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 n on-insulin-dependent diabetes mellitus (NIDDM) -classic insulin-resist ant 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 he althy volunteers after a 3-min incubation with human recombinant insul in (0, 240, 480, 960, and 1,920 pmol/l). Platelet aggregation was eval uated using different ADP doses to measure the ADP concentration deter mined on the basis of a dose-response curve necessary to elicit a maxi mal aggregation of 50% (ED,,). Insulin induced a dose-dependent decrea se 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 incuba ted 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 +/- 1 3.2% 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 obe se subjects (P = 0.031), and 120.0 +/- 8.6% in NIDDM patients (P = 0.0 5). 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 insul in 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 grou p (P = 0.003). In obese subjects and in NIDDM patients, insulin induce d 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, attributabl e 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.