Insulin and insulin‐like growth factor‐1 (IGF‐1) are known to stimulate ENaC‐mediated sodium transport in the collecting duct (CD) cells. Yet, elevated insulin levels favor kaliuresis, whereas IGF‐1 causes renal NaCl retention. The mechanism causing this phenomenon remains unexplored. Electrogenic ENaC‐mediated Na+ transport in the collecting duct establishes driving force for Cl‐ reabsorption and K+ secretion. Basolaterally localized Kir4.1/5.1 channels facilitate sodium reabsorption and potassium secretion in principal cells. Chloride ClC‐K2 channel, expressed at the basolateral membrane of intercalated cells, mediates trans‐cellular Cl‐ transport in this tubular segment. Using patch‐clamp electrophysiology in freshly isolated CD, we found that insulin acutely stimulates basolateral potassium Kir4.1/5.1 channels in a PI3 kinase‐dependent manner in principal cells, but inhibits basolateral chloride ClC‐K2 channels in intercalated cells via a MAPK‐dependent pathway. On the contrary, IGF‐1 markedly activates ClC‐K2 channel in intercalated cells by activating PI3 kinase. Therefore, we conclude that insulin, by stimulating transport in principal cells only, favors coupling of Na+ reabsorption with K+ secretion at the apical membrane contributing to kaliuresis. On the other side, IGF‐1, by activating ENaC in principal cells and ClC‐K2 channels in intercalated cells, promotes net NaCl retention.