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Gut Peptide Agonism in the Treatment of Obesity and Diabetes

Gerald Grandl, Aaron Novikoff, Richard DiMarchi, Matthias H. Tschöp, Timo D. Müller

10.1002/cphy.c180044

Source: Volume 10, Issue 1, January 2020

Published online: December 2019

Full Article on Wiley Online Library



Abstract

Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type‐2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon‐like peptide‐1 (GLP‐1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half‐life and an often dose‐dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP‐1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism. © 2020 American Physiological Society. Compr Physiol 10:99‐124, 2020.

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Figure 1. Figure 1. (A) Schematic of the systemic effects of selected gastrointestinal peptide hormones. Arrows are color codes by the hormone; arrow up indicates an increase, and arrow down a decrease. (B) Monoagonists in clinical use or en route for clinical use.
Figure 2. Figure 2. Schematic of selected unimolecular polyagonists with simultaneous activity at the receptors for GLP‐1, GIP, and glucagon.
Figure 3. Figure 3. Schematic representation of gut‐peptide‐based tissue‐specific delivery of nuclear hormones. Hormones are targeted to tissues expressing GLP‐1R. GLP‐1 activates canonical GLP‐1 signaling. The hypothesis residing in this concept is based on the vision that the ligand‐receptor complex is internalized into the peptide receptor target cell, followed by dissociation of the nuclear hormone cargo and activation of nuclear hormone signaling.


Figure 1. (A) Schematic of the systemic effects of selected gastrointestinal peptide hormones. Arrows are color codes by the hormone; arrow up indicates an increase, and arrow down a decrease. (B) Monoagonists in clinical use or en route for clinical use.


Figure 2. Schematic of selected unimolecular polyagonists with simultaneous activity at the receptors for GLP‐1, GIP, and glucagon.


Figure 3. Schematic representation of gut‐peptide‐based tissue‐specific delivery of nuclear hormones. Hormones are targeted to tissues expressing GLP‐1R. GLP‐1 activates canonical GLP‐1 signaling. The hypothesis residing in this concept is based on the vision that the ligand‐receptor complex is internalized into the peptide receptor target cell, followed by dissociation of the nuclear hormone cargo and activation of nuclear hormone signaling.
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Further Reading
 1.Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ, Chaudhary N, Holland J, Hembree J, Abplanalp W, Grant E, Ruehl J, Wilson H, Kirchner H, Lockie SH, Hofmann S, Woods SC, Nogueiras R, Pfluger PT, Perez‐Tilve D, Dimarchi R, Tschöp MH. A new glucagon and GLP‐1 co‐agonist eliminates obesity in rodents. Nat Chem Biol 5: 749‐757, 2009.
 2.Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM, Fischer K, Campbell JE, Sandoval D, Seeley RJ, Bleicher K, Uhles S, Riboulet W, Funk J, Hertel C, Belli S, Sebokova E, Conde‐Knape K, Konkar A, Drucker DJ, Gelfanov V, Pfluger PT, Müller TD, Perez‐Tilve D, DiMarchi RD, Tschöp MH. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 21: 27‐36, 2015.
 3.Finan B, Yang B, Ottaway N, Stemmer K, Müller TD, Yi CX, Habegger K, Schriever SC, García‐Cáceres C, Kabra DG, Hembree J, Holland J, Raver C, Seeley RJ, Hans W, Irmler M, Beckers J, De Angelis MH, Tiano JP, Mauvais‐Jarvis F, Perez‐Tilve D, Pfluger P, Zhang L, Gelfanov V, Dimarchi RD, Tschöp MH. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 18: 1847‐1856, 2012.
 4.Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP‐1 receptor agonist, in patients with type 2 diabetes: A randomised, placebo‐controlled and active comparator‐controlled phase 2 trial. Lancet 392: 2180‐2193, 2018.
 5.Tschöp MH, Finan B, Clemmensen C, Gelfanov V, Perez‐Tilve D, Müller TD, DiMarchi RD. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab 24: 51‐62, 2016.

Further Reading

Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ, Chaudhary N, Holland J, Hembree J, Abplanalp W, Grant E, Ruehl J, Wilson H, Kirchner H, Lockie SH, Hofmann S, Woods SC, Nogueiras R, Pfluger PT, Perez-Tilve D, Dimarchi R, Tschöp MH. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 5: 749-757, 2009.

Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM, Fischer K, Campbell JE, Sandoval D, Seeley RJ, Bleicher K, Uhles S, Riboulet W, Funk J, Hertel C, Belli S, Sebokova E, Conde-Knape K, Konkar A, Drucker DJ, Gelfanov V, Pfluger PT, Müller TD, Perez-Tilve D, DiMarchi RD, Tschöp MH. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 21: 27-36, 2015.

Finan B, Yang B, Ottaway N, Stemmer K, Müller TD, Yi CX, Habegger K, Schriever SC, García-Cáceres C, Kabra DG, Hembree J, Holland J, Raver C, Seeley RJ, Hans W, Irmler M, Beckers J, De Angelis MH, Tiano JP, Mauvais-Jarvis F, Perez-Tilve D, Pfluger P, Zhang L, Gelfanov V, Dimarchi RD, Tschöp MH. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 18: 1847-1856, 2012.

Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 392: 2180-2193, 2018.

Tschöp MH, Finan B, Clemmensen C, Gelfanov V, Perez-Tilve D, Müller TD, DiMarchi RD. Unimolecular Polypharmacy for Treatment of Diabetes and Obesity. Cell Metab 24: 51-62, 2016.


 

Teaching Material

Grandl G, Novikoff A, DiMarchi R, Tschöp M.H, Müller T.D. Gut Peptide Agonism in the Treatment of Obesity and Diabetes. Compr Physiol 10: 2020, 99-124.

Didactic Synopsis

Major Teaching Points:

-A variety of peptide hormones are secreted from the gut in response to food intake.

-Gut peptides regulate meal size and satiety via binding to specific receptors expressed on target tissues in the brain and the periphery

-GLP1 and GIP constitute a specific class of gut peptides, called incretins, which directly influence the release of insulin from the pancreas after a meal.

-Agonists for various gut peptide receptors have been explored for the clinical treatment of obesity, the metabolic syndrome and type 2-diabetes.

-Long-lasting agonists at the GLP-1 receptor have proven to be useful in the treatment of type-2 diabetes.

-The concept of combining gut peptides into unimolecular multi-agonists has been explored with great promise for the enhancement of incretin-based pharmacology.

-In parallel, the concept of using gut peptides to deliver small molecule drugs to specific cell types has been explored.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching Points: This figure provides an overview of well-studied gut peptides directly involved in satiety and meal size. The various actions of the peptides have been described next to the relevant depicted tissue. The arrows illustrate whether the peptide elevates or reduces the described action.

Figure 2. Teaching Points: This figure demonstrates the principle classes of gut peptide polyagonism that have been explored so far. Through the unimolecular combination of two or three distinct peptide hormone sequences, and following careful testing and fine-tuning, peptides with equal activation of the respective receptors can be designed. These multi-agonist compounds can interact with each relevant receptor individually or in combination, creating a unique capacity for activating downstream intracellular signalling events.

Figure 3. Teaching Points: This figure illustrates the principle of using gut peptides for the targeted delivery of small molecule hormones. The small molecule is linked to a peptide sequence which precisely targets the small molecule to tissues and cell types expressing the carrier peptide receptor. After binding to the peptide receptor, the small molecule that is attached is internalized. Once inside the cell, through a mechanism not clearly elucidated yet, the small molecule is released from the peptide for subsequent nuclear receptor activation.

 


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Article Title: Gut Peptide Agonism in the Treatment of Obesity and Diabetes
 

How to Cite

Gerald Grandl, Aaron Novikoff, Richard DiMarchi, Matthias H. Tschöp, Timo D. Müller. Gut Peptide Agonism in the Treatment of Obesity and Diabetes. Compr Physiol 2019, 10: 99-124. doi: 10.1002/cphy.c180044