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Innovative Medicines & Omics Incretin mimetics in diabetes management

insulinotropic polypeptide, play a critical role in glucose of hypoglycemia as their insulinotropic effects are
homeostasis by stimulating insulin release from pancreatic glucose-dependent, activating only at higher glucose
β-cells. These hormones are rapidly degraded by the concentrations. GLP-1 improves insulin gene expression
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DPP-4. The “incretin effect” refers to the heightened and synthesis and has trophic and protective effects on
insulin secretion in response to oral glucose compared β-cells, while also suppressing pancreatic glucagon release
to intravenous glucose – a phenomenon notably reduced in a glucose-dependent manner. Conversely, GIP has been
in patients with diabetes. This reduction is due to a shown to increase glucagon secretion. Both hormones
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diminished capacity of GIP to induce insulin release, exert insulinotropic effects through G-protein-coupled
possibly stemming from general β-cell dysfunction or receptors on pancreatic β-cells. 17
specific abnormalities in the GIP signaling pathway. This Beyond their influence on the endocrine pancreas,
decrease in incretin action contributes to impaired glycemic these incretin hormones play various roles in other
control, particularly in regulating postprandial glucose physiological systems. GLP-1 receptors are present in
levels. In contrast, the insulinotropic effects of GLP-1 several brain regions, where they are believed to stimulate
remain relatively preserved, allowing exogenous GLP-1 to satiety, particularly when combined with GLP-1-induced
stimulate insulin release, inhibit glucagon secretion, and slowing of gastrointestinal motility through vagal
lower plasma glucose during both fasting and postprandial signaling, ultimately reducing food intake and aiding in
states. This understanding has propelled the development body weight control. GLP-1 also delays gastric emptying,
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of incretin-based glucose-lowering medications. helping to attenuate postprandial glucose spikes. On the
Incretin hormones secreted by the gastrointestinal other hand, GIP does not affect gastric emptying, and this
tract epithelium play a critical role in maintaining normal effect is specific to GLP-1 RAs, though repeated doses of
glucose tolerance by preventing excessive postprandial GLP-1 mimetics may reduce the gastric emptying delay. 18
glucose spikes through glucose-dependent insulin The enzyme DPP-4 plays a key role in glucose
release. The incretin effect is dose-dependent, ensuring metabolism by inactivating GLP-1 and GIP, thereby
stable postprandial glucose levels even as carbohydrate diminishing their effects on insulin secretion and glucose
intake varies. To assess the incretin effect, researchers regulation, contributing to higher postprandial glucose
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compare insulin responses to oral and intravenous glucose levels. DPP-4 inhibitors, such as sitagliptin, saxagliptin,
administrations that produce similar glucose excursions. and linagliptin, are used in treating T2DM to inhibit DPP-4
Findings suggest that the incretin effect may account for up activity, prolonging the action of GLP-1 and GIP. This action
to a fivefold increase in postprandial glucose clearance, as enhances insulin secretion and reduces glucagon levels in
evidenced by the differential glucose infusion requirements a glucose-dependent manner, thus improving glycemic
needed to replicate the glucose levels induced by oral control without significantly increasing hypoglycemia risk.
intake. 13 DPP-4 inhibitors are often used in combination with other
Oral glucose intake triggers the release of GIP and antidiabetic agents, such as metformin, and are generally
GLP-1 from the gut, enhancing insulin secretion and well-tolerated with minimal side effects. 19
facilitating glucose disposal. This role of GIP and GLP-1 The GLP-1 receptor, a 463-amino acid protein with
in enhancing insulin secretion explains why the incretin eight hydrophobic domains, is expressed in tissues such
effect is closely linked to carbohydrate intake. The as the heart, kidneys, gut, pancreatic islets, stomach, and
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amount of carbohydrates affects both incretin secretion lungs, with a highly conserved N-terminal extracellular
and the subsequent insulin response (Figure 1). In healthy domain. On GLP-1 receptor activation, intracellular
individuals, the incretin effect accounts for up to 70% of calcium and cyclic adenosine monophosphate levels rise
insulin secretion in response to glucose intake. GLP-1, a rapidly, resulting in glucose-dependent insulin secretion.
30-amino acid polypeptide, is produced by endocrine However, DPP-4 quickly inactivates GLP-1, which has a
L-cells in the mucosa of the distal small intestine and colon, half-life of only 1 – 2 min. Specific amino acid modifications
whereas GIP, a 42-amino acid polypeptide, is secreted by at the C- and N-termini of GLP-1 also enhance receptor
endocrine K-cells located in the duodenum and upper engagement and resistance to DPP-4 degradation, thereby
jejunum. 16 prolonging GLP-1’s half-life and action. 20
Glucagon-like peptide-1 is rapidly degraded by the Only a small fraction of circulating GLP-1 is
enzyme DPP-4, with a short half-life of approximately physiologically active. GLP-1 amide, a key secretory
1.5 minutes, while GIP has a slightly longer half-life product, represents the active form of GLP-1. Once in the
of around 7 min. Despite their ability to stimulate bloodstream, GLP-1 amide has a half-life of <2 min, as
insulin secretion, these hormones do not pose a risk it is rapidly cleaved by DPP-4 at positions 8 and 9. This

Volume 2 Issue 1 (2025) 3 doi: 10.36922/imo.4911