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

Brian D Green, Nigel Irwin, Nicola A Duffy, Victor Gault, Finbarr O'Harte, Peter Flatt

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Abstract

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 IC50 values of 38 mu m for normal mice and 29 mu m for ob/ob mice. In vivo metformin lowered plasma DPP TV 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-I and improving glycaemic control. (c) 2006 Elsevier B.V. All rights reserved.
LanguageEnglish
Pages192-199
JournalEuropean Journal of Pharmacology
Volume547
Issue number1-3
DOIs
Publication statusPublished - Oct 2006

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Dipeptidyl Peptidase 4
Glucagon-Like Peptide 1
Metformin
Hypoglycemic Agents
Insulin
Incretins
Glucose
Type 2 Diabetes Mellitus
Hormones
Biguanides
Inhibitory Concentration 50
Oral Administration
Insulin Resistance

Cite this

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title = "Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1",
abstract = "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 IC50 values of 38 mu m for normal mice and 29 mu m for ob/ob mice. In vivo metformin lowered plasma DPP TV 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-I and improving glycaemic control. (c) 2006 Elsevier B.V. All rights reserved.",
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AU - Gault, Victor

AU - O'Harte, Finbarr

AU - Flatt, Peter

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