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 normal mice and 29 microM for ob/ob mice. In vivo metformin lowered plasma DPP IV activity in ob/ob mice, and improved glucose-lowering and insulin-releasing effects of exogenous GLP-1 administration. This was associated with increased circulating concentrations of active GLP-1(7-36)amide. In contrast metformin had minor effects on in vitro GLP-1-stimulated insulin release from clonal beta cells. Long-term (12 day) oral metformin administration to ob/ob mice resulted in lower DPP IV activity but had no effect on basal glucose and insulin levels. These findings indicate that metformin decreases the plasma DPP IV activity, limiting the inactivation of exogenously administered GLP-1 and improving glycaemic control.
Green
Brian D
BD
School of Biological Sciences, Queens University Belfast, David Keir Building, Stranmillis Road, Belfast BT9 5AG, Northern Ireland. b.green@qub.ac.uk <b.green@qub.ac.uk>
Irwin
Nigel
N
Duffy
Nicola A
NA
Gault
Victor A
VA
O'harte
Finbarr P M
FP
Flatt
Peter R
PR
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology / Q000517:prevention & control*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005215:Fasting / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D013997:Time Factors
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D018819:Dipeptidyl Peptidase 4; D005947:Glucose