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Study · Animal study (in vivo) · mouse · 2020

8 results

Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.

Pickford P, Lucey M, Fang Z, Bitsi S, de la Serna JB, Broichhagen J, Hodson DJ, Minnion J, Rutter GA, Bloom SR, Tomas A, Jones B

British journal of pharmacology19 Jun 2020Cited by 45 (Europe PMC)

PMID32436216 (opens in a new tab)PMCIDPMC7429481 (opens in a new tab)DOI10.1111/bph.15134 (opens in a new tab)PepBankPUB-32436216
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Summary

Background and purposeAmino acid substitutions at the N-termini of glucagon-like peptide-1 (GLP-1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1 receptor agonists exendin-4 and lixisenatide lead to similar phenomena.Experimental approachExendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand and their biased derivatives were assessed in mice.Key resultsLixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was fivefold less potent for cAMP signalling. Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide. N-terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose.Conclusion and implicationsChanges to the C-terminus of exendin-4 affect signalling potency and GLP-1 receptor trafficking via mechanisms unrelated to GLP-1 receptor occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In mice, lixisenatide had a reduced anti-hyperglycaemic effect compared with exendin-4.

    In plain wordsIn mice, lixisenatide lowered blood glucose less than exendin-4.

    Peptide
    Lixisenatide
    Outcome
    DecreaseAnti-hyperglycaemic effect
    Study

    micen: not reported in source

    Mice in glucoregulatory and anorectic assays
    Comparator
    Exendin-4
    Outcome group
    Glycemic control · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide.
    1 context sentence
    Summary · context
    Anti-hyperglycaemic and anorectic effects of each parent ligand and their biased derivatives were assessed in mice.
  2. 02AnimalAnimal study (in vivo)Efficacy outcome

    In mice, lixisenatide had a reduced anorectic effect compared with exendin-4.

    In plain wordsIn mice, lixisenatide reduced appetite less than exendin-4.

    Peptide
    Lixisenatide
    Outcome
    DecreaseAnorectic effect
    Study

    micen: not reported in source

    Mice in glucoregulatory and anorectic assays
    Comparator
    Exendin-4
    Outcome group
    Appetite and food intake · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide.
    1 context sentence
    Summary · context
    Anti-hyperglycaemic and anorectic effects of each parent ligand and their biased derivatives were assessed in mice.
  3. 03LabIn vitro (cells)Activity measurement

    In cell assays, lixisenatide and exendin-4 showed equal binding affinity.

    In plain wordsIn cells, lixisenatide and exendin-4 showed equal binding affinity.

    Peptide
    Lixisenatide
    Outcome
    No significant changeBinding affinity
    Study

    n: not reported in source

    Cells in trafficking and signalling assays
    Comparator
    Exendin-4
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was fivefold less potent for cAMP signalling.
    1 context sentence
    Summary · context
    Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types.
  4. 04LabIn vitro (cells)Activity measurement

    In cell assays, lixisenatide was fivefold less potent for cAMP signalling than exendin-4.

    In plain wordsIn cells, lixisenatide was fivefold less potent for cAMP signalling than exendin-4.

    Peptide
    Lixisenatide
    Outcome
    DecreasecAMP signalling potency
    Study

    n: not reported in source

    Cells in trafficking and signalling assays
    Comparator
    Exendin-4
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was fivefold less potent for cAMP signalling.
    1 context sentence
    Summary · context
    Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types.
  5. 05LabIn vitro (cells)Mechanism

    In cell assays, lixisenatide induced extensive GLP-1 receptor clustering in the plasma membrane.

    In plain wordsIn cells, lixisenatide caused extensive receptor clustering in the cell membrane.

    Peptide
    Lixisenatide
    Outcome
    IncreaseGLP-1 receptor clustering
    Study

    n: not reported in source

    Cells in trafficking and signalling assays
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor recycled more slowly to the cell surface after lixisenatide treatment.
    1 context sentence
    Summary · context
    Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types.
  6. 06LabIn vitro (cells)Mechanism

    In cell assays, lixisenatide underwent rapid endocytosis.

    In plain wordsIn cells, lixisenatide entered cells rapidly.

    Peptide
    Lixisenatide
    Outcome
    Not applicableEndocytosis
    Study

    n: not reported in source

    Cells in trafficking and signalling assays
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor recycled more slowly to the cell surface after lixisenatide treatment.
    1 context sentence
    Summary · context
    Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types.
  7. 07LabIn vitro (cells)Mechanism

    In cell assays, GLP-1 receptors recycled more slowly to the cell surface after lixisenatide than exendin-4 treatment.

    In plain wordsIn cells, receptors returned to the surface more slowly after lixisenatide than exendin-4 treatment.

    Peptide
    Lixisenatide
    Outcome
    DecreaseGLP-1 receptor recycling
    Study

    n: not reported in source

    Cells in trafficking and signalling assays
    Comparator
    Exendin-4
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor recycled more slowly to the cell surface after lixisenatide treatment.
    1 context sentence
    Summary · context
    Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types.
  8. 08LabIn vitro (cells)Mechanism

    In cell assays, lixisenatide produced lower maximal sustained insulin secretion than exendin-4.

    In plain wordsIn cells, lixisenatide produced less sustained insulin secretion than exendin-4.

    Peptide
    Lixisenatide
    Outcome
    DecreaseMaximal sustained insulin secretion
    Study

    n: not reported in source

    Cells in trafficking and signalling assays
    Comparator
    Exendin-4
    Outcome group
    Glycemic control · Endocrine and hormones
    Studied dose
    Dose not stated

    Source sentences

    Summary
    These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide.
    1 context sentence
    Summary · context
    Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    28 Oct 2026, 02:03 UTC

    Study results updated

  2. Version 1

    27 Oct 2026, 16:36 UTC

    First added · source update from Europe PMC

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