Decreased platelet phosphoinositide turnover and enhanced platelet activation in IDDM.
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 beta-thromboglobulin (beta-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 less than .005). [32P]orthophosphate (32Pi) incorporation into the individual phosphoinositides and phosphatidic acid (PA) reached isotopic equilibrium by 120 min for IDDM and control subjects. Specific activity (dpm 32P/micrograms phosphorus) of phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) was not different between IDDM and control subjects. Under these conditions, basal 32Pi 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 less than .005) in the platelets from IDDM (0.71 +/- 0.23 nmol/10(9) platelets) compared with control (1.65 +/- 0.53 nmol/10(9) platelets) subjects. Similarly, PIP was lower (P less than .001) in IDDM (0.66 +/- 0.09 nmol/10(9) platelets) than in control (2.92 +/- 0.43 nmol/10(9) platelets) subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Bastyr
E J
EJ
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0331.
Kadrofske
M M
MM
Dershimer
R C
RC
Vinik
A I
AI
D000328:Adult; D001792:Blood Platelets / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D006801:Humans; D006868:Hydrolysis; D010712:Phosphatidic Acids / Q000097:blood; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000097:blood*; D011197:Potassium Radioisotopes; D001620:beta-Thromboglobulin / Q000032:analysis
D010712:Phosphatidic Acids; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011197:Potassium Radioisotopes; D001620:beta-Thromboglobulin; C037178:phosphatidylinositol 4-phosphate