First, we analyze the phenotype of high‐fat diet (HFD)‐fed SSTR5 knockout (KO) mice and evaluate the therapeutic potential of SSTR5 antagonism for diabetic phenotypes, including insulin resistance, using a novel selective SSTR5 antagonist (compound‐1)36 in male KK‐Ay/Ta Jcl mice (KK‐Ay mice), a model of obese type 2 diabetes with severe insulin resistance. The gene discussed is SSTR5; the disease is type 2 diabetes mellitus.