1. In insulin-dependent diabetes mellitus, hyperglycaemia has a profound effect on renal and systemic haemodynamic function. The mechanism for this is unknown. 2. We conducted a study in 11 males with insulin-dependent diabetes mellitus, within 6 years of diagnosis. We examined the neurohumoral, haemodynamic and renal variables during euglycaemia (4.0-6.0 mmol/l) and after a 12 h period of hyperglycaemia (8.5-10.5 mmol/l). Subjects were examined in a sodium-replete state during supine rest and during simulated orthostatic stress induced by lower body negative pressure at -15 mmHg. 3. Variations in glycaemia markedly influenced plasma renin activity, which was increased at baseline during hyperglycaemia (3.82 +/- 0.66 pmol of angiotensin I h-1 ml-1 compared with 2.13 +/- 0.33 pmol of angiotensin I h-1 ml-1 during euglycaemia, P = 0.009), and rose further during simulated orthostatic stress. Mean arterial pressure was also elevated during hyperglycaemia (89 +/- 2 mmHg compared with 81 +/- 3 mmHg during euglycaemia, P = 0.03), both at rest and during orthostatic stress. 4. The renal haemodynamic effects of hyperglycaemia included maintenance of glomerular filtration rate in the face of significant declines in renal blood flow, and a probable increase in filtration fraction (0.21 +/- 0.01 compared with 0.18 +/- 0.01 during euglycaemia, P = 0.06). The responses of mean arterial pressure and renal blood flow to simulated orthostatic stress were not affected by hyperglycaemia, but the forearm vascular response was significantly augmented. 5. These data suggest that sustained hyperglycaemia activates the renin-angiotensin system, thereby increasing systemic and renal vasomotor tone. Over time such changes may have deleterious microvascular consequences.