In this study, we demonstrated for the first time that circulating CETP, 1) exacerbate glucose intolerance, lower plasma insulin concentrations but increase insulin sensitivity; 2) increase free cholesterol accumulation in the islets; 3) reduce the expression of the genes which participate in beta cell proliferation and differentiation, resulting in fewer and smaller islet number and size; 4) induced the expression of the genes which are involved in inflammation, ER stress, and apoptosis; and 5) finally and most importantly, circulating CETP decreased insulin secretion from islet beta cells. The gene discussed is INS; the disease is Glucose intolerance.