Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1

GLP-1 and GIP are insulin-releasing 'incretin' hormones inactivated following degradation by dipeptidyl peptidase IV. Incretin hormone analogues resistant to degradation by DPP IV, as well as, inhibitors of DPP IV are in development as novel treatments for type 2 diabetes. The biguanide metformin is an oral agent commonly prescribed to treat type 2 diabetes. Antidiabetic actions of metformin involve the reduction of hepatic glucose production and/or insulin resistance. Recent reports indicate that metformin may have the additional property of inhibiting DPP IV activity. Here we examine the effects of metformin on plasma DPP IV activity of normal and ob/ob diabetic mice. DPP IV activity present in mouse plasma was concentration-dependently inhibited by metformin generating IC(50) values of 38 microM for…