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

The Drucker lab has also generated humanized GLP-1R mice that express the humanGLP-1R under the control of the pdx1 promoter in the Glp1r-/- mouse background. These mice express the hGLP-1R in islets at levels comparable to those detected for the normal mouse GLP-1R and exhibit functional restoration of human GLP-1R expression and activity in Glp1r-/- islets, without confounding issues arising from enhanced basal GLP-1R signaling or functional hGLP-1R expression in peripheral glucoregulatory tissues.  Lamont, B., Li, Y., Kwan, E.,  Brown, T. J., Gaisano, H., and Drucker D. J. Pancreatic GLP-1 receptor activation is sufficient for GLP-1R-dependent control of glucose homeostasis in mice J Clin Invest 2012 Jan 3;122(1):388-402

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

Normal feeding behaviour and body weight on regular chow

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

Abnormal intestinal lipoprotein secretion

 

Tissue-specific inactivation of the Glp1r in mice

Finan et al used the nestin-Cre driver line to inactivate a subset of CNS GLP-1R and demonstrate that the weight loss-inducing effects of native GLP-1 or a GLP-1-estrogen conjugate were lost in nestin-Cre:Glp1r−/− mice, although the effect of native GLP-1 on reduction in food intake seemed to be comparable in control WT vs. nestin-Cre:Glp1r−/− mice Targeted estrogen delivery reverses the metabolic syndrome Nat Med. 2012 Dec;18(12):1847-56.

Subsequent studies from Sisley and colleagues compared the actions of liraglutide in nestin-Cre:Glp1r−/− vs. Phox2b:Glp1r−/−. Nestin-Cre:Glp1r−/−exhibited marked reduction of Glp1r expression in hypothalamus and brainstem, and ~ 50% reduction of Glp1r expression in pancreas. Phox2b:Glp1r−/− mice exhibited almost complete elimination of Glp1r expression in the nodose ganglia. Basal body weight or composition was not significantly different in chow or high fat diet fed knockout mice over 5 weeks.  Liraglutide significantly suppressed food intake in WT, nestin-Cre:Glp1r−/− and Phox2b:Glp1r−/− mice over 4 h, however liraglutide failed to significantly reduce 24h food intake, generate a conditioned taste aversion or produce weight loss over 14 days in nestin-Cre:Glp1r−/− mice. Basal glucose tolerance and the glucose-lowering effects of liraglutide were completely normal/preserved in nestin-Cre:Glp1r−/−- and Phox2b:Glp1r−/− mice. Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect J Clin Invest. 2014 Apr 24. pii: 72434. doi: 10.1172/JCI72434

Ussher et al used the tamoxifen-inducible myosin heavy chain (MHC)-Cre mouse to conditionally inactivate Glp1r expression in adult cardiomyocytes. Basal cardiac structure and function, and glucoregulatory responses to a GLP-1R agonist wsa normal in MHC-Cre:Glp1r−/− mice. Although MHC-Cre:Glp1r−/− mice exhibit basal dysregulation of gene expression in the ventricles, and to a greater extent, in atria following induction of ischemia, survival, infarct size and ventricular remodeling were not affected by loss of the cardiomyocyte (predominantly atrial) Glp1r. Surprisingly, administration of liraglutide produced robust cardioprotection (increased survival, reduced infarct size, better LV remodeling) and increased heart rate to the same extent in control mice vs. MHC-Cre:Glp1r−/− mice. Nevertheless, 24h basal heart rate was significantly lower in MHC-Cre:Glp1r−/− mice. Hence basal cardiomyocyte GLP-1R signaling is not important for cardioprotection but essential for control of heart rate in mice. Inactivation of the cardiomyocyte Glucagon-Like Peptide-1 Receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection Molecular Metabolism http://dx.doi.org/10.1016/j.molmet.2014.04.009

Smith and colleagues used the mouse insulin promoter (MIP)-Cre mouse and RIP-Cre mice to conditionally eliminate Glp1r expression from b cells. Approximately 70-80% Glp1r knockdown was detected in islets, with elimination of GLP-1R-dependent cAMP accumulation. Glp1rBetacell-/- mice had increased levels of fasting glucose and normal islet expression of insulin and proglucagon mRNA transcripts. Surprisingly, oral glucose tolerance and GSIS was normal in Glp1rBetacell-/- mice, with normal levels of GLP-1 and reduced levels of GIP, however exendin(9-39) increased glycemia (during OGTT) in these mice, consistent with the important of extrapancreatic GLP-1Rs in control of glucose tolerance. Furthermore, Glp1rBetacell-/- mice exhibit abnormal intraperitoneal glucose tolerance and Ex-9 failed to further deteriorate intraperitoneal glucose tolerance. Curiously, intraperitoeanl GLP-1 lowered glucose with no increase in insulin during an IPGTT in Glp1rBetacell-/- mice, whereas intravenous GLP-1 had no effect on glucose or insulin. The Role of β Cell Glucagon-like Peptide-1 Signaling in Glucose Regulation and Response to Diabetes Drugs Cell Metab. 2014 Jun 3;19(6):1050-7.

 

Double incretin receptor knockout (DIRKO) mice

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.

Jun and colleagues have generated and characterized a mouse that either expressed an hGLP-1R cDNA and a C-terminl FLAG tag under the control of Glp1r regulatory elements, or can be further bred by crossing with Rosa26Cre mice to generate global Glp1r-/- mice. The human hGLP-1R transcriptional unit contains the mouse 5'-UTR and start and signal peptide sequences, followed by exon2 of the hGLP-1R and at the 3'-end, a polyA signal sequence (not completely described) from the hGH gene was inserted. In the global Glp1r KO mouse generated here, a frame shift occurs that is predicted to give rise to a 98 amino acid truncated protein. In the Glp1r-/- mice reported here, basal IP glucose tolerance, basal gastric empting or food inatke were not reported; oral glucose tolerance was minimally different (glucose higher at the 10 minute time point) in Glp1r-/- mice. Fasting glucose appeared higher (110 vs. 92) but glycemic excusrion in response to oral gavage of Ensure Plus was normal; interestingly, basal oral glucose tolerance appeared improved at all time points studied in the hGLP-1R mouse (Fig. 3D), and expression of the hGLP-1R transgene appeared much more abundant relative to the native hGLP-1R in human pancreas (Fig. 7), implying either the possiblity of constitutive hGLP-1R receptor signaling or enhanced sensitivity to endogenous GLP-1 reflecting increased numbers of functional hGLP-1Rs. In isolated static islet cultures, hGLP-1R mice displayed a blunted response to 11.2 mM glucose relative to findings in mGlp-1r mice (Fig. 4), but preserved insulinotropic responses to GLP-1, Oxyntomodulin, GIP and exendin-4. Interestingly, the isulin secretory response to glucose in Glp1r-/- islets appeared to be much less robust than that observed in control Glp1r+/+ islets. Immunocytochemistry using an antibody (R&D MAB28141) detected hGLP-1 expression in transfected HEK cells and in human pancreas A Novel Humanized GLP-1 Receptor Model Enables Both Affinity Purification and Cre-LoxP Deletion of the Receptor. PLoS One. 2014 Apr 2;9(4):e93746

 

 

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

Ye, J., Hao, Z., Mumphrey, M. B., Townsend, R. L., Patterson, L. M., Stylopoulos, N., Münzberg, H. Morrison, C. D., Drucker, D. J., Berthoud, H.-R. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents Am J Physiol 2014 Mar;306(5):R352-62

Mokadem, M., Zechner, J. F., Margolskee, R. F., Drucker, D. J., Aguirre, V. Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency Molecular Metabolism, 2013 Dec 11;3(2):191-201. doi: 10.1016/j.molmet.2013.11.010

Wichmann, A., Allahyar, A., Greiner, T. U., Plovier, H., Östergren Lundén, G., Larsson, T., Drucker, D. J., Delzenne, N. M., Cani, P. D., Bäckhed, F. Microbial Modulation of Energy Availability in the Colon Regulates Intestinal Transit Cell Host and Microbe 2013 14(5)582-590

Nguyen, A., Thoai., Mandard, S.,  Dray, C., Deckert, V., Besnard, P., Drucker, D. J., Lagrost, L., Grober, J. Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: Involvement of the glucagon-like peptide 1 (GLP1) pathway. Diabetes 2014 Feb;63(2):471-82

Finan, B., Ma, T., Ottaway, N.,Timo, Müller, D., Habegger, K.M., Heppner, K. M., Kirchner, H., Holland, J., Hembree, J., Raver, C. Lockie, S. H. Smiley, D. L., Gelfanov, V., Yang, B., Hofmann, S., Bruemmer, D., Drucker, D. J., Pfluger, P. T., Perez-Tilve, D., Gidda, J., Vignati, L., Zhang, L., Hauptman, J. B. Lau, M., Brecheisen, M., Uhles, S., Riboulet, W., Hainaut, E., Sebokova, E. Conde-Knape, K., Konkar, A., DiMarchi, R. D., Tschöp M. H., Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans  Sci Translational Med 30 October 2013 Vol 5 Issue 209 209ra151

Fujita, H.,  Morii, T., Fujishima, H., Sato, T., Shimizu, T., Hosoba, M., Tsukiyama, K., Narita, T., Takahashi, T., Drucker, D. J., Seino, Y., Yamada, Y. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential Kidney International 2014 Mar;85(3):579-89

Mukharji, A., Drucker, D. J., Charron, M. J., and Swoap, S. J. Oxyntomodulin increases intrinsic heart rate through the glucagon receptor Physiological Reports  20 OCT 2013, DOI: 10.1002/phy2.112

Kim, M., Platt, M., Shibasaki, T., Quaggin, S., Backx, P. H., Seino, S., Simpson, J.,  Drucker, D. J. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure Nature Medicine 2013 May;19(5):567-7

Burmeister MA, Ayala JE, Drucker DJ, Ayala JE Central Glucagon-Like Peptide 1 Receptor (Glp1r)-Induced Anorexia Requires Glucose Metabolism-Mediated Suppression of AMPK and is Impaired by Central Fructose Am J Physiol Endocrinol Metab. 2013 Apr 1;304(7):E677-85

Flock, G. B., Cao, X., Maziarz, M., and Drucker D. J. Activation of enteroendocrine membrane progesterone receptors promotes incretin secretion and improves glucose tolerance in mice Diabetes 2013 62:283-290

Lockie, S. H., Heppner, K. M.,  Chaudhary, N., Chabenne, J. R., Morgan, D. A., Veyrat-Durebex, C., Ananthakrishnan, G., Rohner-Jeanrenaud, F., Drucker, D. J., DiMarchi, R., Rahmouni, K., Oldfield, B. J., Tschöp, M. H., Perez-Tilve, D. Direct control of Brown Adipose Tissue thermogenesis by Central Nervous System Glucagon-Like Peptide-1 receptor signaling Diabetes 2012 ;61(11):2753-62

Martin, C., Passilly-Degrace, P., Chevrot, M., Ancel, D., Sparks, S. M., Drucker, D. J., and Besnard, P. Lipid- mediated release of GLP-1 by mouse taste buds from circumvallate papillae: putative involvement of GPR120 and impact on taste sensitivity J Lipid Res 2012 in press

Burmeister M.A., Bracy D.P., James F.Y., Holt R.M., Ayala J., King E.M., Wasserman D.H., Drucker D.J. and Ayala J.E. Regulation of glucose kinetics during exercise by the glucagon-like peptide-1 receptor J Physiol. 2012 Aug 13. in press

Rieg, T., Gerasimova, M., Murray, F., Masuda, T., Tang, T., Rose, M.,  Drucker, D.J., and Vallon, V. The natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice Am J Physiol Renal Physiol. 2012 Jul 25.

Lamont, B., Li, Y., Kwan, E.,  Brown, T. J., Gaisano, H., and Drucker D. J. Pancreatic GLP-1 receptor activation is sufficient for GLP-1R-dependent control of glucose homeostasis in mice J Clin Invest 2012 Jan 3;122(1):388-402

Ellingsgaard, H., Hauselmann, I.,  Schuler, B., Habib, A. M., Baggio, L. L., Meier, D. T.,  Eppler, E.,  Bouzakri, K.,  Wueest, S., Muller, Y. D., Hansen, A. M., Reinecke, M., Konrad, D., Gassmann, M., Reimann, F., Halban, P. A., Gromada, J., Drucker, D. J., Gribble, F. M., Ehses, J. A., and Donath, M. Y.  Interleukin-6 enhances insulin secretion by increasing L cell and a cell glucagon-like peptide-1 secretion Nature Medicine 2011 Oct 30;17(11):1481-9.

Cabou, C., Vachoux, C., Campistron, G., Drucker,  D. J. and Burcelin, R. Brain GLP-1 signaling regulates controls femoral artery blood flow and insulin sensitivity through hypothalamic PKC-δ Diabetes 2011 Sep;60(9):2245-2256

Himeno, T., Kamiya, H., Naruse, K., Harada, N., Ozaki, N., Seino, Y., Shibata, T., Kondo, M., Kato, J., Okawa, T., Fukami, A., Hamada, Y., Inagaki, N., Seino, Y., Drucker, D. J., Oiso, Y., and  Nakamura, J. Beneficial effects of exendin-4 on experimental polyneuropathy in diabetic mice Diabetes 2011 Sep;60(9):2397-2406

Chen, M., Mema, E., Kelleher, Nemechek, J. N., Berger, A., Wang, J., Xie, T., Gavrilova, O., Drucker, D. J., Weinstein, L. S. Absence of the Glucagon-Like Peptide-1 Receptor Does Not Affect the Metabolic Phenotype of Mice with Liver-Specific Gsa Deficiency Endocrinology 2011 Sep;152(9):3343-50

Dao T. M., Waget A., Klopp P., Serino M., Vachoux C., Pechere L., Drucker D. J., Champion S., Barthélemy S., Barra Y., Burcelin R., Sérée E. Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice: A Mechanism which Contributes to the Glycemic Control PLoS One. 2011;6(6):e20700

Waget, A., Cabou, C., Masseboeuf, M., Cattan, P., Armanet, M., Karaca, M., Castel, J., Garret, C., Payros, G., Maida, A., Sulpice, T., Holst, J.J., Drucker, D. J., Magnan, C., Burcelin, R. Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice Endocrinology 2011 Aug;152(8):3018-29

Ali, S., Lamont, B.J., Charron, M., and Drucker D. J. Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis J Clinical Investigation J Clin Invest 2011;121(5):1917–1929. doi:10.1172/JCI43615

Kyle, K.A., Willett, T.L., Baggio, L.L., Drucker, D. J., Grynpas, M. Differential Effects of PPAR-g Activation vs. Chemical or Genetic reduction of DPP-4 Activity on Bone Quality in Mice Endocrinology 2011 Feb 152(2):457-67

                                                                                                                                       

Flock, G., Cao, X., Seino, Y., and Drucker D. J. GPR119 Regulates Murine Glucose Homeostasis Through Incretin Receptor-Dependent and Independent Mechanisms Endocrinology 2011 Feb;152(2):374-83

Maida, A., Lamont, B. J., Cao, X., and Drucker, D. J. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice Diabetologia 2011 54;339-349

Ayala, J. E., Bracy, D. P., James, F. D., Burmeister, M. A., Wasserman, D. H.and Drucker, D. JGlucagon-like Peptide-1 Receptor Knockout Mice are Protected from High Fat Diet-Induced Insulin Resistance Independent of Effects on Body Composition Endocrinology 2010 Oct;151(10):4678-87

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

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