Reversal of increased lymphocyte PC-1 activity in patients with type 2 diabetes treated with metformin

The plasma cell differentiation antigen (PC-1) is an inhibitor of insulin receptor tyrosine kinase activity, and has been implicated in the pathogenesis of insulin resistance in Type 2 diabetes. Metformin increases peripheral insulin sensitivity and, therefore, we have studied the effect of metformin treatment on lymphocyte PC-1 (ecto-alkaline phosphodiesterase I, APD) in patients with Type 2 diabetes.

Basal, concanavalin A (Con A)-, and phorbol-12-myristate-13-acetate (PMA)-stimulated lymphocyte PC-1, aminopeptidase N (APN), and dipeptidylpeptidase IV (DPP IV) activities were determined in 16 patients with Type 2 diabetes before and after 3 months of metformin treatment.

Lymphocyte PC-1 in patients with Type 2 diabetes was increased significantly (p<0.001) over control; however, metformin treatment brought its activity in unstimulated and Con A-stimulated lymphocytes to the control level. PMA-stimulated PC-1 in patients with Type 2 diabetes was 17-times higher than in controls, and was reduced to near the control level by 3-month metformin treatment. In Type 2 diabetes, PMA-stimulated ecto-DPP IV was significantly (p<0. 005) increased over control, but was reduced after metformin treatment.

This study has shown an increased activity of lymphocyte PC-1 in Type 2 diabetes and its reversal by 3-month metformin treatment, corresponding to the improvement of insulin sensitivity. Data obtained are consistent with a role of PC-1 in insulin resistance and suggest a new mechanism of action for metformin via PC-1 inhibition.