Does exenatide provide a meaningful new treatment option for patients with type 2 diabetes?
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Journal Article↗
Biomedical subjects
Daniel J Drucker
Publications and source records attributed to Daniel J Drucker.
Mucosal adaptation to enteral nutrients is dependent on the physiologic actions of glucagon-like peptide-2 in mice.
BACKGROUND & AIMS: Our understanding of the intestinotropic actions of glucagon-like peptide-2 (GLP-2)(1-33) is based on pharmacologic studies involving exogenous administration. However, the physiologic role of GLP-2 in mucosal growth and adaptation to nutritional stimulation remains poorly understood. METHODS: The properties of GLP-2(3-33), a GLP-2(1-33) metabolite, were determined in baby-hamster kidney cells transfected with the mouse GLP-2 receptor complementary DNA and in isolated murine intestinal muscle strips. To investigate the role of endogenous GLP-2(1-33) in gut adaptation, GLP-2(3-33) was administered to mice that were re-fed for 24 hours after 24 hours of fasting, and the small intestine was analyzed. GLP-2(3-33) also was injected into rats for analysis of circulating GLP-2(1-33) levels. RESULTS: GLP-2(3-33) antagonized the actions of GLP-2(1-33) in vitro and ex vivo. Fasting mice exhibited small intestinal atrophy (37% +/- 1% decrease in small intestinal weight, 19% +/- 2% decrease in crypt-villus height, and 99% +/- 35% increase in villus apoptosis, P < .05-.01). Adaptive growth in re-fed mice restored all these parameters, as well as crypt-cell proliferation, to normal control levels (P < .05 vs. fasting); these adaptive changes were prevented partially or completely by co-administration of GLP-2(3-33) to refeeding mice (by 32% +/- 19% to 103% +/- 15%, P < .05-.01 vs re-fed mice). Exogenous GLP-2(3-33) did not affect endogenous GLP-2(1-33) levels. CONCLUSIONS: These data show that endogenous GLP-2 regulates the intestinotropic response in re-fed mice through modulation of crypt-cell proliferation and villus apoptosis. GLP-2 is therefore a physiologic regulator of the dynamic adaptation of the gut mucosal epithelium in response to luminal nutrients.
Adaptation, Physiological↗
Energy homeostasis and gastrointestinal endocrine differentiation do not require the anorectic hormone peptide YY.
The gastrointestinal hormone peptide YY is a potent inhibitor of food intake and is expressed early during differentiation of intestinal and pancreatic endocrine cells. In order to better understand the role of peptide YY in energy homeostasis and development, we created mice with a targeted deletion of the peptide YY gene. All intestinal and pancreatic endocrine cells developed normally in the absence of peptide YY with the exception of pancreatic polypeptide (PP) cells, indicating that peptide YY expression was not required for terminal differentiation. We used recombination-based cell lineage trace to determine if peptide YY cells were progenitors for gastrointestinal endocrine cells. Peptide YY(+) cells gave rise to all L-type enteroendocrine cells and to islet partial differential and PP cells. In the pancreas, approximately 40% of pancreatic alpha and rare beta cells arose from peptide YY(+) cells, suggesting that most beta cells and surprisingly the majority of alpha cells are not descendants of peptide YY(+)/glucagon-positive/insulin-positive cells that appear during early pancreagenesis. Despite the anorectic effects of exogenous peptide YY(3-36) following intraperitoneal administration, mice lacking peptide YY showed normal growth, food intake, energy expenditure, and responsiveness to peptide YY(3-36). These observations suggest that targeted disruption of the peptide YY gene does not perturb terminal endocrine cell differentiation or the control of food intake and energy homeostasis.
Animals↗
Proglucagon-derived peptides: mechanisms of action and therapeutic potential.
Glucagon is used for the treatment of hypoglycemia, and glucagon receptor antagonists are under development for the treatment of type 2 diabetes. Moreover, glucagon-like peptide (GLP)-1 and GLP-2 receptor agonists appear to be promising therapies for the treatment of type 2 diabetes and intestinal disorders, respectively. This review discusses the physiological, pharmacological, and therapeutic actions of the proglucagon-derived peptides, with an emphasis on clinical relevance of the peptides for the treatment of human disease.
Animals↗
Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.
Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.
Adipose Tissue↗
Tales beyond the crypt: glucagon-like peptide-2 and cytoprotection in the intestinal mucosa.
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Animals↗
beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1.
Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet beta-cell for GLP-1 actions remains unclear. We determined the role of the islet beta-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with beta-cell-specific inactivation of the Pdx1 gene (beta-cell(Pdx1-/-) mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (beta-cell(Pdx1+/+) mice) but not in beta-cell(Pdx1-/-) mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in beta-cell(Pdx1-/-) mice. Furthermore, Ex-4 significantly increased beta-cell proliferation and reduced beta-cell apoptosis in beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in beta-cell(Pdx1-/-) mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R-dependent signals regulating alpha-cell glucagon secretion and for the growth, differentiated function, and survival of islet beta-cells.
Animals↗
Pdx-1 is not sufficient for repression of proglucagon gene transcription in islet or enteroendocrine cells.
Pdx-1 plays a key role in the development of the pancreas and the control of islet gene transcription and has also been proposed as a dominant regulator of the alpha- vs. beta-cell phenotype via extinction of proglucagon expression. To ascertain the relationship between Pdx-1 and proglucagon gene expression, we examined the effect of enhanced pdx-1 expression on proglucagon gene expression in murine islet alphaTC-1 and GLUTag enteroendocrine cells. Although adenoviral transduction increased the levels of pdx-1 mRNA transcripts and nuclear Pdx-1 protein, overexpression of pdx-1 did not repress endogenous proglucagon gene expression in alphaTC-1 or GLUTag cells or murine islets. Immunohistochemical analysis of cells transduced with Ad-pdx-1 demonstrated multiple individual islet or enteroendocrine cells exhibiting both nuclear Pdx-1 and cytoplasmic glucagon-like peptide-1 immunopositivity. The failure of pdx-1 to inhibit endogenous proglucagon gene expression was not attributable to defects in Pdx-1 nuclear translocation or DNA binding as demonstrated using Western blotting and EMSA analyses. Furthermore, Ad-pdx-1 transduction did not repress proglucagon promoter activity in alphaTC-1 or GLUTag cells. Taken together, these findings demonstrate that pdx-1 alone is not sufficient for specification of the hormonal phenotype or extinction of proglucagon gene expression in islet or enteroendocrine cells.
Animals↗
The role of central glucagon-like peptide-1 in mediating the effects of visceral illness: differential effects in rats and mice.
In rats, central administration of glucagon-like peptide-1 (GLP-1) elicits symptoms of visceral illness like those caused by the toxin lithium chloride (LiCl), including anorexia, conditioned taste aversion (CTA) formation, and neural activation in the hypothalamus and hindbrain including activation of brainstem preproglucagon cells. Most compellingly, pharmacological antagonists of the GLP-1 receptor (GLP-1R) block several effects of LiCl in rat. The major goal of these experiments was to further test the hypothesis that the central nervous system GLP-1 system is critical to the visceral illness actions of LiCl by using mice with a targeted disruption of the only described GLP-1R. First, we observed that, like the rat, LiCl activates preproglucagon neurons in wild-type mice. Second, GLP-1R -/- mice demonstrated normal anorexic and CTA responses to LiCl. To test the possibility that alternate GLP-1Rs mediate aversive effects, we examined the ability of GLP-1 to produce a CTA in GLP1R -/- mice. Although lateral ventricular GLP-1 produced a CTA in wild-type mice, it did not produce a CTA in GLP-1R -/- mice. Furthermore, the same GLP-1R antagonist that can block the aversive effects of LiCl in the rat failed to do so in the mouse. These results support the conclusion that in mouse, unlike in rat, GLP-1R signaling is not required for the visceral illness response to LiCl. Such species differences are an important consideration when comparing results from rat and mouse studies.
Animals↗
Lipid raft-dependent glucagon-like peptide-2 receptor trafficking occurs independently of agonist-induced desensitization.
The intestinotrophic and cytoprotective actions of glucagon-like peptide-2 (GLP-2) are mediated by the GLP-2 receptor (GLP-2R), a member of the class II glucagon-secretin G protein-coupled receptor superfamily. Although native GLP-2 exhibits a short circulating half-life, long-acting degradation-resistant GLP-2 analogues are being evaluated for therapeutic use in human subjects. Accordingly, we examined the mechanisms regulating signaling, internalization, and trafficking of the GLP-2R to identify determinants of receptor activation and desensitization. Heterologous cells expressing the transfected rat or human GLP-2R exhibited a rapid, dose-dependent, and prolonged desensitization of the GLP-2-stimulated cAMP response and a sustained GLP-2-induced decrease in levels of cell surface receptor. Surprisingly, inhibitors of clathrin-dependent endocytosis failed to significantly decrease GLP-2R internalization, whereas cholesterol sequestration inhibited ligand-induced receptor internalization and potentiated homologous desensitization. The hGLP-2R localized to both Triton X-100-soluble and -insoluble (lipid raft) cellular fractions and colocalized transiently with the lipid raft marker caveolin-1. Although GLP-2R endocytosis was dependent on lipid raft integrity, the receptor transiently associated with green fluorescent protein tagged-early endosome antigen 1-positive vesicles and inhibitors of endosomal acidification attenuated the reappearance of the GLP-2R on the cell surface. Our data demonstrate that GLP-2R desensitization and raft-dependent trafficking represent distinct and independent cellular mechanisms and provide new evidence implicating the importance of a clathrin- and dynamin-independent, lipid raft-dependent pathway for homologous G protein-coupled receptor internalization.
Animals↗
Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2.
The glucagon-like peptides (glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)) are released from enteroendocrine cells in response to nutrient ingestion. GLP-1 enhances glucose-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying and feeding. GLP-1 also has proliferative, neogenic and antiapoptotic effects on pancreatic beta-cells. More recent studies illustrate a potential protective role for GLP-1 in the cardiovascular and central nervous systems. GLP-2 is an intestinal trophic peptide that stimulates cell proliferation and inhibits apoptosis in the intestinal crypt compartment. GLP-2 also regulates intestinal glucose transport, food intake and gastric acid secretion and emptying, and improves intestinal barrier function. Thus, GLP-1 and GLP-2 exhibit a diverse array of metabolic, proliferative and cytoprotective actions with important clinical implications for the treatment of diabetes and gastrointestinal disease, respectively. This review will highlight our current understanding of the biology of GLP-1 and GLP-2, with an emphasis on both well-characterized and more novel therapeutic applications of these peptides.
Animals↗
Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure.
BACKGROUND & AIMS: Gut-derived peptides including ghrelin, cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide (GLP-1), and GLP-2 exert overlapping actions on energy homeostasis through defined G-protein-coupled receptors (GPCRs). The proglucagon-derived peptide (PGDP) oxyntomodulin (OXM) is cosecreted with GLP-1 and inhibits feeding in rodents and humans; however, a distinct receptor for OXM has not been identified. METHODS: We examined the mechanisms mediating oxyntomodulin action using stable cell lines expressing specific PGDP receptors in vitro and both wild-type and knockout mice in vivo. RESULTS: OXM activates signaling pathways in cells through glucagon or GLP-1 receptors (GLP-1R) but transiently inhibits food intake in vivo exclusively through the GLP-1R. Both OXM and the GLP-1R agonist exendin-4 (Ex-4) activated neuronal c-fos expression in the paraventricular nucleus of the hypothalamus, the area postrema, and the nucleus of the solitary tract following intraperitoneal (i.p.) injection. However, OXM transiently inhibited food intake in wild-type mice following intracerebroventricular (i.c.v.) but not i.p. administration, whereas Ex-4 produced a more potent and sustained inhibition of food intake following both i.c.v. and i.p. administration. The anorectic effects of OXM were preserved in Gcgr(-/-) mice but abolished in GLP-1R(-/-) mice. Although central Ex-4 and OXM inhibited feeding via a GLP-1R-dependent mechanism, Ex-4 but not OXM reduced VO2 and respiratory quotient in wild-type mice. CONCLUSIONS: These findings demonstrate that structurally distinct PGDPs differentially regulate food intake and energy expenditure by interacting with a GLP-1R-dependent pathway. Hence ligand-specific activation of a common GLP-1R increases the complexity of gut-central nervous system pathways regulating energy homeostasis and metabolic expenditure.
Amino Acid Sequence↗
Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors.
The role of the gluco-incretin hormones GIP and GLP-1 in the control of beta cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R(-/-) but not in Gipr(-/-) mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on beta cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a beta cell autonomous secretion defect when both receptors are inactivated.
Animals↗
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.
Peptide hormones exert unique actions via specific G protein-coupled receptors; however, the therapeutic potential of regulatory peptides is frequently compromised by rapid enzymatic inactivation and clearance from the circulation. In contrast, recombinant or covalent coupling of smaller peptides to serum albumin represents an emerging strategy for extending the circulating t(1/2) of the target peptide. However, whether larger peptide-albumin derivatives will exhibit the full spectrum of biological activities encompassed by the native peptide remains to be demonstrated. We report that Albugon, a human glucagon-like peptide (GLP)-1-albumin recombinant protein, activates GLP-1 receptor (GLP-1R)-dependent cAMP formation in BHK-GLP-1R cells, albeit with a reduced half-maximal concentration (EC(50)) (0.2 vs. 20 nmol/l) relative to the GLP-1R agonist exendin-4. Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type but not GLP-1R(-/-) mice and reduced food intake after both intracerebroventricular and intraperitoneal administration. Moreover, intraperitoneal injection of Albugon inhibited gastric emptying and activated c-FOS expression in the area postrema, the nucleus of the solitary tract, the central nucleus of the amygdala, the parabrachial, and the paraventricular nuclei. These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo.
Albumins↗
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.
Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and inhibits food intake, gastric emptying, and glucagon secretion, actions that promote reduction of fasting and postprandial glycemia in subjects with type 2 diabetes. The rapid degradation of native GLP-1 has engendered interest in more stable longer-acting GLP-1 receptor agonists such as exendin-4 (Ex-4); however, the potential consequences of sustained GLP-1 receptor activation leading to receptor desensitization has not been extensively studied. We have now examined a range of GLP-1 receptor-dependent responses following treatment with Ex-4 using INS-1 cells in vitro and both wild-type control and MT-Ex-4 transgenic mice in vivo. Although both GLP-1 and Ex-4 acutely desensitized GLP-1 receptor-dependent cAMP accumulation in INS-1 cells, Ex-4 produced more sustained receptor desensitization, relative to GLP-1, in both acute (5-120 min) and chronic (24-72 h) experiments. PMA (4-phorbol 12-myristate 13-acetate) but not glucagon, glucose-dependent insulinotropic polypeptide (GIP), or epinephrine produced heterologous desensitization in vitro. MT-Ex-4 transgenic mice exhibited a reduced glycemic response to oral but not intraperitoneal glucose challenge following acute Ex-4 administration. In contrast, no differences in glycemic excursion or plasma insulin were observed after 1 week of twice-daily Ex-4 administration to wild-type versus MT-Ex-4 mice. Similarly, the levels of insulin, pdx-1, and GLP-1 receptor mRNA transcripts were comparable in wild-type and MT-Ex-4 transgenic mice after 1 week of Ex-4 administration. However, repeated Ex-4 administration significantly reduced food intake in MT-Ex-4 but not in wild-type mice. These findings illustrate that although Ex-4 is more potent than native GLP-1 in producing GLP-1 receptor desensitization in vitro, chronic exposure to Ex-4 in normal or transgenic mice is not associated with significant downregulation of GLP-1 receptor-dependent responses coupled to glucose homeostasis in vivo.
Animals↗
Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.
Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.
Administration, Intranasal↗
Glucagon-like peptide-2 receptor activation in the rat intestinal mucosa.
Glucagon-like peptide-2 (GLP-2) increases small intestinal growth and function in rodents and human subjects. GLP-2 exerts its effects through a seven-transmembrane domain, G protein-coupled receptor (GLP-2R), stimulating cAMP generation and activating protein kinase A signaling in heterologous cell lines transfected with the GLP-2R. As intestinal cell lines expressing the GLP-2R have not been identified, we developed methods for studying GLP-2R signaling in the rat small intestinal mucosa in vitro. Isolated rat intestinal mucosal cells expressed mRNA transcripts for the GLP-2R, as well as for chromogranin A and beta-tubulin III, markers for enteroendocrine and neural cells, respectively. cAMP production in response to [Gly2]GLP-2, a degradation-resistant analog of GLP-2, was maximal at 10-11 m (268 +/- 93% of control, P < 0.001), with reduced cAMP accumulation observed at higher doses. The cAMP response was diminished by pretreatment with 10-9 m GLP-2, and was abolished by pretreatment with 10-6 m GLP-2 (P < 0.05), indicating receptor desensitization. GLP-2 treatment of isolated mucosal cells increased 3H-thymidine incorporation (to 128 +/- 8% of controls, P < 0.05), and this was prevented by inhibition of the protein kinase A pathway with H89. In contrast, GLP-2 did not affect p44/p42 MAPK phosphorylation or the levels of cytosolic calcium in the mucosal cell preparation. These results provide the first evidence that activation of the endogenous rat mucosal GLP-2 receptor is linked to activation of a cAMP/protein kinase A-dependent, growth-promoting pathway in vitro.
Animals↗
Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites.
Glucagon-like peptide-1 (GLP-1) released from the gut is an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that has diverse central actions, including inhibition of food and water intake, gastric emptying, and stimulation of neuroendocrine responses characteristic of visceral illness. Both intravenous and intracerebroventricular administration of GLP-1 receptor (GLP-1R) agonists increase blood pressure and heart rate and induce Fos-like immunoreactivity (Fos-IR) in autonomic regulatory sites in the rat brain. The area postrema (AP) is a circumventricular organ and has been implicated in processing visceral sensory information. GLP-1Rs are densely expressed in the AP, and peripheral GLP-1R agonists induce Fos-IR in AP neurons to a greater degree than intracerebroventricular administration. Because the AP lacks a blood-brain barrier, we hypothesized that the AP is a key site for peripheral GLP-1 to activate central autonomic regulatory sites. In this study, we found that many tyrosine hydroxylase (TH)-containing neurons in the AP expressed GLP-1Rs and Fos-IR after intravenous GLP-1R agonists. Furthermore, intravenous but not intracerebroventricular GLP-1R agonists induced TH transcription in the AP in vivo. In addition, GLP-1R agonists directly activated TH transcription in an in vitro cell system. Finally, we found that GLP-1-responsive TH neurons in the AP innervate autonomic control sites, including the parabrachial nucleus, nucleus of solitary tract, and ventrolateral medulla. These findings suggest that catecholamine neurons in the AP link peripheral GLP-1 and central autonomic control sites that mediate the diverse neuroendocrine and autonomic actions of peripheral GLP-1.
Animals↗