Effects of the Alpha Glucosidase Inhibitor Acarbose on Endothelial Function after a Mixed Meal in Newly Diagnosed Type 2 Diabetes

Abstract

Endothelial dysfunction (ED) has been suggested as a possible causal link between postprandial hyperglycemia and cardiovascular events in patients with type 2 diabetes. Recent trials demonstrated a reduction of cardiovascular events by treatment with α-glucosidase inhibitor acarbose – a drug which mainly reduces postprandial glucose excursions. We were interested to know whether patients with newly diagnosed type 2 diabetes showed postprandial ED and if so whether acarbose was able to improve this condition. Forearm blood flow (FBF) measurements for assessment of ED were performed in the fasting and postprandial state in 20 newly diagnosed type 2 diabetic patients and 10 healthy control subjects. After baseline examination, patients were randomly assigned to a 20-week treatment of acarbose 100 mg t.i.d or matching placebo, thereafter FBF measurements were repeated. FBF of patients in the fasting state was significantly impaired compared to healthy control subjects (max. FBF 5.3±0.7 vs. 8.0±0.9 ml/100 ml, p<0.02) and did not change in the postprandial state (max. FBF 5.6±0.7 ml/100 ml). In contrast, healthy controls showed a significant improvement of FBF in the postprandial state (11.5±1.2 ml/100 ml), which is compatible with postprandial ED in the group of patients. Twenty weeks of acarbose treatment did not affect either fasting or postprandial FBF in patients. Early type 2 diabetes is a state of both fasting and postprandial ED, which is not sensitive to acarbose treatment. Protective cardiovascular effects of acarbose might involve other mechanisms.

forearm blood flow - endothelial dysfunction - postprandial - type 2 diabetes - acarbose

References

• 1 Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in Type II diabetes: the epidemiological evidence.  Diabetologia. 2001;  44 2107-2114
• 2 Hanefeld M, Ceriello A, Schwarz PE, Bornstein SR. The metabolic syndrome – a postprandial disease?.  Horm Metab Res. 2006;  38 435-436
• 3 Schwarz PE, Reimann M, Li J, Bergmann A, Licinio J, Wong ML, Bornstein SR. The Metabolic Syndrome – a global challenge for prevention.  Horm Metab Res. 2007;  39 777-780
• 4 Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited.  Arterioscler Thromb Vasc Biol. 2004;  24 816-823
• 5 Behrendt D, Ganz P. Endothelial function. From vascular biology to clinical applications.  Am J Cardiol. 2002;  90 40L-48L
• 6 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 2601-2610
• 7 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
• 8 Raitakari OT, Lai N, Griffiths K, MacCredie R, Sullivan D, Celermajer DS. Enhanced peripheral vasodilation in humans after a fatty meal.  J Am Coll Cardiol. 2000;  36 417-422
• 9 Reed AS, Charkoudian N, Vella A, Shah P, Rizza RA, Joyner MJ. Forearm vascular control during acute hyperglycemia in healthy humans.  Am J Physiol Endocrinol Metab. 2004;  286 E472-E480
• 10 Strey CH, Young J, Collier M, Florkowski CM, Shand BI, Scott RS. The postprandial state does not impair endothelial function in women with type 2 diabetes irrespective of glycaemic control.  Diabetologia. 2004;  47 1838-1846
• 11 Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, Creager MA. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.  Circulation. 1998;  97 1695-1701
• 12 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial.  JAMA. 2003;  290 486-494
• 13 Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies.  Eur Heart J. 2004;  25 10-16
• 14 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
• 15 Lind L, Sarabi M, Millgard J. Methodological aspects of the evaluation of endothelium-dependent vasodilatation in the human forearm.  Clin Physiol. 1998;  18 81-87
• 16 Pistrosch F, Koehler C, Wildbrett J, Hanefeld M. Relationship between diurnal glucose levels and HbA1c in type 2 diabetes.  Horm Metab Res. 2006;  38 455-459
• 17 Colette C, Monnier L. Acute glucose fluctuations and chronic sustained hyperglycemia as risk factors for cardiovascular diseases in patients with type 2 diabetes.  Horm Metab Res. 2007;  39 683-686
• 18 Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications.  Br J Clin Pharmacol. 2001;  52 631-646
• 19 MacVeigh GE, Brennan GM, Johnston GD, MacDermott BJ, MacGrath LT, Henry WR, Andrews JW, Hayes JR. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus.  Diabetologia. 1992;  35 771-776
• 20 Lee IK, Kim HS, Bae JH. Endothelial dysfunction: its relationship with acute hyperglycaemia and hyperlipidemia.  Int J Clin Pract Suppl. 2002;  (129) 59-64
• 21 Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E.  J Am Coll Cardiol. 2000;  36 2185-2191
• 22 Wascher TC, Schmoelzer I, Wiegratz A, Stuehlinger M, Mueller-Wieland D, Kotzka J, Enderle M. Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance.  Eur J Clin Invest. 2005;  35 551-557
• 23 Zheng H, Patel M, Cable R, Young L, Katz SD. Insulin sensitivity, vascular function, and iron stores in voluntary blood donors.  Diabetes Care. 2007;  30 2685-2689
• 24 Cleland SJ, Petrie JR, Ueda S, Elliott HL, Connell JM. Insulin-mediated vasodilation and glucose uptake are functionally linked in humans.  Hypertension. 1999;  33 554-558
• 25 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
• 26 Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site.  J Clin Invest. 2001;  108 1341-1348

Correspondence