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Biomedical subjects

Daniel J Drucker

Publications and source records attributed to Daniel J Drucker.

At least 55 records · Page 3Linked to original sources
PubMed2003

Hypoglycemia, defective islet glucagon secretion, but normal islet mass in mice with a disruption of the gastrin gene.

BACKGROUND AND AIMS: Both cholecystokinin (CCK)-A and CCK-B receptors are expressed in the pancreas, and exogenous gastrin administration stimulates glucagon secretion from human islets. Although gastrin action has been linked to islet neogenesis, transdifferentiation, and beta-cell regeneration, an essential physiologic role(s) for gastrin in the pancreas has not been established. METHODS: We examined glucose homeostasis, glucagon gene expression, glucagon secretion, and islet mass in mice with a targeted gastrin gene disruption. RESULTS: Gastrin -/- mice exhibit fasting hypoglycemia and significantly reduced glycemic excursion following glucose challenge. Insulin sensitivity was normal and levels of circulating insulin and insulin messenger RNA transcripts were appropriately reduced in gastrin -/- mice. In contrast, levels of circulating glucagon and pancreatic glucagon messenger RNA transcripts were not up-regulated in hypoglycemic gastrin -/- mice. Furthermore, the glucagon response to epinephrine in isolated perifused islets was moderately impaired in gastrin -/- versus gastrin +/+ islets (40% reduction; P < 0.01, gastrin +/+ vs. gastrin -/- mice). Moreover, the glucagon response but not the epinephrine response to hypoglycemia was significantly attenuated in gastrin -/- compared with gastrin +/+ mice (P < 0.05). Despite gastrin expression in the developing fetal pancreas, beta-cell area, islet topography, and the islet proliferative response to experimental injury were normal in gastrin -/- mice. CONCLUSIONS: These findings show an essential physiologic role for gastrin in glucose homeostasis; however, the gastrin gene is not essential for murine islet development or the adaptive islet proliferative response to beta-cell injury.

Animals↗
PubMed2003

Dual regulation of cell proliferation and survival via activation of glucagon-like peptide-2 receptor signaling.

Peptide hormones regulate cell viability and tissue integrity, directly or indirectly, through activation of G-protein-coupled receptors via diverse mechanisms including stimulation of cell proliferation and inhibition of cell death. Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide hormone released from intestinal endocrine cells following nutrient ingestion. GLP-2 stimulates intestinal crypt cell proliferation leading to expansion of the gastrointestinal mucosal epithelium. Exogenous GLP-2 administration attenuates intestinal injury in experimental models of gastrointestinal disease and improves intestinal absorption and nutritional status in human patients with intestinal failure secondary to short bowel syndrome. GLP-2 also promotes mucosal integrity via reduction of injury-associated apoptosis in the intestinal mucosa and directly reduces apoptosis in cells expressing the GLP-2 receptor in vitro. Hence, the regenerative and cytoprotective properties of GLP-2 contribute to its therapeutic potential for the treatment of patients with intestinal disease.

Animals↗
PubMed2003

International Union of Pharmacology. XXXV. The glucagon receptor family.

Peptide hormones within the secretin-glucagon family are expressed in endocrine cells of the pancreas and gastrointestinal epithelium and in specialized neurons in the brain, and subserve multiple biological functions, including regulation of growth, nutrient intake, and transit within the gut, and digestion, energy absorption, and energy assimilation. Glucagon, glucagon-like peptide-1, glucagon-like peptide-2, glucose-dependent insulinotropic peptide, growth hormone-releasing hormone and secretin are structurally related peptides that exert their actions through unique members of a structurally related G protein-coupled receptor class 2 family. This review discusses advances in our understanding of how these peptides exert their biological activities, with a focus on the biological actions and structural features of the cognate receptors. The receptors have been named after their parent and only physiologically relevant ligand, in line with the recommendations of the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR).

Amino Acid Sequence↗
PubMed2003

Aberrant regulation of human intestinal proglucagon gene expression in the NCI-H716 cell line.

Despite interest in understanding glucagon-like peptide-1 (GLP-1) production, the factors important for GLP-1 biosynthesis remain poorly understood. We examined control of human proglucagon gene expression in NCI-H716 cells, a cell line that secretes GLP-1 in a regulated manner. Insulin, phorbol myristate acetate, or forskolin, known regulators of rodent proglucagon gene expression, had no effect, whereas sodium butyrate decreased levels of NCI-H716 proglucagon mRNA transcripts. The inhibitory effect of sodium butyrate was mimicked by trichostatin A but was not detected with sodium acetate or isobutyrate. The actions of butyrate were not diminished by the ERK1/2 inhibitor PD98059, p38 inhibitor SB203580, or soluble guanylate cyclase inhibitor LY83583 or following treatment of cells with KT5823, a selective inhibitor of cGMP-dependent protein kinase. NCI-H716 cells expressed multiple proglucagon gene transcription factors including isl-1, pax-6, pax-2, cdx-2/3, pax-4, hepatocyte nuclear factor (HNF)-3 alpha, HNF-3beta, HNF-3 gamma, and Nkx2.2. Nevertheless, the butyrate-dependent inhibition of proglucagon gene expression was not associated with coordinate changes in transcription factor expression and both the human and rat transfected proglucagon promoters were transcriptionally inactive in NCI-H716 cells. Hence, NCI-H716 cells may not be a physiologically optimal model for studies of human enteroendocrine proglucagon gene transcription.

Adenocarcinoma↗
PubMed2003

Cardiac function in mice lacking the glucagon-like peptide-1 receptor.

Glucagon-like peptide-1 (GLP-1) acts via its G protein-coupled receptor (GLP-1R) to regulate blood glucose. Although the GLP-1R is widely expressed in peripheral tissues, including the heart, and exogenous GLP-1 administration increases heart rate and blood pressure in rodents, the physiological importance of GLP-1R action in the cardiovascular system remains unclear. We now show that 2-month-old mice with genetic deletion of the GLP-1R (GLP-1R(-/-)) exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure compared with CD-1 wild-type controls. At the age of 5 months, echocardiography and histology demonstrate increased LV thickness in GLP-1R(-/-) mice. Although baseline hemodynamic parameters of GLP-1R(-/-) did not differ significantly from those of wild type, GLP-1R(-/-) mice displayed impaired LV contractility and diastolic function after insulin administration. The defective cardiovascular response to insulin was not attributable to a generalized defect in the stress response, because GLP-1R(-/-) mice responded appropriately to insulin with increased c-fos expression in the hypothalamus and increased circulating levels of glucagon and epinephrine. Furthermore, LV contractility after exogenous epinephrine infusion was also reduced in GLP-1R(-/-) mice. These findings provide new evidence implicating an essential role for GLP-1R in the control of murine cardiac structure and function in vivo.

Animals↗
PubMed2003

Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis.

Peptide hormones are secreted from endocrine cells and neurons and exert their actions through activation of G protein-coupled receptors to regulate a diverse number of physiological systems including control of energy homeostasis, gastrointestinal motility, neuroendocrine circuits, and hormone secretion. The glucagon-like peptides, GLP-1 and GLP-2 are prototype peptide hormones released from gut endocrine cells in response to nutrient ingestion that regulate not only energy absorption and disposal, but also cell proliferation and survival. GLP-1 expands islet mass by stimulating pancreatic beta-cell proliferation and induction of islet neogenesis. GLP-1 also promotes cell differentiation, from exocrine cells or immature islet progenitors, toward a more differentiated beta-cell phenotype. GLP-2 stimulates cell proliferation in the gastrointestinal mucosa, leading to expansion of the normal mucosal epithelium, or attenuation of intestinal injury in experimental models of intestinal disease. Both GLP-1 and GLP-2 exert antiapoptotic actions in vivo, resulting in preservation of beta-cell mass and gut epithelium, respectively. Furthermore, GLP-1 and GLP-2 promote direct resistance to apoptosis in cells expressing GLP-1 or GLP-2 receptors. Moreover, an increasing number of structurally related peptide hormones and neuropeptides exert cytoprotective effects through G protein-coupled receptor activation in diverse cell types. Hence, peptide hormones, as exemplified by GLP-1 and GLP-2, may prove to be useful adjunctive tools for enhancement of cell differentiation, tissue regeneration, and cytoprotection for the treatment of human disease.

Animals↗
PubMed2003

Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes.

Incretins are peptide hormones, exemplified by glucose-dependent insulinotropic peptide and glucagon-like peptide 1 that are released from the gut in response to nutrient ingestion and enhance glucose-stimulated insulin secretion. Incretin action is terminated due to N-terminal cleavage of the peptides by the aminopeptidase dipeptidyl peptidase IV (DPP-IV). Hence, inhibition of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 degradation via reduction of DPP-IV activity represents an innovative strategy for enhancing incretin action in vivo. This review summarises the biology of incretin action, the structure, expression and pleiotropic biological activities of DPP-IV and provides an overview of the rationale, potential merits and theoretical pitfalls in the development of DPP-IV inhibitors for the treatment of type 2 diabetes.

Animals↗
PubMed2003

Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy.

A reduction in beta-cell mass is an important causative factor in type 1 and type 2 diabetes. Glucagon-like peptide-1 (GLP-1) and the long-acting agonist exendin 4 (Ex-4) expand beta-cell mass by stimulating neogenesis and proliferation. In the partial pancreatectomy (Ppx) model, exogenous Ex-4 promotes islet regeneration, leading to sustained improvement in glucose tolerance. In this study, we investigate the potential role of endogenous GLP-1 in islet growth. We examined beta-cell mass regeneration after 70% Ppx in mice receiving the GLP-1 antagonist Ex9-39 and in GLP-1R(-/-) mice. In Ex9-39-treated sham-operated mice, persistent fasting hyperglycemia was observed, but beta-cell mass was not diminished. In pancreatectomized mice, persistent glucose intolerance was noted, but this was not further exacerbated by Ex9-39. Accordingly, beta-cell mass recovery of Ppx mice was not impaired by Ex9-39. In contrast, GLP-1R(-/-) CD1 mice showed worse glucose intolerance after Ppx compared with wild-type CD1 Ppx mice, and this correlated with a significant defect in beta-cell mass regeneration. The recovery of beta-cell mass differed markedly in the BALB/c and CD1 control mice, indicating a significant role of genetic background in the regulation of beta-cell mass. These studies point to a role for endogenous GLP-1 in beta-cell regeneration after Ppx in mice.

Animals↗
PubMed2003

Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium.

The proglucagon gene encodes pancreatic glucagon and the glucagon-like peptides, which exert diverse effects on nutrient absorption and assimilation. The therapeutic potential of glucagon-like peptide-1 (GLP-1) has fostered interest in development of cellular engineering approaches to augment endogenous intestinal-derived GLP-1 for the treatment of type 2 diabetes. We have used adenovirus technology to examine the potential roles of the transcription factors Cdx-2/3 and Pax-6 as activators of endogenous proglucagon gene expression in enteroendocrine cell lines and in nontransformed rat intestinal cells. Adenoviral-expressed Cdx-2/3 and Pax-6 activated proglucagon promoter-luciferase activity in baby hamster kidney (BHK) fibroblasts, HEK 293 cells, and enteroendocrine cell lines. Pax-6, but not Cdx-2/3, induced expression of the endogenous proglucagon gene in enteroendocrine cell lines, but not in heterologous fibroblasts. Furthermore, transduction of primary rat intestinal cell cultures in vitro, or the rat colonic epithelium in vivo, with Ad-Pax-6 activated endogenous proglucagon gene expression. These data demonstrate that Pax-6, but not Cdx-2/3, is capable of activating the endogenous proglucagon gene in both immortalized enteroendocrine cells and the nontransformed intestinal epithelium in vivo.

Animals↗
PubMed2003

Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo.

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP-1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R. CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R-/- mice. Basal glucose and glycemic excursion following glucose challenge remained significantly reduced 10-12 h following a single injection of CJC-1131. Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period. Levels of random fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and remained significantly lower even 1 week following discontinuation of CJC-1131 administration. CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1 mimics the action of native GLP-1 and represents a new approach for prolonged activation of GLP-1R signaling.

Animals↗
PubMed2003

Enhancing incretin action for the treatment of type 2 diabetes.

OBJECTIVE: To examine the mechanisms of action, therapeutic potential, and challenges inherent in the use of incretin peptides and dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: The scientific literature describing the biological importance of incretin peptides and DPP-IV inhibitors in the control of glucose homeostasis has been reviewed, with an emphasis on mechanisms of action, experimental diabetes, human physiological experiments, and short-term clinical studies in normal and diabetic human subjects. RESULTS: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert important effects on beta-cells to stimulate glucose-dependent insulin secretion. Both peptides also regulate beta-cell proliferation and cytoprotection. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of GLP-1, but not GIP, are preserved in subjects with type 2 diabetes. However, native GLP-1 is rapidly degraded by DPP-IV after parenteral administration; hence, degradation-resistant, long-acting GLP-1 receptor (GLP-1R) agonists are preferable agents for the chronic treatment of human diabetes. Alternatively, inhibition of DPP-IV-mediated incretin degradation represents a complementary therapeutic approach, as orally available DPP-IV inhibitors have been shown to lower glucose in experimental diabetic models and human subjects with type 2 diabetes. CONCLUSIONS: GLP-1R agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. The need for daily injections of potentially immunogenic GLP-1-derived peptides and the potential for unanticipated side effects with chronic use of DPP-IV inhibitors will require ongoing scrutiny of the risk-benefit ratio for these new therapies as they are evaluated in the clinic.

Diabetes Mellitus, Type 2↗
PubMed2002

Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis.

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments beta cell mass via activation of beta cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce beta cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced beta cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased beta cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat beta cells exposed to interleukin 1beta, tumor necrosis fator alpha, and interferon gamma in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of beta-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of beta cell mass in vivo.

Animals↗
PubMed2002

Foxa3 (HNF-3gamma) binds to and activates the rat proglucagon gene promoter but is not essential for proglucagon gene expression.

Members of the Forkhead box a (Foxa) transcription factor family are expressed in the liver, pancreatic islets and intestine and both Foxa1 and Foxa2 regulate proglucagon gene transcription. As Foxa proteins exhibit overlapping DNA-binding specificities, we examined the role of Foxa3 [hepatocyte nuclear factor (HNF)-3gamma] in control of proglucagon gene expression. Foxa3 was detected by reverse transcriptase PCR in glucagon-producing cell lines and binds to the rat proglucagon gene G2 promoter element in GLUTag enteroendocrine cells. Although Foxa3 increased rat proglucagon promoter activity in BHK fibroblasts, augmentation of Foxa3 expression did not increase proglucagon promoter activity in GLUTag cells. Furthermore, adenoviral Foxa3 expression did not affect endogenous proglucagon gene expression in islet or intestinal endocrine cell lines. Although Foxa3(-/-) mice exhibit mild hypoglycaemia during a prolonged fast, the levels of proglucagon-derived peptides and proglucagon mRNA transcripts were comparable in tissues from wild-type and Foxa3(-/-) mice. These findings identify Foxa3 as a member of the proglucagon gene G2 element binding-protein family that, unlike Foxa1, is not essential for control of islet or intestinal proglucagon gene expression in vivo.

Animals↗
PubMed2002

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.

Activation of glucagon-like peptide-2 receptor (GLP-2R) signaling promotes expansion of the mucosal epithelium indirectly via activation of growth and anti-apoptotic pathways; however, the cellular mechanisms coupling direct GLP-2R activation to cell survival remain poorly understood. We now demonstrate that GLP-2, in a cycloheximide-insensitive manner, enhanced survival in baby hamster kidney cells stably transfected with the rat GLP-2R; reduced mitochondrial cytochrome c efflux; and attenuated the caspase-dependent cleavage of Akt, poly(ADP-ribose) polymerase, and beta-catenin following inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002. The prosurvival effects of GLP-2 on LY294002-induced cell death were independent of Akt, p90(Rsk), or p70 S6 kinase activation; were mimicked by forskolin; and were abrogated by inhibition of protein kinase A (PKA) activity. GLP-2 inhibited activation of glycogen synthase kinase-3 (GSK-3) through phosphorylation at Ser(21) in GSK-3alpha and at Ser(9) in GSK-3beta in a PI3K-independent, PKA-dependent manner. GLP-2 reduced LY294002-induced mitochondrial association of endogenous Bad and Bax and stimulated phosphorylation of a transfected Bad fusion protein at Ser(155) in a PI3K-independent, but H89-sensitive manner, a modification known to suppress Bad pro-apoptotic activity. These results suggest that GLP-2R signaling enhances cell survival independently of PI3K/Akt by inhibiting the activity of a subset of pro-apoptotic downstream targets of Akt in a PKA-dependent manner.

Animals↗
PubMed2002

Biological actions and therapeutic potential of the glucagon-like peptides.

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.

Animals↗
PubMed2002

Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression.

The glucagon-like peptides (GLPs) are synthesized and secreted in a nutrient-dependent manner in rodents; however, the factors regulating human GLP-1 and GLP-2 biosynthesis remain unclear. To understand how nutrients regulate human proglucagon gene expression, we studied the expression of a human proglucagon promoter-growth hormone (GH) transgene in 1.6 human glucagon-GH transgenic mice. Fasting-refeeding significantly decreased and increased the levels of circulating mouse insulin and transgene-derived hGH (P < 0.05 fasting vs. refeeding) and decreased and upregulated, respectively, the levels of endogenous mouse proglucagon RNA in the ileum but not in the jejunum or colon. High-fiber feeding significantly increased the levels of glucose-stimulated circulating hGH and upregulated levels of mouse intestinal proglucagon gene expression in the jejunum, ileum, and colon (P < 0.05, 0 vs. 30% fiber diet). In contrast, neither fasting-refeeding nor a high-fiber diet upregulated the expression of the human proglucagon promoter-hGH transgene. These findings demonstrate that human proglucagon gene regulatory sequences specifying tissue-specific expression in gut endocrine cells are not sufficient for recognition of energy-derived signals regulating murine glucagon gene expression in enteroendocrine cells in vivo.

Animal Nutritional Physiological Phenomena↗
PubMed2002

Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons.

Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo.

Adrenal Glands↗