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Department of Medicine, Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario M5G 2C4 Canada
Address all correspondence and requests for reprints to: Dr. D. J. Drucker, Toronto General Hospital, 200 Elizabeth Street CCRW3–845, Toronto Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca
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Abstract |
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 Top Abstract IntroductionSynthesis, Secretion, and...Physiological Actions and...Biological Actions and...GLP-1 and GLP-2: Future...References |
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Introduction |
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TopAbstractIntroductionSynthesis, Secretion, and...Physiological Actions and...Biological Actions and...GLP-1 and GLP-2: Future...References |
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Synthesis, Secretion, and Degradation of GLP-1 and GLP-2 |
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TopAbstractIntroductionSynthesis, Secretion, and...Physiological Actions and...Biological Actions and...GLP-1 and GLP-2: Future...References |
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). The generation of an
intestinal profile of PGDPs is contingent on the expression of the
prohormone convertase enzyme PC1/3 in the L cell (4). The
biological actions and physiological importance of glicentin and
oxyntomodulin, cosecreted with the glucagon-like peptides (GLPs) from
gut endocrine cells (Fig. 1), remain uncertain.
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Following an initial nutrient-stimulated rise in circulating levels of GLP-1 and GLP-2, the levels of the bioactive forms of these peptides fall rapidly, largely due to renal clearance and the N-terminal degradation of both peptides by dipeptidyl peptidase IV (11, 12, 13, 14, 15, 16). This widely expressed enzyme cleaves GLP-1 and GLP-2 at the position 2 alanine, resulting in the generation of inactive GLP-19–36amide, GLP-19–37, and GLP-23–33, respectively. The expression of DP IV in the gut and vascular endothelium is consistent with findings that the majority of immunoreactive GLP-1 entering the portal venous circulation has already been inactivated by N-terminal cleavage, accounting for its short t1/2 of several minutes (17). Although the t1/2 of GLP-2 is several times greater than that of GLP-1 (18), the biological importance of DP IV for GLP-2 inactivation is illustrated by studies in wild-type and DP IV mutant rats demonstrating that larger doses of exogenous GLP-2 are required to achieve comparable intestinotrophic effects in the presence of active DP IV enzyme (15).
The rapid DP IV-mediated inactivation of GLP-1 suggests that DP IV inhibition may represent a useful strategy for prolonging GLP-1 action leading to sustained lowering of blood glucose in vivo. DP IV inhibitors stimulate insulin secretion and improve glucose tolerance in diabetic rodents (19). Furthermore, mice with genetic disruption of the DP IV gene exhibit increased levels of bioactive GLP-1 and GIP and enhanced glucose clearance following oral glucose challenge (20). GLPs are also cleared by the kidney (13) and by non-DP IV-dependent mechanisms, including the enzyme neutral endopeptidase 24.11 (GLP-1) (21).
The importance of a colon in continuity with the small bowel for maintaining normal to enhanced levels of GLP-1 and GLP-2 has been demonstrated in human subjects with ileostomies and colonic resections (22, 23). Little is known about the levels of circulating GLP-2 in the setting of intestinal disease. Patients with mild to moderate intestinal inflammation exhibit increased levels of bioactive GLP-2 (24), due in part to a decrease in levels of circulating DP IV. In contrast, patients with major small bowel resection or patients with inflammatory bowel disease exhibit reduced levels of circulating GLP-2 (24, 25).
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Physiological Actions and Therapeutic Potential of GLP-1 |
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TopAbstractIntroductionSynthesis, Secretion, and...Physiological Actions and...Biological Actions and...GLP-1 and GLP-2: Future...References |
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50% amino acid identity to mammalian GLP-1 and
functions as a potent GLP-1 agonist, eat normally and do
not exhibit growth disturbances despite months of continuous exendin-4
expression (33). Taken together, these observations
suggest that GLP-1 is not essential for physiological
control of nutrient intake and body weight regulation in
vivo. An alternative explanation for the anorexic effects of CNS GLP-1 derives from studies demonstrating that GLP-1R+ neurons are activated as part of the stress response, such as following lithium chloride or lipopolysaccharide administration. ICV administration of GLP-1 produces conditioned taste aversion (34) and GLP-1 and lithium chloride induce similar patterns of neuronal c-fos activation (35, 36), demonstrating that CNS GLP-1R signaling is activated in response to aversive stimuli. Conversely, GLP-1 antagonists attenuate stress-induced increases in colonic motility (37) and abrogate the activation of CNS neurons in response to lithium chloride or lipopolysaccharide (38, 39). The finding of an exaggerated corticosterone response to restraint stress in GLP-1R-/- mice provides further evidence linking GLP-1R signaling with the central response to stress-associated stimulation (40). The available evidence suggests that GLP-1 induced anorexia and taste aversion are mediated by different CNS pathways (41).
GLP-1 may also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion (42, 43, 44). These GLP-1 actions do not appear to be essential for HPA function, as GLP-1R-/- mice cycle normally, are fertile, and exhibit normal basal levels of plasma osmolarity, corticosterone, thyroid hormones, estradiol, and testosterone (40). Conversely, transgenic mice with sustained elevations in circulating exendin-4 are fertile and do not exhibit significant disturbances in eating or drinking behavior (33).
GLP-1 and ß cell function
GLP-1 increases levels of ß cell cAMP and insulin
gene transcription and stimulates glucose-dependent insulin release
(45); however, unlike other depolarizing agents such as
the sulfonylureas, ß cell GLP-1R signaling is glucose
dependent (46). Despite the presumed importance of protein
kinase A for ß cell GLP-1 signaling,
GLP-1-stimulated activation of insulin gene transcription
and cytosolic calcium influx is PKA-independent (47, 48).
GLP-1 also increases pdx-1 gene expression and binding
activity, likely via a PI-3-kinase-dependent pathway
(49). Elimination of GLP-1 receptor signaling
in ß cells is associated with reduced intracellular cAMP, and
defective glucose-stimulated calcium influx (50).
Studies using GLP-1 antagonists reveal an essential role for GLP-1 as an incretin mediating postprandial nutrient disposal. Elimination of GLP-1 action using GLP-1 immunoneutralizing antisera or the antagonist exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) increased glycemic excursion and reduced insulin secretion following oral nutrient ingestion in baboons, rats, and humans (51, 52, 53, 54). Surprisingly, GLP-1 action is also essential for control of fasting glycemia and glucose clearance following nonenteral glucose challenge (30, 55). These latter observations are likely attributable to the importance of GLP-1 for basal ß cell function and for inhibition of glucagon secretion. Whether the inhibitory effect of GLP-1 on glucagon secretion is direct, or indirect, perhaps mediated via insulin and/or somatostatin, remains unclear. In contrast to the role of GLP-1 for glucose homeostasis following both enteral and nonenteral glucose challenge, the role of GIP appears more restricted as GIP regulates glucose absorption and glycemic excursion only following enteral glucose challenge (55).
GLP-1 and regulation of islet growth and
differentiation
Exogenous GLP-1 stimulates islet cell proliferation
in Umea +/? mice (56) and increases islet cell
proliferation in INS-1 cells via a PI3-kinase-dependent pathway
(49). Incubation of pancreatic exocrine AR4J cells with
exendin-4 or GLP-1 induced differentiation to an endocrine
islet phenotype, with expression of GLUT-2 and glucokinase associated
with acquisition of islet cell-like properties including glucagon and
insulin immunopositivity and glucose-dependent insulin secretion
(57). Administration of GLP-1 or exendin-4
for 10 days to neonatal diabetic rats following partial pancreatectomy
stimulated expansion of ß cell mass via induction of islet
proliferation and islet neogenesis (58). Similarly,
GLP-1 and exendin-4 enhanced ductal pdx-1 expression,
stimulated insulin secretion, lowered blood glucose and increased islet
size and ß cell neogenesis in +/+ and diabetic db/db mice
(59). These findings using both cell and animal
models strongly suggest that activation of ductal and islet GLP-1R
signaling leads to increased ß cell mass. Nevertheless, GLP-1R
signaling is not invariably sufficient or necessary for induction of
islet neogenesis and ß cell hyperplasia as evident from studies of
metallothionein promoter-exendin-4 and ob:ob:GLP-1R-/- mice
(32, 33).
Extrapancreatic actions of GLP-1
The glucagon-like peptide 1 receptor (GLP-1R) is expressed in the
pancreatic islets, the gastrointestinal tract, kidney, heart, lungs,
CNS, and possibly in adipose tissue (60, 61, 62). Although
several studies have suggested that GLP-1 may enhance
glucose clearance in an insulin-independent manner, more recent data
suggests that the majority of GLP-1 actions on glucose
clearance are mediated by changes in the insulin to glucagon ratio
(63). The putative importance and physiological
significance of GLP-1 actions in muscle and adipose tissue
remain unclear. GLP-1 administered iv or by ICV injection
increases heart rate and blood pressure in rats (64).
These effects can be blocked by iv or ICV administration of the
antagonist exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) and bilateral vagotomy blocked
the cardiovascular effects of ICV, but not peripherally administered
GLP-1 (65). Clinically significant effects of
GLP-1 on heart rate and blood pressure in human studies
have not yet been reported.
GLP-1 and the treatment of diabetes
Studies in diabetic rodents demonstrate that GLP-1
and exendin-4 reduce blood glucose and hemoglobin A1c, increase insulin
secretion and insulin mRNA, and promote weight loss and reduced adipose
tissue mass (59, 66, 67, 68). The ideal mode and frequency of
GLP-1 agonist administration for the treatment of diabetes
remains under investigation. Although once daily administration of
exendin-4 lowers glucose and HbA1c, twice daily exendin-4
administration was required to reduce food intake and decrease visceral
fat deposition and body weight in Zucker rats (67). The
glucose-lowering actions of GLP-1 in studies of diabetic
patients are secondary to inhibition of gastric emptying and glucagon
secretion, and stimulation of insulin secretion. GLP-1
also lowers appetite in short-term studies of patients with type 2
diabetes (69, 70); however the long-term effects of
GLP-1 or exendin-4 on body weight in diabetic subjects
have not yet been reported. The finding that short-term
GLP-1 infusion normalized fasting plasma glucose in
patients with type 2 diabetes following secondary sulfonylurea failure
suggests that activation of GLP-1R signaling may reverse
diabetes-associated defects in the failing ß cell (71, 72). Although results from long-term clinical studies using
GLP-1 to treat human diabetes are not yet available,
preliminary evidence suggests that GLP-1 maintains its
glucose-lowering effects after several weeks in human subjects with
type 2 diabetes (73).
The rapid inactivation and short t1/2 of GLP-1 has stimulated interest in longer-acting GLP-1 analogs that exhibit a more prolonged duration of action in vivo. Sustained GLP-1 action may be achieved by the use of selective amino acid substitutions that confer DP IV-resistance or related molecules such as lizard exendin-4, fatty acid derivation of the molecule, and optimization of GLP-1 formulations to achieve enhanced levels of the bioactive peptide. Alternatively, inhibition of GLP-1 degradation through use of DP IV inhibitors may also represent a viable strategy for lowering blood glucose (74). A potential advantage of DP IV inhibitors is the concomitant potentiation of the activity of GIP and PACAP (11), GLP-1-related peptides that also exhibit insulinotropic activity in vivo. The long-term safety and optimal mode of DP IV inhibitor administration requires further investigation in light of findings that DP IV, also known as CD26 modulates cleavage of numerous chemokines with possible implications for regulation of immune and inflammatory responses (75). Complementary strategies for enhancing the effectiveness of GLP-1 treatment regimens including the development of enteral or mucosal GLP-1 delivery systems (76, 77). The multiple glucose-lowering actions of GLP-1, taken together with its effects on suppression of food intake and stimulation of islet neogenesis, provides a powerful rationale for evaluating the clinical effectiveness of agents that enhance GLP-1R signaling for the treatment of diabetes.
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Biological Actions and Therapeutic Potential of GLP-2 |
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TopAbstractIntroductionSynthesis, Secretion, and...Physiological Actions and...Biological Actions and...GLP-1 and GLP-2: Future...References |
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GLP-2 rapidly stimulates intestinal hexose transport and inhibits both meal-stimulated gastric acid secretion and gastric motility, actions that appear independent of the trophic effects of the peptide (84, 85, 86). GLP-2 also enhances barrier function in the murine intestinal epithelium via effects on both transcellular and paracellular pathways, with significant changes in tissue conductance noted within 4 h of GLP-2 administration (87). The importance of enteral nutrition for intestinal mucosal epithelial growth may be explained in part by the stimulatory effects of nutrients on GLP-2 secretion (14, 16), as GLP-2 infusion prevented parenteral nutrition-associated gut mucosal hypoplasia in rats (88).
Therapeutic potential of GLP-2
The intestinotrophic and antiapoptotic properties of GLP-2 in the
small and large bowel of normal rodents (83, 89, 90)
suggests that exogenous GLP-2 administration may prevent or ameliorate
the effects of intestinal injury. Administration of GLP-2 to rats
following major small bowel resection enhanced endogenous intestinal
adaptation, with significant increases in mucosal weight, villus
height, sucrase activity, and D-xylose absorption detected
in GLP-2-treated rats (91). Similarly, sc administration
of GLP-2 for 35 days produced increases in bowel histology, energy
retention, weight gain, and lean body mass in human subjects with short
bowel syndrome (92).
GLP-2 significantly ameliorated the extent of inflammation-associated injury in the murine small bowel following indomethacin administration, as evidenced by significant reductions in mortality, disease activity scores, intestinal cytokine expression, and bacterial infection in GLP-2-treated mice (93). The reparative effects of GLP-2 are not confined to the small bowel, as mice with dextran sulfate-induced colitis exhibit reduced weight loss and attenuation of intestinal injury following GLP-2 administration (94). The finding that GLP-2 enhanced mucosal mass and reduced mortality in rats with vascular intestinal ischemia (95), taken together with data demonstrating the functional integrity of the GLP-2-GLP-2R axis in the neonatal rat (96), suggests that GLP-2 may be useful for preventing ischemic intestinal injury in the neonatal gut in vivo.
The GLP-2 receptor
The actions of GLP-2 are transduced by a recently cloned GLP-2
receptor (GLP-2R), a new member of the glucagon/GLP-1
receptor superfamily (97). The GLP-2R was cloned from
stomach, small bowel, and hypothalamus complementary DNA libraries, is
highly specific for GLP-2, and does not recognize supraphysiological
concentrations (10 nM) of glucagon, GLP-1,
exendin-4, and GIP (97). The GLP-2R gene was localized to
human chromosome 17p13.3 and GLP-2R expression is highly tissue
specific, with RNA transcripts detected in the stomach, small and large
bowel, and central nervous system (97, 98). GLP-2R
expression has been localized to distinct subpopulations of gut
endocrine cells in the stomach, small bowel, and colon
(98). These findings suggest a model for GLP-2 action
whereby the biological effects of GLP-2 are mediated by
GLP-2-stimulated factors liberated from gut endocrine cells in
different regions of the gastrointestinal epithelium (Fig. 1
).
As gut endocrine cell lines expressing the endogenous GLP-2 receptor have not yet been reported, studies of GLP-2 receptor signaling have been carried out in transfected heterologous cell types (97, 99, 100). Activation of GLP-2R signaling in fibroblasts transfected with the GLP-2 receptor increases cAMP and AP-1-dependent pathways but has no effect on intracellular calcium (99). Consistent with the putative indirect effects of GLP-2 on intestinal growth, 10 nM GLP-2 had no direct effect on stimulation of fibroblast cell proliferation in vitro (99). The finding that GLP-2 significantly reduces apoptosis in the intestinal crypt compartment following gut injury (93) has prompted studies of GLP-2 receptor signaling and apoptotic pathways. Remarkably, BHK-GLP-2R cells exhibit decreased apoptotic cell death and reduced activation of caspase-3 following GLP-2 treatment in vitro (100). The effects of GLP-2 on apoptosis were independent of protein kinase A and associated with reduced activation of caspase-8 and caspase-9-like activities, decreased cleavage of polyADP ribose polymerase, and diminished cytochrome c release (100). These findings, taken together with data from animal studies, suggest that GLP-2 may also act directly on gut endocrine cells to reduce cellular injury, which in turn permits the enteroendocrine cell to liberate additional factors that protect the adjacent crypt compartment from apoptotic stimuli in vivo.
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GLP-1 and GLP-2: Future Research Directions |
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TopAbstractIntroductionSynthesis, Secretion, and...Physiological Actions and...Biological Actions and...GLP-1 and GLP-2: Future...References |
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Footnotes |
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Received September 6, 2000.
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References |
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 G. S. Meneilly, N. Greig, H. Tildesley, J. F. Habener, J. M. Egan, and D. Elahi Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2835 - 2841. [Abstract] [Full Text] [PDF]
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M. A. Magnuson, P. She, and M. Shiota Gene-altered Mice and Metabolic Flux Control J. Biol. Chem., August 29, 2003; 278(35): 32485 - 32488. [Full Text] [PDF]
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R. Gros, X. You, L. L. Baggio, M. G. Kabir, A. M. Sadi, I. N. Mungrue, T. G. Parker, Q. Huang, D. J. Drucker, and M. Husain Cardiac Function in Mice Lacking the Glucagon-Like Peptide-1 Receptor Endocrinology, June 1, 2003; 144(6): 2242 - 2252. [Abstract] [Full Text] [PDF]
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 J. M. Egan, G. S. Meneilly, and D. Elahi Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1072 - E1079. [Abstract] [Full Text] [PDF]
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X. Cao, G. Flock, C. Choi, D. M. Irwin, and D. J. Drucker Aberrant Regulation of Human Intestinal Proglucagon Gene Expression in the NCI-H716 Cell Line Endocrinology, May 1, 2003; 144(5): 2025 - 2033. [Abstract] [Full Text] [PDF]
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 K. E. Mayo, L. J. Miller, D. Bataille, S. Dalle, B. Goke, B. Thorens, and D. J. Drucker International Union of Pharmacology. XXXV. The Glucagon Receptor Family Pharmacol. Rev., March 1, 2003; 55(1): 167 - 194. [Abstract] [Full Text] [PDF]
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 R. W. Gelling, X. Q. Du, D. S. Dichmann, J. Romer, H. Huang, L. Cui, S. Obici, B. Tang, J. J. Holst, C. Fledelius, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice PNAS, February 4, 2003; 100(3): 1438 - 1443. [Abstract] [Full Text] [PDF]
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D. J. Drucker Glucagon-Like Peptides: Regulators of Cell Proliferation, Differentiation, and Apoptosis Mol. Endocrinol., February 1, 2003; 17(2): 161 - 171. [Abstract] [Full Text] [PDF]
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D. K.Y. Trinh, K. Zhang, M. Hossain, P. L. Brubaker, and D. J. Drucker Pax-6 Activates Endogenous Proglucagon Gene Expression in the Rodent Gastrointestinal Epithelium Diabetes, February 1, 2003; 52(2): 425 - 433. [Abstract] [Full Text] [PDF]
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J. A. Wagner Early Clinical Development of Pharmaceuticals for Type 2 Diabetes Mellitus: From Preclinical Models to Human Investigation J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5362 - 5366. [Full Text] [PDF]
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P. E. MacDonald, W. El-kholy, M. J. Riedel, A. M. F. Salapatek, P. E. Light, and M. B. Wheeler The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion Diabetes, December 1, 2002; 51(90003): S434 - 442. [Abstract] [Full Text] [PDF]
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P. E. MacDonald, A. M. F. Salapatek, and M. B. Wheeler Glucagon-Like Peptide-1 Receptor Activation Antagonizes Voltage-Dependent Repolarizing K+ Currents in {beta}-Cells: A Possible Glucose-Dependent Insulinotropic Mechanism Diabetes, December 1, 2002; 51(90003): S443 - 447. [Abstract] [Full Text] [PDF]
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G. Flock and D. J. Drucker 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., October 1, 2002; 16(10): 2349 - 2359. [Abstract] [Full Text] [PDF]
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H. Hui, R. Yu, C. Bousquet, and R. Perfetti Transfection of Pancreatic-Derived {beta}-Cells with a Minigene Encoding for Human Glucagon-Like Peptide-1 Regulates Glucose-Dependent Insulin Synthesis and Secretion Endocrinology, September 1, 2002; 143(9): 3529 - 3539. [Abstract] [Full Text] [PDF]
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F. Reimann and F. M. Gribble Glucose-Sensing in Glucagon-Like Peptide-1-Secreting Cells Diabetes, September 1, 2002; 51(9): 2757 - 2763. [Abstract] [Full Text] [PDF]
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E. E. Daniel, M. Anvari, J. E. T. Fox-Threlkeld, and T. J. McDonald Local, exendin-(939)-insensitive, site of action of GLP-1 in canine ileum Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G595 - G602. [Abstract] [Full Text] [PDF]
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X. Zhu, L. Orci, R. Carroll, C. Norrbom, M. Ravazzola, and D. F. Steiner Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3 PNAS, August 6, 2002; 99(16): 10299 - 10304. [Abstract] [Full Text] [PDF]
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B. Elbrond, G. Jakobsen, S. Larsen, H. Agerso, L. B. Jensen, P. Rolan, J. Sturis, V. Hatorp, and M. Zdravkovic Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide 1 Derivative, in Healthy Male Subjects Diabetes Care, August 1, 2002; 25(8): 1398 - 1404. [Abstract] [Full Text] [PDF]
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B. Yusta, J. Estall, and D. J. Drucker Glucagon-like Peptide-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., July 5, 2002; 277(28): 24896 - 24906. [Abstract] [Full Text] [PDF]
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C. Tourrel, D. Bailbe, M. Lacorne, M.-J. Meile, M. Kergoat, and B. Portha Persistent Improvement of Type 2 Diabetes in the Goto-Kakizaki Rat Model by Expansion of the {beta}-Cell Mass During the Prediabetic Period With Glucagon-Like Peptide-1 or Exendin-4 Diabetes, May 1, 2002; 51(5): 1443 - 1452. [Abstract] [Full Text] [PDF]
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M. Tsutsumi, T. H. Claus, Y. Liang, Y. Li, L. Yang, J. Zhu, F. Dela Cruz, X. Peng, H. Chen, S. L. Yung, et al. A Potent and Highly Selective VPAC2 Agonist Enhances Glucose-Induced Insulin Release and Glucose Disposal: A Potential Therapy for Type 2 Diabetes Diabetes, May 1, 2002; 51(5): 1453 - 1460. [Abstract] [Full Text] [PDF]
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 D J Drucker Gut adaptation and the glucagon-like peptides Gut, March 1, 2002; 50(3): 428 - 435. [Abstract] [Full Text] [PDF]
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 M.R. Davids, Y. Edoute, S. Stock, and M.L. Halperin Severe degree of hyperglycaemia: insights from integrative physiology QJM, February 1, 2002; 95(2): 113 - 124. [Abstract] [Full Text] [PDF]
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M. Nian, J. Gu, D. M. Irwin, and D. J. Drucker Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R173 - R183. [Abstract] [Full Text] [PDF]
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P. A. Halban, S. E. Kahn, A. Lernmark, and C. J. Rhodes Gene and Cell-Replacement Therapy in the Treatment of Type 1 Diabetes: How High Must the Standards Be Set? Diabetes, October 1, 2001; 50(10): 2181 - 2191. [Abstract] [Full Text]
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J. Lovshin, J. Estall, B. Yusta, T. J. Brown, and D. J. Drucker Glucagon-like Peptide (GLP)-2 Action in the Murine Central Nervous System Is Enhanced by Elimination of GLP-1 Receptor Signaling J. Biol. Chem., June 8, 2001; 276(24): 21489 - 21499. [Abstract] [Full Text] [PDF]
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