382, p<0.01) during OGTT in FH+ subjects.

Conclusion: Significant endothelial dysfunction is present in the fasting state, hyperglycemia in response to oral glucose loading rapidly suppresses endothelium-dependent arterial dilation in FH+ subjects, probably through increased production of oxygen-derived free radicals.

Key words

type 2 diabetes mellitus - first-degree relatives - endothelial dysfunction - acute hyperglycemia

References

• 1 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
• 2 Haffner SM, Stem MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?.  JAMA. 1990;  263 2893-2898
• 3 Haffner SM, Lehto S, Ronnemaa T, Pvorala 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;  339 229-234
• 4 Boneti PO, Lerman LO, Lerman A. Endothelial dysfunction, a marker of atherosclerotic risk.  Arterioscler Thromb Vasc Biol. 2003;  23 168-175
• 5 Yki-Jarvinen H. Insulin resistance and endothelial dysfunction.  Best Pract Res Clin Endocrinol Metab. 2003;  17 411-430
• 6 Xiang GD, Xu L, Zhao LS, Yue L, Hou J. The relationship between plasma osteoprotegerin and endothelium-dependent arterial dilation in type 2 diabetes.  Diabetes. 2006;  55 2126-2131
• 7 Martin BC, Warram JH, Krolewski AS, Bergman RN, Soldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study.  Lancet. 1992;  340 925-929
• 8 Sarlund H, Pvorala K, Penttila I, Laakso M. Early abnormalities in coronary heart disease risk factors in relatives of subjects with non-insulin-dependent diabetes.  Arterioscler Thromb. 1992;  12 657-663
• 9 Kraemer de Aguiar LG, Sicuro F, Bahia LR, Wiernsperger N, Villela N, Bottino D, Laflor C, Bouskela E. Metformin improves endothelial vascular reactivity in first-degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance.  Diabetes Care. 2006;  29 1083-1089
• 10 Østergård T, Nyholm B, Hansen TK, Rasmussen LM, Ingerslev J, Sørensen KE, Bøtker HE, Saltin B, Schmitz O. Endothelial function and biochemical vascular markers in first-degree relatives of type 2 diabetic patients: the effect of exercise training.  Metabolism. 2006;  55 1508-1515
• 11 Goldfine AB, Beckman JA, Betensky RA, Devlin H, Hurley S, Varo N, Schonbeck U, Patti ME, Creager MA. Family history of diabetes is a major determinant of endothelial function.  J Am Coll Cardiol. 2006;  47 2456-2461
• 12 Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery.  J Am Coll Cardiol. 1999;  34 146-154
• 13 Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Tsunoda R, Moriyama Y, Miyao Y, Yoshimura M, Ogawa H, Yasue H. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina.  J Am Coll Cardiol. 1998;  32 1672-1679
• 14 Buege JA, Aust SD. Microsomal lipid peroxidation.  Methods Enzymol. 1987;  52 302-310
• 15 Xiang GD, Wu YH. Apolipoprotein e4 allele and endothelium-dependent arterial dilation in type 2 diabetes mellitus without angiopathy.  Diabetologia. 2003;  46 514-519
• 16 Xiang GD, Wang YL. Regular aerobic exercise training improves endothelium-dependent artery dilation in patients with impaired fasting glucose.  Diabetes Care. 2004;  27 801-802
• 17 Caballero AE, Arora S, Saouaf R, Lim SC, Smakowski P, Park JY, King GL, LoGerfo FW, Horton ES, Veves A. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.  Diabetes. 1999;  48 1856-1862
• 18 Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Pett K, Haring HU. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance.  Circulation. 2000;  101 1780-1784
• 19 Lee BC, Shore AC, Humphreys JM, Lowe GD, Rumley A, Clark PM, Hattershey AT, Tooke JE. Skin microvascular vasodilatory capacity in offspring of two parents with type 2 diabetes.  Diabet Med. 2001;  18 541-545
• 20 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;  37 214-216
• 21 Shaw JE, Hodge AM, Courten M de, Chitson P, Zimmer PZ. Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality.  Diabetologia. 1999;  42 1050-1054
• 22 Boneti PO, Lerman LO, Lerman A. Endothelial dysfunction, a marker of atherosclerotic risk.  Arterioscler Thromb Vasc Biol. 2003;  23 168-175
• 23 Balkau B, Shipley M, Jarrett RJ, Pyorala K, Pyorala M, Forhan A, Eschwege E. High blood glucose cncentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.  Diabetes Care. 1998;  21 360-367
• 24 Gryglewski RJ, Palmer RMJ, Moncada S. Superoxide anion is involved in the breakdown of endothelium-dependent vascular relaxing factor.  Nature (Lond). 1986;  320 454-456
• 25 Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose.  Am J Physiol. 1992;  263 H321-326
• 26 Rubanyi GM, Vanhoutte PM. Oxygen-derived free radicals, endothelium, and responsiveness of vascular smooth muscle.  Am J Physiol. 1986;  250 H815-821
• 27 Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology.  Pharmacol Rev. 1991;  43 109-142
• 28 Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly.  Am J Physiol. 1996;  271 C1424-C1437
• 29 Hsueh WA, Quinones MJ. Role of endothelial dysfunction in insulin resistance.  Am J Cardiol. 2003;  92 10-71

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