Defective Activation of p21ras in Peripheral Blood Mononuclear Cells from Patients with Insulin Dependent Diabetes Mellitus

Abstract

We previously reported that a decreased TCR mediated activity of the GTP-GDP binding p21ras protooncogene is associated with prediabetes in non-obese diabetic (NOD) mice. Furthermore, prevention of autoimmune diabetes is associated with reversal of the p21ras signaling defect in NOD T cells. Based on these animal studies we determined the activation of p21ras in PBMC from patients with Insulin Dependent Diabetes Mellitus (IDDM), Non-Insulin Dependent 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-GAP and the guanine nucleotide releasing factor (GNRF) hSOS, was comparable in the three groups. The in vitro proliferative response to PHA was comparable in the IDDM and control groups: stimulation index (SI) of 8.6 +/- 2.5 and 9.4 +/- 3.5 respectively, p < 0.44. No correlations were found in the IDDM patients between the degree of p21ras activation and the mitogen induced in vitro proliferative response or the various clinical parameters including age, gender, disease duration, daily insulin requirements and metabolic control. Taken together these data indicate that PBMC from IDDM patients are characterized by a persistent impairment in the activation of their p21ras. They also suggest that p21ras stimulated activity is a sensitive and independent parameter of PBMC activation in these patients.

Constitutive Up-regulated Activity of MAP kinase is Associated with Down-regulated Early p21Ras Pathway in Lymphocytes of SLE Patients

“…We previously demonstrated that a similar, although not identical, aberration is also detectable in patients with autoimmune type 1 diabetes mellitus [29] and that prevention of this disease by immunomodulation results in normalization of the p21ras signalling defect in NOD mice [30]. Furthermore, we recently demonstrate in patients with another autoimmune disease namely chronic idiopathic urticaria a reduced expression of hSOS associated with aberrant signalling along the p21ras pathway [31].…”

Vitamin D and estrogen receptor gene polymorphisms in type 2 diabetes mellitus and in android type obesity

“…In type 2 diabetes, aromatase activity is decreased (19). Other genes, such as p21-ras and jun that may be involved in the pathogenesis of diabetes, also have response elements for ER (20,21).…”

Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

“…This hyporesponsiveness, characterized by a reduced in vitro TCR/CD3-mediated T cell proliferation (6,7,36,42), is correlated with an inefficient activation of PKC and/or p21 ras activation pathways, low expression of the early T cell activation marker CD69, and IL-2 secretion. The defective T cell response can be compensated by the addition of the PKC-activating drug PMA, and is not observed with a combination of agonistic anti-CD2/CD28 mAbs (7).…”

“…It then activates the p21 ras /MAPK pathway via its SH3 domain (47), leading to CD69 induction. Both CD69 expression (this study and 6) and the MAPK pathway (42) are affected in diabetes. Consequently, our results suggest that the predominant effect of a deficiency in p56 lck function in diabetic individuals might affect late activation events rather the immediate recruitment of ZAP70.…”