Differential antidiabetic efficacy of incretin agonists versus DPP-4 inhibition in high fat fed mice.
OBJECTIVE
We examined whether chronic administration of a glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist D-Ala(2)-GIP (DA-GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4i) des-fluoro-sitagliptin produced comparable antidiabetic actions in high fat-fed mice.


METHODS
High fat-fed mice were administered twice-daily injections of Ex-4, DA-GIP, vehicle (saline), or vehicle with the addition of des-fluoro-sitagliptin (DPP-4i) in food to produce sustained inhibition of DPP-4 activity.


CONCLUSIONS
Mice treated with vehicle alone or DA-GIP exhibited progressive weight gain, whereas treatment with Ex-4 or DPP-4i prevented weight gain. Although Ex-4 improved oral glucose tolerance and insulin-to-glucose ratios after an intraperitoneal glucose tolerance test (IPGTT), DPP-4i had no significant effect after IPGTT but improved glucose excursion and insulin levels after an oral glucose tolerance test. The extent of improvement in glycemic control was more sustained with continuous DPP-4 inhibition, as evidenced by loss of glucose control evident 9 h after peptide administration and a significant reduction in A1C observed with DPP-4i but not with DA-GIP or Ex-4 therapy. DA-GIP, but not Ex-4 or DPP-4i, was associated with impairment in insulin sensitivity and increased levels of plasma leptin and resistin. Although none of the therapies increased beta-cell mass, only Ex-4-treated mice exhibited increased pancreatic mRNA transcripts for Irs2, Egfr, and Gck. These findings highlight significant differences between pharmacological administration of incretin receptor agonists and potentiation of endogenous GLP-1 and GIP via DPP-4 inhibition.
Lamont
Benjamin J
BJ
Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Drucker
Daniel J
DJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002153:Calorimetry, Indirect; D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D002149:Energy Intake; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054795:Incretins / Q000819:agonists*; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D014688:Venoms / Q000494:pharmacology*
D001786:Blood Glucose; D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D014688:Venoms; D000077270:Exenatide; C041086:gastric inhibitory polypeptide receptor