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Targeting the intestinal L-cell for obesity and type 2 diabetes treatment

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Abstract

Degradation-resistant glucagon-like peptide-1 (GLP-1) mimetics and GLP-1 enhancers (inhibitors of dipeptidyl peptidase-4, the enzyme which degrades and inactivates GLP-1) have been used for treatment of type 2 diabetes mellitus since 2005–2006. Cutting-edge research is now focusing on uncovering the secretory mechanisms of the GLP-1-producing cells (L-cells) with the purpose of developing agonists that enhance endogenous hormone secretion. Since GLP-1 co-localizes with other anorectic peptides, cholecystokinin, oxyntomodulin/glicentin and peptide YY, L-cell targeting might cause release of several hormones at the same time, providing additive effects on appetite and glucose regulation. In this review, we explore the role of proglucagon-derived peptides and other L-cell co-localizing hormones, in appetite regulation and the mechanism regulating their secretion.

Acknowledgements

The authors would like to thank M Buyukuslu for professional and outstanding graphic support with Figure 2 and E Balk-Moller for providing help with Figure 3.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

  • Obesity is a global economical burden and impact thousands of lives.

  • Glucagon-like peptide-1 (GLP-1) may co-localize with other anorectic hormones, that is, polypeptide YY (PYY) and oxyntomodulin.

  • The exaggerated increases seen after RYGB in levels of GLP-1, PYY, neurotensin and oxyntomodulin are perhaps the cause of the rapid weight reduction seen in most patients.

  • The brain–gut axis is a pathway that could be used for treatment of obesity.

  • Appetite regulation may be mediated through both a neural and an endocrine pathway regulated by secretion of L-cell-derived and co-localized hormones, that is, GLP-1 and PYY.

  • Agonists targeting endogenous L-cell secretion represent a novel approach to treatment of obesity and type 2 diabetes mellitus.

Notes

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