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The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice

  • Chelsea R. Hutch
  • Karen Roelofs
  • April Haller
  • Joyce Sorrell
  • Kyle Leix
  • David D. D’Alessio
  • Robert Augustin
  • Randy J. Seeley
  • Thomas Klein
  • Darleen A. SandovalEmail author



Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis.


We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRAΔNull) or is expressed exclusively in the intestine (GcgRAΔVilCre) or pancreas and duodenum (GcgRAΔPDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists.


Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRAΔNull mice and control littermates and in GcgRAΔVilCre and GcgRAΔPDX1Cre mice. The potent GLP-1 receptor antagonist, exendin-[9–39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRAΔPDX1Cre mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRAΔNull or in GcgRAΔVilCre mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRAΔNull mice.


Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.


DPP-4 inhibitor GIP GLP-1 Glucose homeostasis Incretin 



Dipeptidyl peptidase-4




Gcg null mouse model


Mouse model with Gcg reactivated in the pancreas


Mouse model with Gcg reactivated in the intestine


Glucose-dependent insulinotropic polypeptide


GIP receptor-antagonising antibody


Glucagon-like peptide-1


GLP-1 receptor


Pancreatic duodenal homeobox-1


Wild-type littermate of GcgRAΔPDX1Cre


Wild-type littermate of GcgRAΔVilCre



We would like to thank J. Magrisso (Department of Surgery, University of Michigan, USA) for his technical assistance.

Contribution statement

KR, JS, KL, RA and AH contributed to data acquisition, data analysis and editing of the manuscript. DD, RJS and TK were responsible for conception and experimental design, interpretation of the data and editing of the manuscript. CRH contributed to all aspects of this manuscript, including data acquisition and analysis and drafting and editing the manuscript. DAS contributed to conception, experimental design and drafting the manuscript, provided final approval of the submitted manuscript and is guarantor of this work.


This work is supported in part by NIH Awards DK107282 (DAS) and DK093848 (RJS). The investigators also received research support from Boehringer Ingelheim (DAS, RJS), Ethicon Endo-Surgery (DAS, RJS), Sanofi (RJS) and Novo Nordisk A/S (DAS, RJS). The study sponsor was not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; or the decision to submit the report for publication.

Duality of interest

RJS has received research support from Ethicon Endo-Surgery, Novo Nordisk, Sanofi and Janssen. RJS has served on scientific advisory boards for Ethicon Endo-Surgery, Daiichi Sankyo, Janssen, Novartis, Nestle, Takeda, Boehringer Ingelheim, Sanofi and Novo Nordisk and is a paid speaker for Ethicon Endo-Surgery. DAS has received research support from Ethicon Endo-Surgery, Novo Nordisk and Boehringer Ingelheim. All other authors declare no duality of interest associated with this manuscript.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Chelsea R. Hutch
    • 1
  • Karen Roelofs
    • 1
  • April Haller
    • 2
  • Joyce Sorrell
    • 2
  • Kyle Leix
    • 1
  • David D. D’Alessio
    • 3
  • Robert Augustin
    • 4
  • Randy J. Seeley
    • 1
  • Thomas Klein
    • 4
  • Darleen A. Sandoval
    • 1
    Email author
  1. 1.Department of SurgeryUniversity of MichiganAnn ArborUSA
  2. 2.Department of Internal Medicine-Endocrinology, Diabetes, and MetabolismUniversity of CincinnatiCincinnatiUSA
  3. 3.Division of Endocrinology, Metabolism, and NutritionDuke University Medical CenterDurhamUSA
  4. 4.Cardiometabolic Diseases Research (Biberach)Boehringer IngelheimIngelheim am RheinGermany

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