Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice.
OBJECTIVE
Dipeptidyl peptidase-4 (DPP4) inhibitors lower blood glucose in diabetic subjects; however, the mechanism of action through which these agents improve glucose homeostasis remains incompletely understood. Although glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) represent important targets for DPP4 activity, whether additional substrates are important for the glucose-lowering actions of DPP4 inhibitors remains uncertain.


METHODS
We examined the efficacy of continuous vildagliptin administration in wild-type (WT) and dual incretin receptor knockout (DIRKO) mice after 8 weeks of a high-fat diet.


RESULTS
Vildagliptin had no significant effect on food intake, energy expenditure, body composition, body weight gain, or insulin sensitivity in WT or DIRKO mice. However, glycemic excursion after oral glucose challenge was significantly reduced in WT but not in DIRKO mice after vildagliptin treatment. Moreover, vildagliptin increased levels of glucose-stimulated plasma insulin and reduced levels of cholesterol and triglycerides in WT but not in DIRKO mice. Vildagliptin treatment reduced the hepatic expression of genes important for cholesterol synthesis and fatty acid oxidation, including phospho-mevalonate kinase (Mvk), acyl-coenzyme dehydrogenase medium chain (Acadm), mevalonate (diphospho)decarboxylase (Mvd), and Acyl-CoA synthetase (Acsl1), in WT but not in DIRKO mice. However, vildagliptin also reduced levels of hepatic mRNA transcripts for farnesyl di-phosphate transferase (Fdft1), acetyl coenzyme A acyltransferase 1 (Acaa1), and carnitine palmitoyl transferase 1 (Cpt 1) in DIRKO mice. No direct effect of GLP-1 receptor agonists was detected on cholesterol or triglyceride synthesis and secretion in WT hepatocytes.


CONCLUSIONS
These findings illustrate that although GLP-1 and GIP receptors represent the dominant molecular mechanisms for transducing the glucoregulatory actions of DPP4 inhibitors, prolonged DPP4 inhibition modulates the expression of genes important for lipid metabolism independent of incretin receptor action in vivo.
Flock
Grace
G
Samuel Lunenfeld Research Institute, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
Baggio
Laurie L
LL
Longuet
Christine
C
Drucker
Daniel J
DJ
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D054795:Incretins / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009570:Nitriles / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use*; D011964:Receptors, Gastrointestinal Hormone / Q000187:drug effects / Q000502:physiology*; D018027:Receptors, Glucagon / Q000187:drug effects / Q000502:physiology*; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000077597:Vildagliptin
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D009570:Nitriles; D011759:Pyrrolidines; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D018000:Receptors, Peptide; C041086:gastric inhibitory polypeptide receptor; D000077597:Vildagliptin; D000218:Adamantane