Individuals with diabetes mellitus may have increased in vivo platelet activity. Abnormal platelet function could contribute to the increased incidence of vascular disease in diabetes mellitus. The biochemical mechanism(s) for platelet hyperactivation is unknown. We examined the hypothesis that platelet phosphoinositide turnover, a key signal-transducing mechanism involved in platelet activation, was abnormal in diabetic subjects. Platelets were harvested from 16 subjects with insulin-dependent diabetes mellitus (IDDM) and 19 healthy, nondiabetic control subjects of comparable age. Plasma β-thromboglobulin (β-TBG), a specific marker of platelet activity in vivo, was increased in IDDM (67.1 ± 7.3 ng/ ml) compared with control (41.0 ± 6.0 ng/ml) subjects (P < .005). [32P]orthophosphate (32P1) incorporation into the individual phosphoinositides and phosphatidic acid (PA) reached isotopie equilibrium by 120 min for IDDM and control subjects. Specific activity (dpm 32P/μg phosphorus) of phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) was not different between IDDM and control subjects. Under these conditions, basal 32P, incorporation into PIP2 and PIP but not phosphatidylinositol (PI) or PA was significantly lower in IDDM subjects. There was significantly decreased [32P]PIP2 and [32P]PIP hydrolysis and decreased [32P]PA formation in IDDM after platelet stimulation with 4 U/ml human thrombin. There were no differences in [32P]PI hydrolysis between the two groups. The mass of PIP2 was reduced (P < .005) in the platelets from IDDM (0.71 ± 0.23 nmol/109 platelets) compared with control (1.65 ± 0.53 nmol/109 platelets) subjects. Similarly, PIP was lower (P < .001) in IDDM (0.66 ± 0.09 nmol/109 platelets) than in control (2.92 ± 0.43 nmol/109 platelets) subjects. There were no differences in PI and PA mass between the two groups. We conclude that increased platelet activation in IDDM is associated with a decrease in platelet polyphosphoinositide content and hydrolysis of PIP and PIP2. These data suggest that altered phosphoinositide turnover may play a role in abnormal platelet function in IDDM.

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