PLATELET RESISTANCE TO NITRATES IN OBESITY AND OBESE NIDDM, AND NORMAL PLATELET SENSITIVITY TO BOTH INSULIN AND NITRATES IN LEAN NIDDM

OBJECTIVE - Previous studies in our laboratory showed that the platele t anti-aggregating effect exerted by insulin, mediated by a nitric oxi de (NO)-induced increase of guanosine-3',5'-cyclic monophosphate (cGMP ), is lost in the insulin-resistant states of obesity and obese NIDDM. It is not clear 1) whether the alterations observed in obese NIDDM pa tients are attributable to the obesity-related insulin resistance or t o diabetes per se and 2) whether insulin-resistant states present a no rmal or a blunted response to NO. This study has been conducted to inv estigate 1) the platelet sensitivity to insulin in lean NIDDM and 2) t he 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 pati ents, after a 3-min incubation with insulin (0, 240, 480, 960, 1,920 p mol/l) and 2) ADP-induced platelet aggregation and platelet cGMP conte nt in PRP obtained from 9 obese subjects, 11 lean and 8 obese NIDDM pa tients, and 18 control subjects, after a 3-min incubation with 0, 20, 40, and 100 mu mol/l GTN. RESULTS-Insulin dose-dependently decreased p latelet aggregation in lean NIDDM patients (P = 0.0001): with 1,920 pm ol/l of insulin, ADP ED50 was 141.5 +/- 6.4% of basal values (P = 0.00 01). 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 sim ilar to those previously described in healthy subjects. GTN reduced pl atelet aggregation in all the groups (P = 0.0001) at all the concentra tions tested (P = 0.0001), but GTN IC50 values were much higher in ins ulin-resistant patients: 36.3 +/- 5.0 mu mol/l in healthy control subj ects, 26.0 +/- 6.0 mu mol/l in lean NIDDM patients (NS vs. control sub jects), 123.6 +/- 24.0 mu mol/l in obese subjects (P = 0.0001 vs. cont rol subjects), and 110.1 +/- 19.2 mu mol/l in obese NIDDM patients (P = 0.0001 vs. control subjects). GTN dose-dependently increased platele t cGMP in all the groups (P = 0.0001 in control subjects, lean NIDDM p atients, and obese subjects; P = 0.04 in obese NIDDM patients). Values reached by obese subjects and obese NIDDM patients, however, were low er than those reached by control subjects (with 100 mu mol/l of GTN, P = 0.001 and P = 0.0001, respectively). In healthy control subjects an d in obese subjects, the insulin:glucose ratio, used as an indirect me asure 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 insu lin anti-aggregating effect is preserved in lean NIDDM; platelet sensi tivity to GTN is 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-resistan ce syndrome.