The kallikrein kinin system has been suggested to participate in control of glucose metabolism. Its role and the role of angiotensin I converting enzyme, major kinin-inactivating enzyme, are however debated. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on development of insulin resistance and diabetes in mouse and man.Mice with inactivation of the tissue kallikrein gene were fed high-fat diet for 3 months, or crossed with obese, leptin deficient (ob/ob) mice to generate double ob/ob-TK deficient mutants. In man, a loss-of-function polymorphism of the tissue kallikrein gene (R53H) was studied in a large general population cohort tested for insulin resistance, the D.E.S.I.R study (4,843 participants, 9 year follow-up).Mice deficient in tissue kallikrein gained less weight on high-fat diet than wild-type littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks of high-fat diet compared to standard diet but tissue kallikrein deficiency had no influence on these parameters. Likewise, ob-TK-/- mice had similar GTT and ITT responses compared to ob-TK+/+ mice. Tissue kallikrein deficiency had no effect on blood pressure in both models. In humans, changes over time in body mass index, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective 53H-coding tissue kallikrein allele. Incidence of diabetes was not influenced by this allele.These data do not support a role for tissue kallikrein-kinin system, protective or deleterious, in development of insulin resistance and diabetes.