Project

Interactions of Glucagon-peptide 1 (GLP-1) and analogues with the endogenous receptor

Publisher

Supervisor

Location

Greater Copenhagen area

GLP-1 analogues are used for the treatment of type-2 Diabetes Mellitus, and some of the analogues are also effective in the treatment for obesity. GLP-1 is an incretin hormone, which is secreted in the gastrointestinal tract upon ingestion of nutrients, and has a stimulating effect on the insulin response. GLP-1 is primarily expressed in the L cells of the ileum and colon. The L cells are polarised enteroendocrine cells with the apical side exposed to the gut lumen. GLP-1 is secreted from the basal side of L cells in response to the nutrient content of the gastrointestinal tract. GLP-1 is secreted only in response to orally ingested nutrient, while intravenous glucose administration fails to evoke a GLP-1 response. Thus, the expression of GLP-1 will increase post-prandially. The increase occurs in 2 phases: one is within minutes of a meal and is believed to be due to nervous stimulation of the GLP-1 producing cells, whereas the other phase is due to direct nutrient stimulation of the secreting cells. Evidence are accumulated that the L cells sense luminal glucose through receptors similar to lingual sweet taste receptors. GLP-1 is responsible for up to 60 % of the post-prandial insulin response. While GLP-1 is interesting for a pharmaceutical application, it cannot be used for routine treatment, since its biological half-life is only few minutes. Different strategies have been used to overcome this short-coming, and those include: i) incorporation of the peptides in injectable microspheres; ii) fusion with larger carrier molecules like albumin or Fc fragments of immunoglobulin G; iii) attachment of a fatty-acid side-chain which allows reversible binding to albumin. The latter approach, for instance, has been utilized in designing the GLP-1 analogue: liraglutide (Victoza®, Novo Nordisk A/S). The project focus on studying the key interactions of the GLP-1 analogues with GLP-1R and the dynamics of the complex using in-silico modeling techniques. Particular focus will be on the nature of interactions of the fatty acid, albumin and immunoglobulin fragments covalently bound to the analogues with the GLP-1 receptor. Computational results will be compared to experimentally results reported in the literature.

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Contact

Company / Organization

DTU Kemi

Name

Günther H.J. Peters

Position

Professor

Mail

ghp@kemi.dtu.dk

Supervisor info

BSc in Biotechnology

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

BSc in Chemistry and Technology

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

BSc in Human Life Science Engineering

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc Eng in Applied Chemistry

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc in Biotechnology

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc in Mathematical Modelling and Computation

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

BSc in Biomedical Engineering

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc in Bioinformatics and Systems Biology

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc in Pharmaceutical Design and Engineering

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc in Chemical and Biochemical Engineering

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

MSc in Biomedical Engineering

Supervisor

Günther H.J. Peters

Co-supervisors

Pernille Harris

Type

BSc project, MSc thesis, Special course

Technical University of Denmark

For almost two centuries DTU, Technical University of Denmark, has been dedicated to fulfilling the vision of H.C. Ørsted – the father of electromagnetism – who founded the university in 1829 to develop and create value using the natural sciences and the technical sciences to benefit society.


Today, DTU is ranked as one of the foremost technical universities in Europe, continues to set new records in the number of publications, and persistently increases and develops our partnerships with industry, and assignments accomplished by DTU’s public sector consultancy.

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CVR-nr. 30 06 09 46

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