Glucagon-Like Peptide I Reduces Postprandial Glycemic Excursions in IDDM

Dupré, J.; Behme, Margaret T.; Hramiak, Irene; McFarlane, P; Williamson, MM; Zabel, Pamela; McDonald, Tom

doi:10.2337/diab.44.6.626

Cited by 113 publications

(44 citation statements)

References 11 publications

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“…This action of the hormone reduces hepatic glucose output and may explain, at least in part, an ability of GLP-1 to lower levels of blood glucose in type 1 (juvenile-onset) diabetic subjects [11,36]. Interestingly, the ability of GLP-1 to suppress pancreatic glucagon secretion also appears to be glucose-dependent.…”

Section: B Glp-1 As a Blood Glucose-lowering Agentmentioning

confidence: 99%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

123

105

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Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing b-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate b-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted. Keywords GLP-1; diabetes mellitus; insulin secretion A. INTRODUCTIONGlucagon-like peptide-1-(7-36)-amide (GLP-1, also known as t-GLP-1 or GLIP) is an intestinally-derived insulinotropic hormone that has attracted considerable attention by virtue of its proven ability to act as a blood glucose lowering agent. The efficacy with which GLP-1 lowers concentrations of blood glucose in type 2 diabetic subjects (adult onset diabetes mellitus) has prompted clinical investigations whereby the therapeutic value of GLP-1 as an antidiabetogenic agent has been substantiated. Earlier studies revealed that © 2003 Bentham Science Publishers Ltd. * Address correspondence to this author at the Department of Physiology and Neuroscience, MSB 442, New York University School of Medicine, 550 First Avenue, NY 10016, New York, USA; Tel: 212-263-5434; Fax: 212-689-9060; holzg01@popmail.med.nyu.edu. NIH Public Access Author ManuscriptCurr Med Chem. Author manuscript; available in PMC 2010 July 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGLP-1 is an ...

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Section: B Glp-1 As a Blood Glucose-lowering Agentmentioning

confidence: 99%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

123

105

View full text Add to dashboard Cite

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“…16 While in humans, the glucose-lowering actions are likely mediated largely through delayed gastric emptying, there is additional evidence that inhibition of glucagon secretion may also play a role. 17 In animal models of type-1 diabetes, administration of GLP-1-receptor agonists has been shown to improve glycemia, in part due to increases in beta-cell mass. 5,18,19 Native GLP-1, as well as currently available GLP-1-receptor agonists, have short biological half-lives.…”

Section: Introductionmentioning

confidence: 99%

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

et al. 2009

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for treatment of diabetes; however, the short biological half-lives of these peptide-based therapeutics requires that frequent injections be administered to maintain sufficient circulating levels. Thus, novel methods of delivering GLP-1 remain an important avenue of active research. It has recently been demonstrated that self-complimentary, double-stranded, adeno-associated virus serotype-8 (DsAAV8) can efficiently transduce pancreatic beta-cells in vivo, resulting in long-term transgene expression. In this study, we engineered a DsAAV8 vector containing a GLP-1 transgene driven by the mouse insulin-II promoter (MIP). Biological activity of the GLP-1 produced from this transgene was assessed using a luciferase-based bioassay. DsAAV8-MIP-GLP-1 was delivered via intraperitoneal injection and beta-cell damage induced by multiple low dose streptozotocin (STZ) administration. Glucose tolerance was assessed following intraperitoneal glucose injections and beta-cell proliferation measured by PCNA expression. Expression of GLP-1 in Min6 beta-cells resulted in glucose-dependent secretion of biologically active GLP-1. Intraperitoneal delivery of DsAAV8-MIP-GLP-1 to mice led to localized GLP-1 expression in beta-cells and protection against development of diabetes induced by multiple low-dose STZ administration. This protection was associated with significant increase in beta-cell proliferation. Results from this study indicate that expression and secretion of GLP-1 from beta-cells in vivo via DsAAV8 represents a novel therapeutic strategy for treatment of diabetes.

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“…Pharmacokinetics studies have revealed that SQV possesses very low oral bioavailability in the range of 4-16% of administered dose (Dupre et al, 1995;Schapiro et al, 1996). Recent investigations have demonstrated that all protease inhibitor (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Several reports speculate that low and variable oral bioavailability of SQV and other protease inhibitors is primarily caused by membrane bound efflux proteins like Pglycoprotein and multi drug resistance proteins (MRPs) and partly due to CYP3A4 mediated metabolism (Dupre et al, 1995;Fitzsimmons and Collins, 1997;Kim et al, 1998;Polli et al, 1999;Williams et al, 2002). Presence of P-gp on blood brain barrier further limits the entry of these drugs into the brain making it a sanctuary site for viral replication (Bachmeier et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

Jain

Duvvuri

Kansara

et al. 2007

International Journal of Pharmaceutics

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Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, ValVal-SQV and Gly-Val-SQV. Equimolar concentration (25 μM) of SQV, Val-Val-SQV and GlyVal-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 μM) and glycyl-sarcosine (20mM). Absorption rate constants in rat jejunum (k a ) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1±3.4 ×10 −3 , 65.8±4.3 ×10 −3 , and 25.6±5.7 ×10 −3 min −1 respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 μM (P-gp inhibitor). However, permeability of ValVal-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.

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Glucagon-Like Peptide I Reduces Postprandial Glycemic Excursions in IDDM

Cited by 113 publications

References 11 publications

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

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