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Second-phase platelet aggregation induced by adenosine diphosphate (ADP) and epinephrine was measured in fasting platelet-rich plasma in normals, “prediabetics”, and diabetics with or without vascular disease. “Plasma factor” potentiation of ADP-induced second-phase platelet aggregation was also estimated, as were megathrombocyte numbers in the same patient groups. There was an increased sensitivity of second-phase platelet aggregation noted with both aggregating agents in all diabetic groups except for the prediabetics. This activity was paralleled by an increase in plasma factor activity. In vivo evidence of an increased turnover of platelets in frank diabetics was suggested by increased numbers of megathrombocytes. These studies demonstrate that platelets from diabetics are sensitive to aggregating agents and that this sensitivity may be related to plasma factor(s) present in diabetics. In vivo platelet aggregation may be present in diabetics. Longitudinal studies will be necessary to establish the relationship of these findings to the genesis of diabetic vascular disease.

Platelets from diabetic patients show both increased platelet adhesiveness and sensitivity to aggregating agents. Plasma levels of the platelet-active von Willebrand Factor and the closely related factor-VIII antigen are significantly elevated, while factor VIII procoagulant activity is not. This may reflect either intravascular coagulation or disproportionate production or degradation. Plasma factors that enhance ADP-induced platelet aggregation are found in 50% of unselected male diabetics. Activity is clearly demonstrated only when plasma is added immediately prior to adding subthreshold doses of ADP to platelet-rich plasma obtained from control subjects. Systematic investigations of the molecular nature of such factors and their interactions with platelets are in progress. In platelets obtained from diabetic subjects, we have previously found increased sensitivity to the aggregating effects of arachidonic acid, and increased synthesis of immunoreactive prostaglandin E-like material. More recent studies have shown that platelets obtained from diabetic subjects are less sensitive to the antiaggregatory effects of imidazole, a thromboxane synthetase inhibitor. These observations suggest that increased synthesis of the labile aggregating substance thromboxane A2 also occurs in platelets obtained from diabetics. Collectively, these platelet and plasma abnormalities may contribute to accelerated vascular disease of diabetes. Prospective studies using antiplatelet agents are presently underway or in the planning stages in diabetics to explore their potential beneficial effects.

Low density lipoproteins (LDL) isolated from poorly controlled diabetic patients are known to be taken up and degraded by fibroblasts at a lower rate than LDL isolated from normal subjects. This aberrant metabolic behavior has been attributed to a diabetic-related abnormality in LDL composition yet to be characterized. The studies reported in this article show that the decrease in uptake and intracellular degradation of LDL from diabetic patients is further enhanced when the cells are exposed to lipoprotein deficient serum (LPDS) isolated from the same poorly controlled diabetic patients. Comparative studies of the composition of LPDS obtained from normal donors and poorly controlled diabetic patients showed an increase in saturated and total unesterified fatty acids (UFA), lecithin, apolipoprotein A1, and immunoreactive insulin in the LPDS from diabetic patients. We postulate that exposure of cells to LPDS obtained from poorly controlled diabetic patients may induce changes in the composition of the fibroblast membrane and alter its fluidity, leading to further decrease in the uptake and degradation of LDL. During poor diabetic control, cell membrane changes, and modification of LDL composition are likely to act either additively or synergistically to induce an abnormal LDL-cell interaction. This abnormal interaction may be a relevant factor to explain the greater incidence of arteriosclerosis in diabetes mellitus.

The alterations in the metabolism of arachidonic acid to prostaglandin I 2 (prostacyclin), a vasodilator antiaggregatory substance, and thromboxane A 2 , a vasoconstrictor proaggregatory substance, in diabetes mellitus are reviewed in this article. When tested in vitro, platelet aggregation is enhanced in some patients with diabetes mellitus. The synthesis of thromboxane B 2 . the stable metabolite of thromboxane A 2 , by platelets is increased in patients with diabetes mellitus compared with control subjects. This increased synthesis appears to play a role in the enhanced platelet aggregation since the latter can be reversed by aspirin treatment and in vitro by the thromboxane receptor-antagonist 13-azaprostanoic acid. Vascular prostacyclin synthesis is decreased in both patients and experimental animals with diabetes mellitus. Treatment of experimental animals with insulin reverses the decreased synthesis of prostacyclin. The etiology of the altered arachidonic acid metabolism remains uncertain but appears to be multifactorial and includes alterations in metabolic control and circulating immune complexes. The increased ratio of thromboxane A 2 to prostacyclin, which favors an enhanced thrombotic state, may play a role in the accelerated vascular disease of diabetes mellitus.