desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon: Long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity

Irwin, Nigel; Franklin, Zara J.; O’Harte, Finbarr

doi:10.1016/j.ejphar.2013.03.041

Cited by 17 publications

(8 citation statements)

References 35 publications

(55 reference statements)

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“…Whereas native glucagon was susceptible to DPP IVmediated degradation, the analogues that possessed either (D-Ser 2 ) or N-acetyl modifications were stable. This is consistent with previous studies indicating that DPP IV cannot cleave N-terminally modified forms of glucagon [25,26]. (D-Ser 2 )glucagon and (D-Ser 2 )glucagon-exe also stimulated insulin secretion from clonal beta cells, whereas N-acetyl-glucagon was ineffective in this regard.…”

Section: Discussionsupporting

confidence: 81%

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

Lynch

Pathak

et al. 2014

Diabetologia

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Section: Discussionsupporting

confidence: 81%

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

Lynch

Pathak

et al. 2014

Diabetologia

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“…Further related analogue development resulted in synthesis and characterisation of desHis 1 Glu 9 (Lys 30 PAL)-glucagon and desHis 1 Glu 9 -glucagon-[mPEG] [( 299 , 354 ); Table 6 ]. These peptides were resistant to DPP-4 degradation ( 344 , 348 , 355 ) and lacked adverse metabolic or islet morphological effects when administered twice daily to lean mice ( 347 ). Preclinical testing of desHis 1 Glu 9 -glucagon and desHis 1 Glu 9 (Lys 30 PAL)-glucagon in HFF obese mice reversed obesity-driven hyperinsulinaemia and insulin resistance together with improvements in lipid profile, glucose tolerance and increased pancreatic insulin stores ( 345 ).…”

Section: Other Possible Glucagon Therapeuticsmentioning

confidence: 99%

Proglucagon-Derived Peptides as Therapeutics

et al. 2021

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Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.

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“…Besides there are some limitations of development of theses drug, including a lack of specificity or efficacy, toxicity, potential for induction of immune responses and side effects such as pancreatic α-cell hyperplasia [68]. With the recent significant improvements in drug delivery systems, and the overall patient acceptance of subcutaneous administration of other antidiabetic drugs, such as GLP-1 analogues [69], there is renewed hope for the therapeutic use of peptide-based glucagon receptor antagonists [70,71]. Recent pilot study using two peptide-based glucagon receptor antagonists (desHis 1 Pro 4 Glu 9 -glucagon or desHis 1 Pro 4 Glu 9 Lys 12 FA-glucagon) can reverse aspects of genetically and dietary-induced obesity-related diabetes in mice [72].…”

Section: Role Of Glucagon As a Therapeutic Target For T2dmentioning

confidence: 99%

Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block

Moon

Won

2015

Diabetes Metab J

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Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from α-cell has languished whereas β-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant α-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted α-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of α-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from α-cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on α-cell dysfunction and therapeutic potentials of targeting α-cell in T2D.

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desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon: Long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity

Cited by 17 publications

References 35 publications

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

Proglucagon-Derived Peptides as Therapeutics

Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block

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