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A research-focused comparison of Melanotan II and PT-141, covering melanocortin receptor selectivity, evidence, safety signals and regulatory status.
In 1964, two research teams independently observed a phenomenon that at first glance seemed to be a measurement anomaly. Glucose given orally to a healthy person caused a much greater insulin release than the same dose of glucose given intravenously – at the same blood glucose level. The difference was not insignificant. An oral glucose load stimulated insulin secretion two to three times more strongly than its intravenous counterpart. Something in the digestive tract enhanced the pancreas’s response to glucose—something that was not present when the glucose bypassed the intestine and went directly into the blood.
The phenomenon was called the “incretin effect” intestinal secretion of insulin), and the detailed molecular mechanism required another two decades of research. Today we know that two peptide hormones are responsible for the incretin effect – GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) — secreted by special intestinal epithelial cells in response to food. Together, incretins account for approximately 70% of postprandial insulin secretion in healthy individuals. The third, antagonistic hormone of classical physiology – glucagon — in modern metabolic pharmacology it begins to play a surprisingly complementary role.
This article brings together in one place the current state of knowledge about three peptide hormones (GLP-1, GIP, glucagon) – their structure, sources of secretion, receptors, molecular mechanisms and pharmacological significance. From the perspective of contemporary diabetes and obesity pharmacology, these are the three main axes around which new ones are built metabolic drugs based on GLP-1 peptides.
📖 The following article is educational and reviews knowledge of the physiology and pharmacology of incretins. The text does not constitute medical advice. Peptides from the One Peptides catalog are intended only for laboratory tests (Research Use Only).
Incretins are peptide hormones secreted by enteroendocrine cells of the intestinal epithelium in response to the presence of food in the gastrointestinal tract. Their main biological function is to modulate the response of the pancreas, stomach and central nervous system to incoming energy. The classic definition includes two hormones – GLP-1 and GIP – although in more recent literature the concept of “incretin” is sometimes extended to the entire system of intestinal metabolic regulators.
| Year | Event |
|---|---|
| 1902 | Bayliss and Starling – discovery of secretin, the first intestinal hormone |
| 1964 | Elrick/McIntyre – Documentation of the incretin effect |
| 1971 | Brown – GIP isolation from intestinal extracts |
| 1985 | Habener – identification of the GLP-1 sequence as a proglucagon product |
| 1995 | First clinical trials of GLP-1 as a drug in diabetes |
| 2005 | Registration of exenatide – the first GLP-1 analogue |
| 2017 | Semaglutide Registration – Breakthrough GLP-1RA with Weekly Dosing |
| 2022 | Registration of tirzepatide – the first GLP-1R/GIPR dual-agonist |
| 2023 | First results of retatrutide – a triple GLP-1R/GIPR/GCGR agonist |
Half a century of development of incretin pharmacology has led to the fact that the GLP-1RA class is today one of the best-selling drug groups in the world.
GLP-1 is a product of the post-translational processing of preproglucagon, the same precursor protein that also produces glucagon (in the pancreas) and GLP-2 (in the intestine). Cutting with different enzymes in different tissues generates different end products:
GLP-1 has two biologically active forms in the body:
Both forms are active on the GLP-1R receptor with comparable potency.
GLP-1 is secreted by L cells located in the distal small intestine (ileum) and colon. Secretion stimulation:
L cells have receptors on the apical surface (facing the intestinal lumen) that detect macronutrients directly during digestion.
Endogenous GLP-1 has a half-life in the bloodstream approximately 2 minutes. Such rapid degradation is forced by the enzyme dipeptidyl peptidase-4 (DPP-4) — a protease present in the endothelium of blood vessels that cleaves the N-terminal two amino acids of GLP-1, generating an inactive metabolite of GLP-1 (9-36).
The short half-life of endogenous GLP-1 has been a major challenge in drug development:
The GLP-1 receptor (GLP-1R) is a class B1 G-protein-coupled receptor. Distribution in the body:
The breadth of GLP-1R distribution explains why GLP-1 agonists have effects in such diverse organ systems.
| Trail | Effect |
|---|---|
| cAMP/PKA (via Gs) | Increased insulin secretion in beta cells |
| PI3K/Act | Beta cell survival |
| MAPK/ERK | Beta cell proliferation |
| EPAC | Enhancing the insulinotropic response |
| Beta-arrestin | Modulation of receptor desensitization |
GIP is a 42 amino acid peptide derived from preproGIP, a separate precursor from preproglucagon. Unlike GLP-1, GIP has one active form and one secretion site.
GIP is secreted by K cells located in the proximal small intestine (duodenum and upper jejunum). Secretion stimulation:
The location of K cells closer to the stomach means that GIP is released more rapidly after a meal than GLP-1 – observed as an earlier peak in response to food.
The GIP receptor (GIPR) is a class B1 G-protein-coupled receptor, structurally similar to GLP-1R. Distribution:
Classically, GIP was perceived as a “pro-obesogenic” hormone – stimulating adipocytes to store energy. The mechanism suggested that GIPR antagonism could be therapeutic in obesity.
The modern picture is more nuanced. Tirzepatide (Mounjaro/Zepbound) — a dual GLP-1R/GIPR agonist — has shown that activation GIPR (contrary to classical expectations) produces a stronger reduction in body weight than GLP-1R monoagonists. The mechanism of this synergy is not fully understood – hypotheses include:
GIPR activity in retatrutide (triple agonist) follows the same pattern.
The informal shorthand used for retatrutide in online searches is explained in a separate entry: what “reta” means in informal usage.
Glucagon is a 29 amino acid peptide derived from preproglucagon (the same precursor as GLP-1). Cutting in the pancreas produces glucagon, in the intestine – GLP-1 and GLP-2.
Glucagon is secreted by pancreatic alpha cells in response to:
In classical physiology, glucagon mobilizes glucose from the liver:
In this classic picture, glucagon is the “anti-insulin” hormone – maintaining glycemia in conditions of starvation.
The glucagon receptor (GCGR) is a class B1 G protein-coupled receptor. Distribution:
In the context of modern metabolic pharmacology (retatrutide, GLP-1R/GCGR dual-agonists), glucagon takes on a new meaning. GCGR activation accompanied by GLP-1R and GIPR activity gives:
The paradox of this mechanism is that glucagon classically increases glycemia, but in the presence of GLP-1R and GIPR, the net effect is hypoglycemic – because GLP-1R and GIPR dominate the insulinotropic effect.
The three hormones—GLP-1, GIP, and glucagon—do not work in isolation. Their effects are integrated into the body’s metabolic response to food and energy status.
| Hormone | Secretion | Main effect |
|---|---|---|
| GLP-1 | Height (from intestine L) | Increase in insulin, reduction in glucagon, delay in gastric emptying |
| GIP | Height (from gut K) | Increase in insulin (synergy with GLP-1) |
| Glucagon | Decrease | Inhibition of glucose production in the liver |
| Hormone | Secretion | Main effect |
|---|---|---|
| GLP-1 | Low | (satiety effect reduced) |
| GIP | Low | (insulinotropic effect reduced) |
| Glucagon | Growth | Mobilization of glucose from the liver |
| Bow | Class | Receptors activated |
|---|---|---|
| Liraglutide, Semaglutide, Dulaglutide | Monoagonist | GLP-1R |
| Tirzepatide | Dual-agonist | GLP-1R + GIPR |
| Cotadutide | Dual-agonist | GLP-1R + GCGR |
| Retatrutide | Triple agonist | GLP-1R + GIPR + GCGR |
Each class produces a different effect profile – more receptors activated usually translate into a stronger effect on body weight, but also a higher side effect profile.
Dipeptidyl peptidase-4 (DPP-4) is an enzyme that deserves a separate section because its activity regulates the duration of the incretin effect.
DPP-4 is a serine protease present in the endothelium of blood vessels (soluble form) and as a transmembrane protein on the surface of many cells. The enzyme cleaves the two N-terminal amino acids (dipeptidyl) of peptides containing proline or alanine at position 2.
DPP-4 substrates include:
Incretin pharmacology uses DPP-4 in two opposing ways:
Strategy 1 – DPP-4 resistant incretin analogues. Structural modifications of the peptide (e.g. Aib at position 8 of semaglutide) block cleavage by DPP-4. The peptide remains active in the bloodstream for hours or days instead of minutes. Examples: liraglutide, semaglutide, tirzepatide, retatrutide.
Strategy 2 – DPP-4 inhibitors. Small molecule drugs that block the activity of the DPP-4 enzyme – endogenous GLP-1 and GIP remain active longer. Examples: sitagliptin, vildagliptin, saxagliptin, linagliptin. This class has weaker clinical effects than GLP-1 agonists, but is available orally and has a more favorable side effect profile.
Both are incretins and have a synergistic role in the incretin effect, but differ in several aspects: origin (GLP-1 from proglucagon, GIP from preproGIP), source of secretion (GLP-1 from L cells in the distal intestine, GIP from K cells in the proximal intestine), receptors (GLP-1R vs GIPR), breadth of effects (GLP-1 has more target tissues), and clinical therapeutic significance (GLP-1RA dominate the market).
A phenomenon in which glucose administered orally causes a much stronger insulin release than the same dose of glucose administered intravenously. In healthy people, the incretin effect is responsible for 50–70% of postprandial insulin secretion. It is mediated by the hormones GLP-1 and GIP secreted by intestinal epithelial cells.
Endogenous GLP-1 has a half-life of approximately 2 minutes due to rapid cleavage by DPP-4. Practical clinical use would require continuous intravenous infusion – impractical on a large scale. All therapeutically used GLP-1 agonists (liraglutide, semaglutide, dulaglutide) have structural modifications that protect against DPP-4 and extend the half-life to hours or days.
Classically it was perceived this way – GIP stimulates adipocytes to store energy, so GIPR antagonism suggested an anti-obesity approach. However, the contemporary picture is complex. Tirzepatide (dual-agonist GLP-1R/GIPR) has shown that GIPR activation produces a stronger reduction in body weight than GLP-1 alone. The mechanism of synergy is not fully understood – it probably involves the enhancement of the insulinotropic effect and the modulation of satiety centers.
Classically yes. Glucagon mobilizes glucose from the liver. In the context of a triple agonist (retatrutide), however, GCGR activity is balanced by the stronger insulinotropic effects of GLP-1R and GIPR. Net retatrutide is effective in lowering glycemia despite activity at the glucagon receptor. GCGR activation increases energy expenditure and improves the metabolic profile of the liver.
DPP-4 is an enzyme (protease) present in the endothelium of blood vessels that degrades GLP-1, GIP and other biologically active peptides. DPP-4 inhibitors (sitagliptin, vildagliptin, etc.) are drugs that block the activity of this enzyme – as a result, endogenous incretins retain their activity longer. This is an alternative pharmacological strategy to the administration of synthetic GLP-1 analogues.
Central mechanism: GLP-1 agonists activate GLP-1R receptors in the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract (NTS) of the brainstem. These structures control satiety and food reward. Effect: increased satiety, reduction of “food noise” (thoughts about food), reduction of portion size. Peripheral mechanism: delay in gastric emptying – food stays longer in the stomach = longer feeling of satiety.
Incretin peptides available in the One Peptides catalog: semaglutide 2 mg (SEMA G), retatrutide 5 mg (TRIPLE G) and GLP-1/GIP 5 mg. Each batch with a certificate of analysis.
ℹ️ Global disclaimer
All One-Peptides products are reagents intended exclusively for laboratory and scientific research (Research Use Only). They are not medicines, dietary supplements or products intended for human consumption. The information in this article is educational in nature and describes the physiology and pharmacology of incretins (GLP-1, GIP, glucagon) and their therapeutic applications; does not constitute medical, pharmaceutical or dietary advice.
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