Diabetes Care, Vol 21, Issue 1 121-126, Copyright © 1998 by American Diabetes Association

ARTICLES

Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM

G Anfossi, EM Mularoni, S Burzacca, MC Ponziani, P Massucco, L Mattiello, F Cavalot and M Trovati
Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy.

OBJECTIVE: Previous studies in our laboratory showed that the platelet anti-aggregating effect exerted by insulin, mediated by a nitric oxide (NO)-induced increase of guanosine-3',5'-cyclic monophosphate (cGMP), is lost in the insulin-resistant of obesity and obese NIDDM. It is not clear 1) whether the alterations observed in obese NIDDM patients are attributable to the obesity-related insulin resistance or to diabetes per se and 2) whether insulin-resistant states present a normal or a blunted response to NO. This study has been conducted to investigate 1) the platelet sensitivity to insulin in lean NIDDM and 2) the platelet sensitivity to an NO donor, glyceryl trinitrate (GTN), in obesity and in both lean and obese NIDDM. RESEARCH DESIGN AND METHODS: We determined 1) ADP-induced platelet aggregation and platelet cGMP content in platelet-rich plasma (PRP) obtained from 11 lean NIDDM patients, after a 3-min incubation with insulin (0, 240, 480, 960, 1,920 pmol/l) and 2) ADP-induced platelet aggregation and platelet cGMP content in PRP obtained from 9 obese subjects, 11 lean and 8 obese NIDDM patients, and 18 control subjects, after a 3-min incubation with 0, 20, 40, and 100 mumol/l GTN. RESULTS: Insulin dose-dependently decreased platelet aggregation in lean NIDDM patients (P = 0.0001): with 1,920 pmol/l of insulin, ADP ED50 was 141.5 +/- 6.4% of basal values (P = 0.0001). Furthermore, insulin increased platelet cGMP (P = 0.0001) from 7.5 +/- 0.2 to 21.1 +/- 3.7 pmol/10(9) platelets. These results were similar to those previously described in healthy subjects. GTN reduced platelet aggregation in all the groups (P = 0.0001) at all the concentrations tested (P = 0.0001), but GTN IC50 values were much higher in insulin-resistant patients: 36.3 +/- 5.0 mumol/l in healthy control subjects, 26.0 +/- 6.0 mumol/l in lean NIDDM patients (NS vs. control subjects), 123.6 +/- 24.0 mumol/l in obese subjects (P = 0.0001 vs. control subjects), and 110.1 +/- 19.2 mumol/l in obese NIDDM patients (P = 0.0001 vs. control subjects). GTN dose-dependently increased platelet cGMP in all the groups (P = 0.0001 in control subjects, lean NIDDM patients, and obese subjects; P = 0.04 in obese NIDDM patients). Values reached by obese subjects and obese NIDDM patients, however, were lower than those reached by control subjects (with 100 mumol/l of GTN, P = 0.001 and P = 0.0001, respectively). In healthy control subjects and in obese subjects, the insulin:glucose ratio, used as an indirect measure of insulin sensitivity, was positively correlated to GTN IC50 (r = 0.530, P = 0.008), further suggesting that the sensitivity to NO is reduced in the presence of insulin resistance. CONCLUSIONS: The insulin anti-aggregating effect is preserved in lean NIDDM; platelet sensitivity to GTN in preserved in lean NIDDM but is reduced in the insulin-resistant states of obesity and obese NIDDM. Resistance to nitrates, therefore, could be considered another feature of the insulin-resistance syndrome.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Russo, P. Del Mese, G. Doronzo, L. Mattiello, M. Viretto, A. Bosia, G. Anfossi, and M. Trovati Resistance to the Nitric Oxide/Cyclic Guanosine 5'-Monophosphate/Protein Kinase G Pathway in Vascular Smooth Muscle Cells from the Obese Zucker Rat, a Classical Animal Model of Insulin Resistance: Role of Oxidative Stress Endocrinology, April 1, 2008; 149(4): 1480 - 1489. [Abstract] [Full Text] [PDF]

				I. Russo, P. Del Mese, G. Doronzo, A. De Salve, M. Secchi, M. Trovati, and G. Anfossi Platelet Resistance to the Antiaggregatory Cyclic Nucleotides in Central Obesity Involves Reduced Phosphorylation of Vasodilator-Stimulated Phosphoprotein Clin. Chem., June 1, 2007; 53(6): 1053 - 1060. [Abstract] [Full Text] [PDF]

				S. R. Willoughby, S. Stewart, A. S. Holmes, Y. Y. Chirkov, and J. D. Horowitz Platelet Nitric Oxide Responsiveness: A Novel Prognostic Marker in Acute Coronary Syndromes Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2661 - 2666. [Abstract] [Full Text] [PDF]

				L. A. Vazquez, F. Pazos, J. R. Berrazueta, C. Fernandez-Escalante, M. T. Garcia-Unzueta, J. Freijanes, and J. A. Amado Effects of Changes in Body Weight and Insulin Resistance on Inflammation and Endothelial Function in Morbid Obesity after Bariatric Surgery J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 316 - 322. [Abstract] [Full Text] [PDF]

				H. Lei, G. Romeo, and A. Kazlauskas Heat Shock Protein 90{alpha}-Dependent Translocation of Annexin II to the Surface of Endothelial Cells Modulates Plasmin Activity in the Diabetic Rat Aorta Circ. Res., April 16, 2004; 94(7): 902 - 909. [Abstract] [Full Text] [PDF]

				M. Frenneaux New tricks for an old drug Eur. Heart J., December 2, 2002; 23(24): 1898 - 1899. [PDF]

				J. Westerbacka, H. Yki-Jarvinen, A. Turpeinen, A. Rissanen, S. Vehkavaara, M. Syrjala, and R. Lassila Inhibition of Platelet-Collagen Interaction: An In Vivo Action of Insulin Abolished by Insulin Resistance in Obesity Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 167 - 172. [Abstract] [Full Text] [PDF]

				N. Haramaki, H. Ikeda, Y. Takajo, A. Katoh, S. Kanaya, S. Shintani, R. Haramaki, T. Murohara, and T. Imaizumi Long-Term Smoking Causes Nitroglycerin Resistance in Platelets by Depletion of Intraplatelet Glutathione Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1852 - 1856. [Abstract] [Full Text] [PDF]

				A. I. Vinik, T. Erbas, T. S. Park, R. Nolan, and G. L. Pittenger Platelet Dysfunction in Type 2 Diabetes Diabetes Care, August 1, 2001; 24(8): 1476 - 1485. [Abstract] [Full Text] [PDF]

				Y. Y. Chirkov, A. S. Holmes, S. R. Willoughby, S. Stewart, R. D. Wuttke, P. R. Sage, and J. D. Horowitz Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1851 - 1857. [Abstract] [Full Text] [PDF]