Defective activation of p21ras in peripheral blood mononuclear cells from patients with insulin dependent diabetes mellitus

We previously reported that a decreased TCR mediated activity of the GTP-GD P binding p21ras protooncogene is associated with prediabetes in non-obese diabetic (NOD) mice. Furthermore, prevention of autoimmune diabetes is asso ciated with reversal of the p21ras signaling defect in NOD T cells. Based o n these animal studies we determined the activation of p21ras in PBMC from patients with Insulin Dependent Diabetes Mellitus (IDDM), Non-Insulin Depen dent Diabetes Mellitus (NIDDM) and normal healthy controls. Stimulation by PHA induced a decrease of 3.7 +/- 1.4% and an increase of 2.44 +/- 2.3%, p < 0.02 and 2.6 +/- 1.6%,p < 0.003 in the basal unstimulated p21ras activity in the IDDM, NIDDM and normal control groups, respectively, Expression of p21ras and its regulatory elements, the GTPase activating protein p120ras-G AP and the guanine nucleotide releasing factor (GNRF) hSOS, was comparable in the three groups. The in vitro proliferative response to PHA was compara ble in the IDDM and control groups: stimulation index (SI) of 8.6 +/- 2.5 a nd 9.4 +/- 3.5 respectively, p < 0.44, No correlations were found in the ID DM patients between the degree of p21ras activation and the mitogen induced in vitro proliferative response or the various clinical parameters includi ng age, gender, disease duration, daily insulin requirements and metabolic control, Taken together these data indicate that PBMC from IDDM patients ar e characterized by a persistent impairment in the activation of their p21ra s, They also suggest that p21ras stimulated activity is a sensitive and ind ependent parameter of PBMC activation in these patients.