This study showed for the first time the stimulating action of peptides of the insulin family, insulin-like growth factor-1, relaxin, and epidermal growth factor (EGF) on the activity of the adenilate cyclase signal system (ACSS) in lymphocytes from the subjects of the control group. These hormonal effects were enhanced in the presence of guanylimidodiphosphate (GIDP). Moreover, leptin was for the first time shown to increase adenilate cyclase activity in lymphocytes from the control subjects and inhibition of this action by antibodies against leptin receptors. The patients presenting with type 2 diabetes mellitus (DM2) showed the enhanced baseline activity of adenilate cyclase in their lymphocytes whereas its stimulation by the above hormones, both in the presence and absence of GIDP, sharply declined. The influence of leptin on adenilate cyclase activity in patients with DM2 was apparent only at its concentrations above 10–8 M; it was inhibited by antibodies to leptin receptors. The results of this study indicate that disturbances of hormonal stimulation of adenilate cyclase activity in lymphocites of diabetic patients may be due to functional defects located at the receptor level in the case of leptin and at the level of Gs protein and its coupling to adenulate cyclase in case of peptides of the insulin family and GF. These findings confirm the concept being developed by the author according to which molecular defects in the hormone-dependent ACSS system constitute one of the main causes underlying the development of DM2.