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Differential anti-diabetic efficacy of incretin agonists vs. DPP-4 inhibition in high fat fed mice

From the Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada

Objective: We examined whether chronic administration of a GLP-1 receptor agonist exendin-4 (Ex-4), a GIP receptor agonist D-Ala₂-GIP (DA-GIP), or a DPP-4 inhibitor (DPP-4i) des-fluoro-sitagliptin produced comparable anti-diabetic actions in high fat-fed mice.

Research Design and 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.

Results and 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:glucose ratios after IPGTT, DPP-4i had no significant effect after IPGTT but improved glucose excursion and insulin levels after OGTT. The extent of improvement in glycemic control was more sustained with continuous DPP-4 inhibition, as evidenced by loss of glucose control evident 9 hrs after peptide administration and a significant reduction in HbA1c 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 ß-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.

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