Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half-life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action.


METHODS
Eight fasting subjects with Type 2 diabetes (5M/3F, age 53.1+/-4.2 years, BMI 36.8+/-1.8 kg/m2, glucose 8.9+/-1.2 mmol/l, HbA1c 7.8+/-0.6%) received placebo or metformin 1 g orally 1 week apart in a random, crossover design.


RESULTS
Following metformin, DPP IV activity was suppressed compared with placebo (AUC0-6 h 3230+/-373 vs. 5764+/-504 nmol ml/l, respectively, P=0.001). Circulating glucose, insulin and total GLP-1 were unchanged. Metformin also concentration-dependently inhibited endogenous DPP IV activity in vitro in plasma from Type 2 diabetic subjects.


CONCLUSIONS
Oral metformin effectively inhibits DPP IV activity in Type 2 diabetic patients, suggesting that the drug may have potential for future combination therapy with incretin hormones.
Lindsay
J R
JR
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Coleraine, Northern Ireland, UK.
Duffy
N A
NA
McKillop
A M
AM
Ardill
J
J
O'Harte
F P M
FP
Flatt
P R
PR
Bell
P M
PM
D000284:Administration, Oral; D001786:Blood Glucose / Q000378:metabolism; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D010446:Peptide Fragments; D011498:Protein Precursors
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin; D018819:Dipeptidyl Peptidase 4