The Na+,K+-ATPase plays akey role in the absorption of electrolytes, water, andnutrients from the small intestine. The effect ofstreptozotocin-induced diabetes mellitus (STZ-DM) on theactivity and expression of Na+,K+-ATPase in therat small intestine was examined in the present study.Diabetes mellitus was induced by a singleintraperitoneal injection of STZ (75 mg/kg) and controland STZ-DM rats were killed at day 30 (chronic diabetic state). Levels ofNa+,K+-ATPase activity and numbersof sodium pumps were increased two- to threefold in thejejunum and ileum. Sodium pump kinetics were unalteredin STZ-DM. The levels ofNa+,K+-ATPase alpha1 and beta1isoform protein, corresponding mRNAs, and levels oftranscription were increased in the jejunal and ilealmucosa of the chronically diabetic rat. The increases in Na+,K+-ATPasefunctional activity, protein expression, and mRNA weremost marked at the level of the ileal mucosa. While aproximal to distal gradient inNa+,K+ATPase activity and subunitisoform protein levels were observed in both control anddiabetic rats, levels of subunit isoform mRNA abundancewere similar in both regions of the small intestine inboth groups of rats. The alterations in small intestinal Na+,K+-ATPase expressionin the chronic diabetic state appear to involvealterations in transcriptional and posttranscriptionalevents and may likely represent an adaptive responsethat leads to increased Na+-coupled monosaccharideabsorption in the context of a perceived state ofnutrient depletion.