Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity

Deacon, Carolyn F.; Knudsen, Lotte Bjerre; Madsen, Kjeld; Wiberg, Finn C.; Jacobsen, Ole Stig; Holst, Jens J.

doi:10.1007/s001250050903

Cited by 271 publications

(214 citation statements)

References 39 publications

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“…This study, therefore, provided "proof-of concept" for the principle of GLP-based therapy of T2DM, and further attempts to utilize the therapeutic potential of GLP-1 have included, on one hand, the development of stable, DPP-4 resistant analogues (99) and, on the other hand, inhibitors of DPP-4 demonstrated to be capable of protecting the peptide from degradation and thereby augmenting its insulinotropic activity(100).…”

Section: Actions Of Glp-1 In T2dm Mellitusmentioning

confidence: 99%

“…It is fairly easy to stabilize the GLP-1 molecule against DPP-4 -a conservative substitution of Ala in position 2 with e. g. valine is sufficient and does not harm the biological activity of the peptide (99). However, the stabilized molecule is still eliminated extremely rapidly in the kidneys (with a half life of 4-5 min), so such analogues are also unsuitable.…”

Section: Glp-1 Receptor Agonistsmentioning

confidence: 99%

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The incretin system and its role in type 2 diabetes mellitus

Holst

Vilsbøll

Deacon

2009

Molecular and Cellular Endocrinology

449

332

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The incretin hormones are released during meals from gut endocrine cells. They potentiate glucoseinduced insulin secretion and may be responsible for up to 70 % of postprandial insulin secretion.The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. Introduction-The incretin effect.

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Section: Actions Of Glp-1 In T2dm Mellitusmentioning

confidence: 99%

Section: Glp-1 Receptor Agonistsmentioning

confidence: 99%

The incretin system and its role in type 2 diabetes mellitus

Holst

Vilsbøll

Deacon

2009

Molecular and Cellular Endocrinology

449

332

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“…Typically, these substitutions have been introduced at position 8 of GLP-1 such that the alanine residue is converted to alpha-aminoisobutyric acid, glycine, serine, or threonine [133]. Such compounds retain their ability to bind to the GLP-1 receptor, are capable of stimulating pancreatic insulin secretion [133,134], and correct fasting hyperglycemia in diabetic mice [135].…”

Section: H Glp-1 Synthetic Analogs Obtained By Chemical Modificationmentioning

confidence: 99%

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

Holz¹,

Chepurny²

2003

CMC

124

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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“…The full amino acid sequence of GLP-1 is 1 HDEFER-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG 37 , whereas the active hormone is the truncated 7 GLP-1 36 amide that has ϳ50% homology with glucagon. Both degradation by dipeptidyl peptidase IV causing inactivity [6] and renal clearance [7] are severe, making once daily administration impossible.…”

mentioning

confidence: 99%

“…Both degradation by dipeptidyl peptidase IV causing inactivity [6] and renal clearance [7] are severe, making once daily administration impossible. These disadvantageous processes can, however, to some extent be circumvented by fatty acid derivatization that facilitates binding to serum albumin [8].…”

mentioning

confidence: 99%

Characterization of an N-acylated glucagon-like peptide-1 derivative by electron capture dissociation

Haselmann

Nielsen

Zubarev

2005

J. Am. Soc. Mass Spectrom.

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An N-acylated glucagon-like peptide 1 derivative was characterized by Fourier transform ion cyclotron resonance mass spectrometry. Both electron capture dissociation (ECD) and sustained off-resonance irradiation collisionally activated dissociation (SORI-CAD) were employed. While ECD revealed full sequence coverage, site of modification, branching point, structure of the palmitoylated modification, SORI-CAD produced less complete and more ambiguous information attributable to facile losses of the fatty acid group from both parent and fragments. Thus, ECD showed a superior characterization performance over SORI-CAD in analysis of N-acylated polypeptides. (J Am Soc Mass Spectrom 2005, 16, 548 -552)

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Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity

Cited by 271 publications

References 39 publications

The incretin system and its role in type 2 diabetes mellitus

The incretin system and its role in type 2 diabetes mellitus

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

Characterization of an N-acylated glucagon-like peptide-1 derivative by electron capture dissociation

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