Human subjects with severe obesity are increasingly treated with bariatric surgery to promote weight loss via procedures that reduce the capacity of the stomach and/or the absorptive surface area of the small bowel, resulting in reduced food intake and/or energy malabsorption. Some of these surgical procedures may also be associated with changes in plasma levels of one or more gut hormones, due to anatomical alterations in gut motility, incomplete nutrient digestion, and disruption of neural innervation. Changes in the levels of circulating gut hormones have been commonly observed after gut surgery, and in some instances, relative changes in the numbers of specific enteroendocrine cell subsets have also been described. Diversion of nutrients away from the proximal gut and consequent exposure of the distal gut to a greater load of incompletely digested nutrients is often associated with a reductions in levels of circulating peptides derived from the proximal gut, and an increase in levels of peptide hormones derived from the distal gut, such as neurotensin, PYY and enteroglucagon (a surrogate for levels of glicentin, oxyntomodulin, GLP-1 and GLP-2) Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity. Int J Obes 1981; 5:471-80. and Plasma enteroglucagon after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio. Scand J Gastroenterol 1979; 14:205-7. and Morphological and functional alterations to a sub-group of regulatory peptides in human pancreas and intestine after jejuno-ileal bypass. Int J Obes Relat Metab Disord 1993 17:109-113.
As many human subjects experience significant weight loss, and even more remarkable improvement or complete resolution of their diabetes within days of the surgical procedure, there is great interest in understanding the potential roles of gut hormones in the amelioration of the diabetic state, and in the factors contributing to weight loss. An increase in the levels of anorectic hormones such as PYY or GLP-1, or a decrease in levels of orexigenic hormones such as ghrelin Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002: 346:1623-1630 may contribute to changes in appetite and body weight in subsets of patients following bypass surgery.
Gastric bypass surgery, GLP-1, and weight loss
Many patients with obesity experience rapid weight loss together with striking amelioration of their diabetes often within days of gastric bypass surgery. As marked amelioration or complete resolution of the associated diabetes frequently precedes weight loss, a role for GI hormones secreted from the distal GI tract, such as GLP-1 has been invoked to explain these impressive clinical improvements. As different surgical procedures result in distinct anatomical rearrangement of the normal proximal-distal gut orientation and integrity, it is important to distinguish between the various surgical procures and associated changes in levels of gut hormones.
Naslund and colleagues assessed plasma levels of GIP and GLP-1 from 9 months to 20 years after jejunoileal bypass surgery. Both fasting and postprandial levels of GIP were markedly elevated in female obese human subjects 20 years after bypass surgery, in association with improvement in glucose tolerance as described in Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg 1998 8:253-260.
Valverde and colleagues studied plasma levels of GLP-1, together with serial analysis of glucose tolerance in two groups of patients; after Larrad's pancreaticobiliary diversion (BPD) or following vertical banded gastroplasty (VBG). Basal and glucose-stimulated plasma GLP-1 increased after surgery, with GLP-1 levels comparatively greater in subjects following BPD. See Changes in glucagon-like peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects. Obes Surg. 2005 Mar;15(3):387-97. Similarly, the GLP-1 response to meal ingestion was flat or absent prior to surgery for obesity, but significantly improved in obese subjects 6 weeks following Roux-en-Y Gastric Bypass (RYGBP) GLP-1, PYY, Hunger and Satiety Following Gastric Bypass Surgery In Morbidly Obese Subjects. J Clin Endocrinol Metab. 2006 Feb 14; [Epub ahead of print]
Le Roux and colleagues examined changes in plasma levels of gut hormones and glucose tolerance following different gastric bypass procedures in rats and human subjects. Patients with Roux-en-Y gastric bypass (RYGB) had increased postprandial levels of plasma PYY and GLP-1 together with early and exaggerated insulin responses, and improved glycemic control. In contrast, these hormonal changes were not seen in subjects after gastric banding.Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg. 2006 Jan;243(1):108-14.
Guidone and colleagues studied glucose tolerance, b-cell function, insulin sensitivity, and plasma levels of b-cell function was observed even 1 week after surgery, prior to the development of significant weight loss. Plasma levels of GIP fell, whereas levels of GLP-1 increased, in association with complete resolution of the diabetes. Whether these changes in gut hormones were simply associated with or contributed to improvement in the diabetic state remains unclear. See Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes. 2006 Jul;55(7):2025-31
Gastric bypass surgery and postprandial hypoglycemia
Six patients with hyperinsulinemic hypoglycemia following meal ingestion were detected 0.5-8 years following Roux-en-Y gastric bypass surgery were found to have histological evidence for nesidioblastosis following resection of pancreatic tissue-one patient was found to have multiple insulinomas as described in the July 21 2005 New England Journal of Medicine Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005 Jul 21;353(3):249-54. The authors speculated, as further discussed in an accompanying editorial, that excessive secretion of gut hormones such as GLP-1 may have contributed to the development of islet proliferation in these human subjects. A similar clinical picture was reported in 3 subjects following gastric bypass, and plasma levels of GLP-1 were markedly elevated in these studies Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005 Sep 30; [Epub ahead of print]. However, a subsequent re-analysis of the pancreas histology, together with control slides obtained from 31 obese subjects and 16 lean control subjects, yielded somewhat modified conclusions. Meier and colleagues reported that b-cell area was not increased in the subjects with gastric bypass-associated hypoglycemia and no evidence of increased islet neogenesis or b-cell proliferation was detected in this group. These findings further emphasis the importance of functional defects, namely changes in gut motility and the acute b-cell response to nutrients/gut hormones in the pathogenesis of the hyperinsulinemic hypoglycemia syndrome seen in some subjects. See Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care. 2006 Jul;29(7):1554-9
The numbers of these patients will likely continue to increase commensurate with the increasing numbers of patients who undergo this type of surgical procedure.
Hadjiyanni, I., and Drucker, D. J. Glucagon-Like Peptide 1 and Type 1 Diabetes: NOD Ready for Prime Time? Endocrinology. 2007 Nov;148(11):5133-5
Wideman, R. D., Covey, S. D., Webb, G. C., Drucker, D. J., Kieffer, T. A Switch from PC2 to PC1/3 Expression in Transplanted {alpha}-cells is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice.
Diabetes. 2007 56:2744-2752, 2007
Macaulay, K., Doble, B. W., Patel, S., Hansotia, T., Sinclair, E. M., Drucker, D. J., Nagy, A., and Woodgett, J. R. Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism Cell Metab 2007 (6) 329-337
Flock, G., Baggio, L. L., Longuet, C., and Drucker, D. J. The incretin receptors for GLP-1 and GIP are essential for the sustained metabolic actions of vildagliptin in mice Diabetes 2007 in press
Cani, P. D., Holst, J.J., Drucker, D. J., Delzenne, N. M., Thorens, B., Burcelin, R., and Knauf, C. GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion. Mol Cell Endocrinol. 2007 Sep 30;276(1-2):18-23;
Baggio, L. L. and Drucker, D. J. Biology of Incretins: GLP-1 and GIP Gastroenterology, Volume 132, Issue 6, May 2007, Pages 2131-2157
Drucker, D. J. Unraveling the complexities of gut endocrinology Nature Clinical Practice Endocrinology & Metabolism April 2007 3(4)317
Drucker, D. J., Easley, C., and Kirkpatrick, P. Sitagliptin Nature Reviews Drug Discovery 2007 (6) 2; 109-110
Drucker D. J. The role of gut hormones in glucose homeostasis. J. Clin. Invest. 2007 117: 24-32
Hansotia, T., Maida, A., Flock, G., Yamada, Y., Tsukiyama, K., Seino, S., and Drucker, D. J. Extrapancreatic incretin receptors modulate glucose homeostasis and energy expenditure J Clin Invest 2007 January 2; 117(1): 143–15
2006
Drucker, D. J. and Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes Lancet 2006 368: 1696-705
Yusta, B., Baggio, L. L., Estall, J. E., Koehler, J. A., Holland, D. P., Li, H., Pipeleers, D., Ling, Z., and Drucker, D. J. GLP-1 receptor activation improves b-cell function and survival following induction of endoplasmic reticulum stress Cell Metabolism 2006 Nov;4(5):391-406
Sowden, G. L., Drucker, D. J., Weinshenker, D., Swoap, S. J.Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor. Am J Physiol Regul Integr Comp Physiol. 2007 Feb;292(2):R962-70. Epub 2006 Oct 12
Drucker, D. J. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology Vol. 147, No. 7 3171-3172
Estall, J. L., and Drucker, D. J. Glucagon and glucagon-like Peptide receptors as drug targets. Curr Pharm Des. 2006;12(14):1731-50
Baggio, L. L., Holland, D., Wither, J., and Drucker D. J. Lymphocytic infiltration and immune activation in metallothionein promoter-exendin-4 (MT-Exendin) transgenic mice Diabetes 2006 Jun;55 (6): 1562-70.
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
Estall, J. L.& Drucker, D. J. Glucagon-Like Peptide-2.Annu Rev Nutr. 2006 2006;26:391-411
Koehler, J. A, and Drucker, D. J. Activation of GLP-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells Diabetes 2006 55: 1369-1379
Drucker, D. J. The biology of incretin hormones. Cell Metab. 2006 Mar;3(3):153-65. Review
Riddle, M. C., Drucker D. J. Emerging therapies mimicking the effects of amylin and glucagon-like Peptide 1. Diabetes Care. 2006 Feb;29(2):435-49
Baggio, L. L. and Drucker, D. J. Therapeutic approaches to preserve islet mass in type 2 diabetes. Annu Rev Med. 2006; 57:265-81
Drucker, D. J. The evidence for achieving glycemic control with incretin mimetics. Diabetes Educ. 2006 Mar-Apr;32(2 Suppl):72S-81S.
Drucker, D. J. Incretin-based therapies: a clinical need filled by unique metabolic effects. Diabetes Educ. 2006 Mar-Apr;32(2 Suppl):65S-71
2005
Knauf, C., Cani, P. D., Perrin, C., Iglesias, M. A., Maury, J.-F., Bernard, E., Benhamed, F., Gremeaux, T., Drucker, D. J., Kahn, C. R., Girard, J., Tanti, J.-F., Delzenne, N. M., Postic, C., and Burcelin, R. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage J. Clin. Invest. 2005;115 3554-3563
Sinclair, E. M. and Drucker, D. J. Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential Physiology, Oct 2005; 20: 357 - 365
Talsania T., Anini Y., Siu S, Drucker D. J., Brubaker P.L. Peripheral Exendin-4 and Peptide YY3-36 Synergistically Reduce Food Intake through Different Mechanisms in Mice. Endocrinology. 2005 Sep;146(9):3748-56. Epub 2005 Jun 2.
Shin, E. D., Estall, J. L., Izzo, A., Drucker, D. J., and Brubaker, P. L. Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice. Gastroenterology. 2005 May;128(5):1340-53.
Schonhoff, S., Baggio, L., Ratineau, C., . Ray, S. K., Lindner, J., Magnuson, M.A., . Drucker, D. J., and Leiter, A. B. Energy Homeostasis and Gastrointestinal Endocrine Differentiation Do Not Require the Anorectic Hormone Peptide YY Mol. Cell. Biol. 2005 25: 4189-4199.
Estall, J. L., Koehler, J. A., Yusta, B., and Drucker, D. J. The GLP-2R C-terminus modulates beta-arrestin-2 association, but is dispensable for ligand-induced desensitization, endocytosis and G-protein-dependent effector activation J. Biol. Chem., Apr 2005; 10.1074/jbc.M500078200
Hansotia, T., Drucker, D. J.
GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regul Pept. 2005 Jun 15;128(2):125-34Maziarz M., Chung C., Drucker D.J., Emili A
Integrating global proteomic and genomic expression profiles generated from islet a cells: Opportunities and challenges to deriving reliable biological inferences. Mol Cell Proteomics. 2005 Apr;4(4):458-474Sinclair, E. M., and Drucker, D. J.
Glucagon-like peptide-1 receptor agonist and DPP-IV inhibitors: new therapeutic agents for the treatment of type 2 diabetes. Current Opinion in Endocrinology and Metabolism 2005 12:146-151Li, Y., Cao, X., Li, L.-X., Brubaker, P.L., Edlund, H., and Drucker, D.J. ß-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-Like Peptide-1. Diabetes 2005 54: 482-491
Reimann F., Maziarz M., Flock G., Habib A.M., Drucker D.J., Gribble F.M.
Characterization and functional role of voltage gated cation conductances in the glucagon-like peptide-1 secreting GLUTag cell line. J Physiol. 2005 Feb 15;563(Pt 1):161-75Koehler, J., Yusta, B., and Drucker, D. J. The HeLa cell glucagon-like peptide-2 receptor is coupled to regulation of apoptosis and ERK1/2 activation through divergent signaling pathways Mol Endocrinol. 2005 Feb;19(2):459-73
Estall, J. L. Drucker, D. J.
Tales beyond the Crypt: Glucagon-Like Peptide-2 and Cytoprotection in the Intestinal Mucosa. Endocrinology. 2005 Jan; 146(1): 19-21Flock, G., Cao, X., and Drucker, D. J. Pdx-1 is not sufficient for repression of proglucagon gene transcription in islet or enteroendocrine cells Endocrinology 2005 146: 441-449
Lachey, J. L., D'Alessio, D. A., Rinaman, L., Elmquist, J. K., Drucker, D. J., Seeley, R. J. The role of central GLP-1 in mediating the effects of visceral illness: Differential effects in rats and mice Endocrinology 2005 146: 458-462
2004
Baggio L.L., Kim J.G., Drucker D.J. Chronic Exposure to GLP-1R Agonists Promotes Homologous GLP-1 Receptor Desensitization In Vitro but Does Not Attenuate GLP-1R-Dependent Glucose Homeostasis In Vivo. Diabetes. 2004 Dec;53 Suppl 3:S205-14
Baggio, L. L., and Drucker, D. J.
Glucagon-like peptide-1 and glucagon-like peptide-2. Best Pract Res Clin Endocrinol Metab. 2004 Dec;18(4):531-54.Baggio, L.L., Huang Q, Brown T. J, Drucker DJ.
A Recombinant Human Glucagon-Like Peptide (GLP)-1–Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor–Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis Diabetes 2004 53: 2492-2500Baggio L. L., Huang Q, Brown T. J, Drucker DJ.
Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004 Aug;127(2):546-58Estall, J. L., Yusta, B., and Drucker, D. J.
Lipid Raft-dependent GLP-2 Receptor Trafficking Occurs Independently of Agonist-induced Desensitization. Mol Biol Cell. 2004 Aug;15(8):3673-87Hansotia, 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: 1326-1335Preitner, 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 113:635-645Lovshin J.A., Huang Q., Seaberg R., Brubaker P.L., Drucker D.J. Extrahypothalamic expression of the glucagon-like peptide-2 receptor is coupled to reduction of glutamate-induced cell death in cultured hippocampal cells. Endocrinology. 2004 Jul;145(7):3495-506.
Brubaker, P. L., Drucker DJ Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004 Jun;145(6):2653-9
2003
Drucker, D. J.
Glucagon-Like Peptide-1 and the Islet ß-Cell: Augmentation of Cell Proliferation and Inhibition of Apoptosis Endocrinology 2003 144: 5145-5148Estall, J. L., Drucker, D. J.
Dual Regulation of Cell Proliferation and Survival via Activation of Glucagon-Like Peptide-2 Receptor Signaling. J Nutr. 2003 Nov;133(11):3708-11Boushey, R. P., Abadir, A., Flamez, D., Baggio, L. L., Li, Y., Berger, V., Marshall, B. A., Finegood, D., Wang, T. C., Schuit, F., and Drucker, D. J.
Hypoglycemia, defective islet glucagon secretion, but normal islet mass in mice with a disruption of the gastrin gene Gastroenterology 2003 125:1164-174Drucker, D. J.
Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care 2003 26: 2929-2940Walsh NA, Yusta B, DaCambra MP, Anini Y, Drucker DJ, Brubaker PL
Glucagon-like Peptide-2 receptor activation in the rat intestinal mucosa. Endocrinology. 2003 Oct;144(10):4385-92. Epub 2003 Jul 03During M.J., Cao L, Zuzga D.S., Francis J.S., Fitzsimons H.L., Jiao X., Bland R.J., Klugmann M., Banks W.A., Drucker DJ, Haile CN Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-1179. Epub 2003 Aug 17
Gros, R., You, X., Baggio, L.
L., Kabir, M. G., Sadi, A-M., Mungrue,
Cao X, Flock G, Choi C, Irwin DM, Drucker DJ.
Aberrant Regulation of Human Intestinal Proglucagon Gene Expression in the NCI-H716 Cell Line. Endocrinology. 2003 May;144(5):2025-33Yamamoto H, Kishi T, Lee CE, Choi BJ, Fang H, Hollenberg AN, Drucker DJ, Elmquist JK.
Glucagon-Like Peptide-1-Responsive Catecholamine Neurons in the Area Postrema Link Peripheral Glucagon-Like Peptide-1 with Central Autonomic Control Sites. J Neurosci. 2003 Apr 1;23(7):2939-2946Mayo, K. E., Miller, L. J., Bataille,
D., Dalle, S., Göke, B., Thorens, B., and Drucker,
D. J.
Kim, J.-G., Baggio, L.L., Bridon, D.P., Castaigne, J.-P., Robitaille, M.F., Jette, L., Benquet, C., and Drucker, D. J.
Development and characterization of a GLP-1-albumin conjugate which retains the ability to activate the GLP-1 receptor in vivo. Diabetes 2003 52(3):751-9Drucker, D. J.
Glucagon-like peptides: Regulators of cell proliferation and apoptosis Mol Endocrinol 2003 17(2)161-171DeLeon, D. D., Deng, S., Madani, R., Ahima, R., Drucker, D.J., Stoffers, D.
A. Role of Endogenous Glucagon-Like Peptide-1 (GLP-1) in Islet Regeneration after Partial Pancreatectomy Diabetes 2003 Feb;52(2):365-371.Trinh, K.Y.T., Zhang, K., Hossain, M., Brubaker, P. L., and Drucker, D. J.
Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium Diabetes 2003 Feb;52(2):425-33.Drucker, D. J.
Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003 Jan;12(1):87-100Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker, D. J. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem. 2003 Jan 3;278(1):471-8
-
2002
Flock, G., and Drucker, D. J. Pax-2 activates the proglucagon gene promoter but is not essential for proglucagon gene expression or development of proglucagon-producing cell lineages in the murine pancreas or intestine. Mol Endocrinol. 2002 Oct;16(10):2349-59.
Brubaker, P.L., and Drucker, D. J. Structure Function of the Glucagon Receptor Family of G Protein Coupled Receptors: The Glucagon, GIP, GLP-1, and GLP-2 Receptors. Receptors and Channels 2002 8:179-188
Adatia, FA, Baggio, LL, Xiao, Q, Drucker DJ, and Brubaker PL. Cellular specificity of proexendin-4 processing in Mammalian cells in vitro and in vivo. Endocrinology. 2002 Sep;143(9):3464-71
Brubaker PL, Drucker DJ, Asa SL, Swallow C, Redston M, Greenberg GR Prolonged Gastrointestinal Transit in a Patient with a Glucagon-Like Peptide (GLP)-1- and -2-Producing Neuroendocrine Tumor. J Clin Endocrinol Metab. 2002 Jul;87(7):3078-83
Yamamoto, H., Lee, C. E., Marcus, J. N., Williams, T. D., Overton, J. M., Lopez, M. E., Hollenberg, A. N., Baggio, L., Saper, C. B. Drucker, D. J., and Elmquist, J. K. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons J. Clin. Invest. 2002;110 43-52
Liu Y, Shen W, Brubaker PL, Kaestner KH, Drucker DJ
Foxa3 (HNF-3gamma) binds to and activates the rat proglucagon gene promoter but is not essential for proglucagon gene expression. Biochem J. 2002 Sep 1;366(Pt 2):633-41Yusta B, Estall J, Drucker DJ. GLP-2 receptor activation engages Bad and glycogen synthase kinase 3 in a protein kinase A-dependent manner and prevents apoptosis following inhibition of phosphatidylinositol 3-kinase. J Biol Chem. 2002 Jul 12;277(28):24896-906
Drucker, D. J. Gut adaptation and the glucagon-like peptides. Gut. 2002 Mar;50(3):428-35
Drucker, D. J. Biological Actions and Therapeutic Potential of the Glucagon-like Peptides Gastroenterology 2002;122 531-544
Nian, M., Irwin, D.M. , Drucker, D. J.,
Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression. Am J Physiol Regul Integr Comp Physiol. 2002 Jan;282(1):R173-R1832001
Burcelin, R., Da Cost, A., Drucker,
D., and Thorens, B. Glucose Competence of the Hepatoportal Vein Sensor
Requires the Presence of an Activated Glucagon-Like Peptide-1 Receptor. Diabetes.
2001 Aug;50(8):1720-8.
Drucker, D. J. Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes. Curr Pharm Des. 2001 Sep 11;7(14):1399-412.
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 Lovshin J, Estall J, Yusta B, Brown
TJ, Drucker D.J. Glucagon-like
peptide-2 action in the murine central nervous system is enhanced by elimination
of GLP-1 receptor signaling. J Biol. Chem. 2001 Vol.
276, Issue 24, 21489-21499, June 15, 2001
Lefebvre D.L., Bai Y., Shahmolky N., Sharma M., Poon R., Drucker D.J., Rosen C.F. Identification and characterization of a novel sucrose-non-fermenting protein kinase/AMP-activated protein kinase-related protein kinase, SNARK. Biochem J 2001 Apr 15;355(Pt 2):297-305
Drucker, D. J. Glucagon-like
peptide 2. J Clin Endocrinol
Metab. 2001 Apr;86(4):1759-64.
Boushey, R. P., Yusta, B., and Drucker, D.J. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res. 2001 Jan 15;61(2):687-93
Drucker, D.J. The glucagon-like peptides Endocrinology 2001 142:521-527,
2000
Lovshin J, Yusta B, Iliopoulos I, Migirdicyan A, Dableh L, Brubaker PL, Drucker DJ Ontogeny of the glucagon-like peptide-2 receptor axis in the developing rat intestine Endocrinology 2000;141(11):4194-201
Baggio, L., Kieffer, T.J., and Drucker, D.J. GLP-1 but not GIP regulates fasting glycemia and non-enteral glucose clearance in mice Endocrinology 2000 Oct;141(10):3703-9
Yusta, B., Huang, L., Munroe, D., Wolff, G., Fantaske, G., Demchyshyn, L., Asa, S.L., and Drucker, D.J. Enteroendocrine Localization of GLP-2 Receptor Expression in Humans and Rodents Gastroenterology 2000 119: 744-755
Scrocchi, L.A., Hill, M.E., Saleh, J., Perkins, B., and Drucker, D.J. Elimination of GLP-1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action Diabetes 2000 49:1552-1560
Baggio, L., Adatia, F., Bock, T., Brubaker, P.L., Drucker, D.J Sustained expression of exendin-4 does not perturb glucose homeostasis, b cell mass or food intake in metallothionein-preproexendin transgenic mice J. Biol. Chem. 2000 275: 34471-34477
- Bernardo Yusta, Robin P. Boushey, and Daniel J. Drucker The Glucagon-like Peptide-2 Receptor Mediates Direct Inhibition of Cellular Apoptosis via a cAMP-dependent Protein Kinase-independent Pathway J. Biol. Chem. 2000 275: 35345-35352.
DaCambra, M.P. Yusta,B., Sumner-Smith,M., Crivici, A., Brubaker, P.L., Drucker, D.J. Structural determinants for activity of Glucagon-like peptide-2. Biochemistry 2000 39: 8888 - 8894
Elias, C.F., Kelly, J.F., Lee, C.E., Ahima, R.S., Drucker, D.J., Saper, C.B., and Elmquist, J.K. Chemical characterization of leptin-activated neurons in the rat brain Journal of Comparative Neurology 2000 43:261-281
Lovshin J, Drucker DJ. New frontiers in the biology of GLP-2. Regul Pept. 2000 Jun 30;90(1-3):27-32
Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, Ribel U, Watanabe T, Drucker DJ, Wagtmann N Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26 Proc Natl Acad Sci U S A 2000 97(12):6874-6879
Xiao Q, Boushey RP, Cino M, Drucker DJ, Brubaker PL Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease. 1: Am J Physiol Regul Integr Comp Physiol 2000 Apr;278(4):R1057-63
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.
1999
Drucker, D.J., DeForest, L., Yusta, B., Boushey, R.P. and Brubaker, P.L. Enhancement of intestinal epithelial repair by h[Gly2]-GLP-2 in a murine model of ulcerative colitis 1999 Am J Physiol 276:G79-G91
Munroe, D.G. Gupta, A.K., Kooshesh,P., Vyas, T.B., Rizkalla, G., Wang,H., Demchyshyn,L., Kamboj, R.K., McCallum, K., Sumner-Smith, M., Drucker, D.J., and Crivici, A. Prototypic G protein coupled receptor for the intestinotrophic factor glucagon-like peptide 2 1999 Proc. Natl. Acad. Sci (USA) 96:1569-1573
Kaestner, K.H., Katz, K., Liu, Y., Drucker, D.J. and Schutz, G. Inactivation of the winged helix transcription factor HNF3a affects glucose homeostasis and islet glucagon gene expression in vivo 1999 Genes & Development 13:495-504
Trinh K.Y., Jin, T., and Drucker, D.J. Identification of domains mediating transcriptional activation and cytoplasmic export in the caudal homeobox protein Cdx-3 1999 J. Biol.Chem. 274:6011-6019
Drucker D. Glucagon-like peptide 2 1999 Trends in Endocrinology and Metabolism 10:153-156
Xiao, Q., Boushey, R.P., Drucker, D.J., and Brubaker, P.L. Secretion of the intestinotropic hormone glucagon-like peptide-2 is differentially regulated by nutrients in humans 1999 Gastroenterology 17:99-105
Hill, F.M., Asa, S.L., and Drucker, D.J. Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription 1999 Mol Endocrinol 13(9):1474-86
Drucker DJ, Boushey RP, Wang F, Hill ME, Brubaker PL, Yusta B Biologic properties and therapeutic potential of glucagon-like peptide-2 1999 J Parenter Enteral Nutr 23:S98-100
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
Yusta, B., Somwar, R., Wang, F., Munroe, D., Grinstein, S., Klip, A., and Drucker, D.J. Identification of GLP-2 activated signaling pathways in BHK fibroblasts expressing the rat GLP-2 receptor 1999 J. Biol. Chem. 274:30459-30467.
Boushey, R.P. Yusta, B., and Drucker, D. J. Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis 1999 Am J Physiol 277: E937-E947
Nian, M., Drucker, D.J., Irwin D. Divergent regulation of human and rat proglucagon gene promoters in vivo. 1999 Am J Physiol 277:G829-37
1998
Drucker D.J. The glucagon-like peptides. Diabetes 1998 47:159-169
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.
Brubaker, P.L., Schloos, J., and Drucker, D.J. Regulation of glucagon-like peptide-1 synthesis and secretion in the GLUTag enteroendocrine cell line 1998 Endocrinology 139:4108-4114
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
1997
Jin T., Trinh, D.K.Y., Wang, F., and Drucker, D.J. The Caudal homeobox gene cdx-2/3 activates endogenous proglucagon gene expression in InR1-G9 islet cells Mol Endocrinol 1997 11:203-209
Chen E., and Drucker, D.J. Tissue-specific expression of mRNAs with different open reading frames that encode proglucagon -derived peptides and exendin 4 in the lizard J. Biol. Chem. 1997 272:4108-4115
Tsai C.-H., Hill, M., and Drucker, D.J. Biological determinants of intestinotrophic properties of GLP-2 in vivo Am. J. Physiol. 1997 272:G662-G668
Brubaker, P.L. Izzo, A., Hill, M., and Drucker, D.J. Intestinal function in mice with small bowel growth induced by glucagon-like peptide 2. Am. J. Physiol.1997 272: E1050 - E1058
Tsai A., Hill, M., Asa, S.L., Brubaker, P.L., and Drucker, D.J. Intestinal growth-promoting properties of glucagon-like peptide 2 in mice. Am. J. Physiol. 1997 G662-G668
Brubaker PL, Crivici A, Izzo A, Ehrlich P, Tsai CH, Drucker DJ. Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide-2. Endocrinology. 1997 Nov;138(11):4837-43
Drucker D.J., Shi, Q., Crivici, A., Sumner-Smith, M., Tavares, W., Hill, M. DeForest, L., Cooper, S., and Brubaker, P.L. Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV Nature Biotechnology 1997 15:673-677
Drucker D.J. Intestinal growth factors. Am. J. Physiol. 1997 273:G3-G6
Fischer K.D., Dhanvantari, S., Drucker, D.J. and Brubaker, P.L. Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats Am. J. Physiol. 1997 273:E815-E820
Drucker D. J., DeForest, L., and Brubaker, P.L. Region-specific differences in the biological activity of intestinal growth factors administered alone or in combination with h[Gly2]-GLP-2 Am. J. Physiol. 1997 273:G1252-G1262
Scrocchi L.A., Brown, T.J., and Drucker, D.J. Leptin sensitivity in non-obese GLP-1 receptor-/- mice Diabetes 1997 46: 2029-2034
1996
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
Jin T., and Drucker D.J.Activation of proglucagon gene transcription through a novel G1 promoter element by the caudal-related homeobox protein cdx-3 Mol Cell Biol 1996 16: 19-28
Slingerland J.M., Petrocelli, T., Poon, R., Drucker D.J. and Rosen, C.F. UVB Radiation mediates S phase checkpoint via induction of p21 Cip/Waf1 Oncogene 1996 12:1387-1396
Wang M., and Drucker D.J. Activation of amylin gene transcription by the LIM domain homeobox gene isl-1 Mol Endo 1996 10:243-251
Asa S.L., Lee, Y.C., and Drucker, D.J. Development of colonic and pancreatic endocrine tumors in mice expressing a glucagon-SV40 T antigen transgene Virchows Archives 1996 427:595-606
Shi Z.Q., Rastogi, K.S., Lekas, M., Efendic, S., Drucker, D.J., and Vranic, M. Glucagon response to hypoglycemia is improved by insulin-independent restoration of normoglycemia in diabetic rats Endocrinology 1996 137:3193-3199
Drucker D.J., Ehrlich, P., Asa, S.L., Brubaker, P.L. Induction of epithelial proliferation by glucagon-like peptide 2. Proc. Natl. Acad. Sci. 1996 93:7911-7916
Lu F., Jin,T., and Drucker, D.J. Proglucagon gene expression is induced by gastrin-releasing peptide in a mouse enteroendocrine cell line. Endocrinology 1996 137:3710-3716.
1995
Rosen C.F., Chang, R., and Drucker D.J.. Identification of novel UVB-induced genes in rat keratinocytes. Am. J. Physiol 1995 268:C846-C855
Wang M., and Drucker D.J. The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription J. Biol. Chem 1995 270:12646-12652
Jin T., and Drucker D.J. Gene transfer and EMSA analyses identify multiple cis-acting DNA sequences and DNA-protein complexes important for intestinal-specific proglucagon gene transcription Mol Endo 1995 9:1306-1320
The publications listed above are provided for information and use for Drucker lab members. Third parties wishing to obtain reprints should, where appropriate, contact the specific Journal.