GLP-1 receptor -/- 'knockout' mice were generated in 1995 in the Drucker lab. Glp1r-/- mice are viable, exhibit mild glucose intolerance, and represent a useful model for studies of:

Key research findings from studies of Glp1r-/- mice include:

Normal feeding behaviour and body weight

Fasting hyperglycemia

Abnormal oral and intraperitoneal glucose tolerance

Normal glucagon secretion

Normal peripheral glucose utilization

Upregulation of GIP synthesis and secretion

Abnormalities in islet adenylate cyclase and β cell calcium signaling

Abnormal neuroendocrine stress response

Abnormal islet size and islet topography

Increased sensitivity to β cell injury

Loss of portal glucose sensor

Enhanced susceptibility to neuronal injury

Increased insulin sensitivity

The importance of GLP-1 and GIP has been examined in studies of mice lacking both incretin receptors, dual incretin receptor knockout  (DIRKO)mice. DIRKO mice develop normally and exhibit modest additional defects in insulin secretion relative to single incretin receptor KO mice Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest. 2004 Feb;113(4):635-45 and Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors Diabetes 2004 53: 1326-1335 Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP  receptors. Studies in mice lacking either the GLP-1 or GIP receptors (single incretin receptor knockout mice) have demonstrated that DPP-4 inhibitors continue to lower glucose if only one incretin receptor gene is inactivated. In contrast, mice with inactivation of both incretin receptors (dual incretin receptor knockout-DIRKO) mice exhibit normal body weight and fail to exhibit an improved glycemic response following exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared to GIPR-/- or GLP-1R-/- mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-4 (DPP-4) inhibitors valine pyrrolidide (Val-Pyr), LAF237 and SYR106124 lowered glucose and increased plasma insulin in wildtype and single incretin receptor knockout mice, the glucose lowering actions of DPP-4 inhibitors were eliminated in DIRKO mice as outlined in Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors Diabetes 2004 53: 1326-1335

Subsequent studies of DIRKO mice assessed the ability of single or double incretin receptor knockout mice to respond to high fat feeding. Remarkably, Gipr-/-, Glp1r-/-, and DIRKO mice exhibited defective upregulation of insulin secretion after high fat feeding, yet glucose control was only modestly  perturbed due to resistance to diet-induced obesity and preservation of insulin sensitivity. Furthermore, both single incretin receptor KO mice and DIRKO mice exhibit increased energy expenditure likely in part due to increased locomotor activity. See Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007 Jan 2;117(1):143-152.

The original data from studies of Glp1r-/- mice can be reviewed in the following publications:

Ayala, J. E., Bracy, D. P., James, F. D., Burmeister, M. A., Wasserman, D. H.and Drucker, D. J.  Glucagon-like Peptide-1 Receptor Knockout Mice are Protected from High Fat Diet-Induced Insulin Resistance Independent of Effects on Body Composition Endocrinology published August 4, 2010 as doi:10.1210/en.2010-0289

Knudsen, L. B., Madsen, L.W., Andersen, S., Almholt, K., de Boer, A. S., Drucker, D. J., Gotfredsen, C., Egerod, F. L., Hegelund, A. C., Jacobsen, H., Jacobsen, S. D.,  Moses, A. C., Molck, A. M., Nielsen, H. S., Nowak, J., Solberg, H., Thi, T. D. L., Zdravkovic, M. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation Endocrinology 2010 151: 1473-1486

Ban, K., Kim, K.-H., Cho, C.-K., Sauvé, S., Diamandis, E. P., Backx, P. H., Drucker, D. J., and Husain, M. GLP-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor Endocrinology 2010 151: 1520-1531

Sauve, M., Ban, K., Momen, M. A.,  Zhou, Y-Q., Henkelman, R. M., Husain, M., and Drucker, D. J. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes following myocardial infarction in mice Diabetes 2010 Apr;59(4):1063-73

Hadjiyanni, I., Siminovitch, K. A., Danska, J. S., Drucker D. J. Glucagon-like peptide-1 receptor (GLP-1R) signaling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells Diabetologia 2010 Apr;53(4):730-40

Hsieh, J., Longuet, C., Baker, C. L., Qin, B., Federico, L. M., Drucker, D. J., Adeli, K. The glucagon-like peptide-1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice Diabetologia 2010 Mar;53(3):552-61.

Barrera, J. G., D'Alessio, D. A., Drucker, D. J., Woods, S. C., and Seeley, R. J. Differences in the central anorectic effects of GLP-1 and exendin-4 in rats Diabetes 2009 Dec;58(12):2820-7

Maida, A., Hansotia, T., Longuet, C., Seino, Y., Drucker, D. J. Differential importance of GIP vs. GLP-1 receptor signaling for beta cell survival in mice Gastroenterology 2009 137 (6), December 2009, 2146-2157

Belsham, D. D., Fick, L. J., Dalvia, P. S., Centeno, M.-L., Chalmers, J. A., Lee, P. K. P., Yang, Y., Drucker, D. J., and Koletar, M. M. Ciliary neurotrophic factor recruitment of glucagon-like peptide-1 mediates neurogenesis allowing immortalization of adult murine hypothalamic neurons FASEB J. 2009 Dec; 23 (12):4256-65

Day, J., Ottaway, N., Patterson, J., Gelfanov, V., Smiley,  D., Gidda, J., Findeisen, H., Bruemmer, D., Drucker, D.J., Chaudhary, N., Holland, J., Hembree, J., Abplanalp, W., Grant, E., Ruehl, J., Wilson, H., Kirchner, H., Lockie, S., Hofmann, S., Woods, S., Nogueiras, R., Pfluger, P., Perez-Tilve, D., DiMarchi, R., and Tschop, M. A novel glucagon/GLP-1 co-agonist eliminates obesity in rodents Nature Chemical Biology 2009 Oct;5(10):749-57

Koehler, J. K., Baggio, L. L., Lamont, B. J., Ali, S., and Drucker D. J. GLP-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice  Diabetes 2009 58:2148-2161

Hansotia, T., Maida, A., Flock, G., Yamada, Y., Tsukiyama, K., Seino, S., and Drucker, D. J Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007 Jan 2;117(1):143-152.

Cani, P. D., Knauf, C., Iglesias, M. A., Drucker, D. J., Delzenne, N. M., and Burcelin, R.  Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor Diabetes 2006 55: 1484-1490

Knauf, C.,  Perrin, C., Cani, P. D., Iglesias, M. A.,  Maury, J. F., Bernard, E., Benhamed, F., Grémeaux, T., Drucker, D. J., Kahn, C. R., Girard, J., Tanti, J. F., Delzenne,, N. M., Postic, C. M., Burcelin, R. M. Brain Glucagon-Like Peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage J Clin Invest. 2005 Dec 1;115(12):3554-3563

Hansotia, T., Baggio, L. L., Delmeire, D., Hinke, S. A.,  Yamada, Y., Tsukiyama, K., Seino, Y., Holst, J. J., Schuit, F., and Drucker, D. J. Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors Diabetes 2004 53: 1326-1335

Preitner, F., Ibberson, M., Franklin, I., Binnert, C., Pende, M., Gjinovci, A., Hansotia, T., Drucker, D. J., Wollheim, C., Burcelin, R., Thorens, B. Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors J Clin Invest 2004 113:635-645

During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9.

Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, Parker TG, Huang Q, Drucker DJ, Husain M Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003 Jun;144(6):2242-52

De Leon DD, Deng S, Madani R, Ahima RS, Drucker DJ, Stoffers DA Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes. 2003 Feb;52(2):365-71

Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem. 2003 Jan 3;278(1):471-8.

Ling Z, Wu D, Zambre Y, Flamez D, Drucker DJ, Pipeleers DG, Schuit FC Glucagon-like peptide 1 receptor signaling influences topography of islet cells in mice. Virchows Arch 2001 Apr;438(4):382-7

MacLusky, N.J., Cook, S., Scrocchi, L.A., Shin, J., Kim, J., Vaccarino, F., Asa, S.L. and Drucker, D.J. Neuroendocrine function in mice with complete disruption of GLP-1 receptor signaling Endocrinology 2000 141:752-62.

Daisy Flamez, Patrick Gilon, Karen Moens, An Van Breusegem, Dominique Delmeire, Louise A. Scrocchi, Jean-Claude Henquin, Daniel J. Drucker, and Frans Schuit  Altered cAMP and Ca2+ signaling in mouse pancreatic islets with GLP-1 receptor null phenotype 1999 Diabetes 48:1979-1986

Flamez, D., Breusegem, A.V., Scrocchi, L.A., Quartier, E., Pipeleers, D., Drucker, D.J., Schuit, F. Mouse pancreatic ß cells exhibit preserved glucose competence after disruption of the GLP-1 Receptor gene 1998 Diabetes 47: 646-652

Scrocchi, L.A., Marshall, B.A., Cook, S.M., Brubaker, P.L. and Drucker, D.J. Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling 1998 Diabetes 47: 632-639

Scrocchi, L.A. and Drucker D.J. Effects of aging and a high fat diet on body weight and glucose tolerance in GLP-1R-/- mice 1998 Endocrinology 139:3127-32

Pederson,R.A., Satkunarajah,M. McIntosh,C.H.S., Scrocchi,L.A., Flamez,D., Schuit,F., Drucker, D.J. and Wheeler, M.B. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice 1998 Diabetes 47:1046-52.

Serre,V., Dolci,W., Scrocchi,L.A., Drucker, D.J., Efrat,S., and Thorens, B. Exendin-(9-39) as an inverse agonist of the GLP-1 receptor. Implications for basal intracellular cAMP levels and ß cell glucose competence 1998 Endocrinology 139(11):4448-54

Scrocchi, L.S., Brown,T.J., MacLusky,N., Brubaker, P.L., Auerbach,A.B., Joyner, A.L. and Drucker, D.J. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene Nature Medicine 1996 2:1254-1258