IMPAIRED INSULIN-INDUCED PLATELET ANTIAGGREGATING EFFECT IN OBESITY AND IN OBESE NIDDM PATIENTS

To investigate the effects of insulin on platelets in obesity and in non-insulin-dependent diabetes mellitus (NIDDM) -classic insulin-resistant states-we determined ADP-induced platelet aggregation and platelet cGMP (guanosine 3',5'-cyclic monophosphate) content in platelet-rich plasma obtained from nine obese subjects and nine age-matched healthy volunteers and from eight NIDDM obese patients and nine age-matched healthy volunteers after a 3-min incubation with human recombinant insulin (0, 240, 480, 960, and 1,920 pmol/l). Platelet aggregation was evaluated using different ADP doses to measure the ADP concentration determined on the basis of a dose-response curve necessary to elicit a maximal aggregation of 50% (ED,,). Insulin induced a dose-dependent decrease of platelet aggregation to ADP (P = 0.0001) in healthy subjects. A significant effect was evident starting from an insulin concentration of 240 pmol/l. On the contrary, in insulin-resistant subjects, insulin reduced platelet sensitivity to ADP only at a concentration of 1,920 pmol/l. When ADP ED(50) values obtained in platelet-rich plasma incubated with insulin were expressed in percentage of the ADP ED(5)0 values obtained in platelet-rich plasma without insulin, considered as 100%, we observed that ADP ED(50) with 1,920 pmol/l insulin was 153.6 +/- 13.2% in the younger healthy subject group (P = 0.004), 150.0 +/- 3.8% in the older healthy subject group (P = 0.0001), 116.1 +/- 6.1% in obese subjects (P = 0.031), and 120.0 +/- 8.6% in NIDDM patients (P = 0.05). In healthy subjects, insulin induced a dose-depentdent increase of platelet cGMP (P = 0.0001). A significant effect was evident starting from an insulin concentration of 240 pmol/l; cGMP values rose from 7.9 +/- 1.4 to 14.6 +/- 2.5 pmol/10(9) platelets with 1,920 pmol/l insulin in the younger healthy subject group (P = 0.0001) and from 7.5 +/- 0.1 to 13.4 +/- 1.4 pmol/l platelets in the older healthy subject group (P = 0.003). In obese subjects and in NIDDM patients, insulin induced an increase of cGMP only at 1,920 pmol/l: from 7.6 +/- 0.7 to 9.8 +/- 1.4 pmol/10(9) platelets in obese subjects (P = 0.07) and from 7.5 +/- 0.5 to 9.5 +/- 0.9 pmol/10(9) platelets in NIDDM patients (P = 0.07). The platelet antiaggregating effect exerted by insulin, attributable to the increase of platelet cGMP content, is impaired in obesity and in obese NIDDM patients. These data indicate that human platelets are a site of insulin resistance.