The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by ~25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk. Plasma IGF-I decreased 61% in the untreated diabetic group but increased toward control levels with insulin therapy. Changes in the kidney weight of these animals paralleled the changes in GFR, which was increased in insulin-treated moderately hyperglycemic animals but unchanged in untreated diabetic rats. Uncontrolled experimental diabetes is a state of sodium retention and volume expansion, with an increase in plasma ANP and urinary cGMP levels and a decrease in PRA and plasma IGF-I. Despite these changes in sodium and volume status and vasoactive hormones, untreated STZ-D was not associated with an increase in GFR or kidney size. Hyperfiltration and increased kidney growth occurred in diabetic rats with moderate hyperglycemia during insulin therapy, whereas parameters of sodium and volume status reverted toward normal. Thus, changes in GFR cannot be explained solely by sodium and volume status, the renin-angiotensin system, ANP, or plasma IGF-I, but they may be more closely related to other factors, such as the level of glycemia, the direct effects of insulin, or factors controlling kidney growth.