The effect of progressive increases in intraluminal glucose concentration on proximal tubule sodium absorption was studied in normal and streptozotocin diabetic rats by microperfusion. Each tubule was perfused twice, with and without glucose added to the perfusion fluid. Net sodium and water absorption were markedly enhanced by 300-500 mg% intraluminal glucose in both normal and diabetic rats. Substituting the transported but nonmetabolized glucose analogue, alpha-methyl D-glucoside for glucose also resulted in marked stimulation of sodium absorption, whereas substituting bicarbonate and acetate for chloride in the perfusion solution inhibited the effect of glucose. These observations suggest that the stimulation of sodium absorption by glucose was mediated by the brush border Na/glucose cotransporter. Sodium concentration and osmolality were found to fall markedly to hypotonic levels when high glucose concentrations were in the perfusion fluid. This luminal hypotonicity may be an important driving force for proximal fluid absorption. In poorly controlled diabetes, high filtered glucose concentrations may lead to enhanced proximal sodium and water absorption, which could in turn contribute to volume expansion, hypertension, and renal hypertrophy.