We demonstrated that i) deletion of SSTR5 in mice suppresses insulin resistance induced by high‐fat diet feeding, ii) an SSTR5 antagonist exhibits antidiabetic effects and improves hepatic insulin sensitivity in obese diabetic KK‐Ay mice, and iii) an SSTR5 antagonist alleviates the suppression effect of somatostatin agonist on insulin‐induced Akt phosphorylation in the liver in mice. This evidence concerns the gene SSTR5 and Insulin resistance.