The effect of insulin treatment on the renal hypertrophy and elevated renal Na+, K+-ATPase activity in rats with streptozotocin (STZ)-induced diabetes was examined. Rats with STZ-diabetes of 6- to 8-week duration had significantly lower body weights, higher plasma and urinary glucose concentrations, greater urinary volumes, increased kidney weights, and increased kidney/body weights and protein/kidney weight ratios compared to those in saline-citrate-injected controls. Specific Na+, K+-ATPase activity per mg protein in both cortical and outer medullary kidney homogenates was significantly elevated in diabetic us. control animals, as was total renal Na+, K+- ATPase activity. One week of insulin treatment returned elevated plasma glucose, urinary volume, the protein/kidney weight ratio, and cortical and outer medullary Na+, K+-ATPase activity per mg protein to control values. Kidney weights and kidney/ body weight ratios of diabetic animals remained elevated, as did absolute total renal Na+, K+-ATPase activity. After 3 weeks of insulin treatment, kidney weight and total renal Na+, K+-ATPase activity in diabetic animals returned to control values, but body weights remained lower than those in the controls, resulting in continued elevation of kidney/body weight ratios in the diabetic animals. The concurrent regression of both renal hypertrophy and elevated Na+, K+-ATPase activity to normal levels after insulin treatment of STZ-diabetic animals implicates renal growth rather than a direct effect of insulin as the primary factor controlling elevation and regression of Na+, K+-ATPase activity in the diabetic kidney. This finding demonstrates that the effect of renal hypertrophy can outweigh the intrinsic effects of insulin on an important renal transport system and that this effect may be as important as lack of hormone in determining the renal physiological responses in the disease. It is suggested that the increased renal tubular Na+, K+-ATPase activity is a key component of the renal hypertrophy and hyperfunction seen in diabetes. © 1987 by The Endocrine Society.