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Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.
Have you ever wondered how your body knows exactly what to do after you eat a meal?Â
It’s like an internal symphony orchestrated by hormones, and one of the key players is GLP-1, or glucagon-like peptide-1. This incretin hormone is produced in your intestines right when food arrives. Incretin hormones are a group of metabolic hormones produced by the gut in response to eating. Think of GLP-1 as a messenger that announces, “Food’s here—let’s get to work!”
Here’s what GLP-1 does:
Now, imagine if we could harness these effects to help manage conditions like type 2 diabetes and obesity.
That’s where GLP-1 receptor agonists come into play. An agonist is a drug or substance that binds to a receptor inside a cell or on its surface and causes the same action as the substance that normally binds to the receptor. The GLP-1 receptor agonists are like GLP-1’s enthusiastic assistants—they bind to the same receptors and mimic its actions in the body.
By taking GLP-1 receptor agonists, patients can:
In essence, GLP-1 receptor agonists leverage the body’s natural mechanisms to provide a double benefit: better blood sugar management and assistance with weight loss. It’s like giving your body’s own system a helpful boost, making these medications valuable tools in treating diabetes and obesity.
GLP-1 receptor agonists have revolutionized the management of type 2 diabetes mellitus and obesity. Medications like exenatide, liraglutide, and semaglutide not only improve glycemic control but also promote weight loss, offering dual benefits for patients. However, not everyone experiences the same degree of efficacy or tolerability with these treatments.Â
Emerging research suggests that genetic variations play a significant role in modulating individual responses to GLP-1 medications. Understanding these genetic factors could pave the way for more personalized and effective therapies.
Clinical observations have revealed considerable variability in how patients respond to GLP-1 medications. While some individuals achieve significant reductions in blood glucose levels and body weight, others exhibit minimal benefits or experience adverse effects like gastrointestinal discomfort. This variability suggests that factors beyond lifestyle and adherence influence treatment outcomes.
The GLP1R (Glucagon-Like Peptide-1 Receptor) gene encodes the GLP-1 receptor, the primary target of GLP-1 medications. Variations in this gene can alter receptor function and expression.
Certain SNPs in the GLP1R gene have been associated with differential responses to GLP-1 agonists. A 2018 study found that individuals who carry the minor A-allele of the genetic variant GLP1R rs6923761 tend to experience a greater delay in gastric emptying when treated with GLP-1 receptor agonists like liraglutide and exenatide. Gastric emptying is the process by which food moves from the stomach to the small intestine. A delayed gastric emptying means food stays in the stomach longer, which can increase feelings of fullness and reduce appetite, potentially leading to weight loss.
A study published in January this year (2024) investigated whether two specific genetic variations SNPs) in the GLP-1 receptor gene (named rs6923761 and rs10305420) affect how well people with type 2 diabetes respond to the medication liraglutide. Individuals who had two copies of the T-allele at the rs10305420 SNP were significantly more likely to have an optimal response to the medication.
The TCF7L2 (Transcription Factor 7-Like 2) is a gene that provides instructions for making a protein involved in regulating blood sugar levels and the function of insulin-producing cells in the pancreas. Variants in TCF7L2 can impair insulin secretion, which may influence how effectively GLP-1 medications stimulate insulin release. Studies suggest that individuals with certain TCF7L2Â variants (such as rs7903146) may experience reduced glycemic benefits from GLP-1 agonists due to altered signaling pathways. A 2011 research study involving 62 adults discovered that stomachs of people carrying the T-allele of rs7903146 emptied liquids faster than those with the CC genotype.
Another study published in March this year (2024) investigated whether specific genetic differences in the TCF7L2, CTRB1/2, and GLP1R genes affect how well Greek patients with type 2 diabetes respond to GLP-1 receptor agonist medications. They included 191 patients who had been on these medications for at least six months and checked for particular genetic variants. The results showed that female patients and those with a lower initial weight experienced better improvements in blood sugar levels and weight loss.
Read more on the genetic aspects of the insulin hormone:
DPP4 (Dipeptidyl peptidase-4) degrades endogenous GLP-1. Genetic differences in the DPP4 gene can affect enzyme activity levels, influencing GLP-1 availability and, consequently, the efficacy of GLP-1 receptor agonists.Â
According to a 2017 study individuals with rs6741949 variant in the DPP4 gene, especially those with higher body fat, may have impaired blood sugar regulation. Understanding DPP4 variations can help tailor combination therapies, such as adding DPP4 inhibitors to enhance endogenous GLP-1 levels alongside GLP-1 agonists.
The MC4R (melanocortin 4 receptor) gene is associated with appetite regulation. Variants in MC4R may affect how GLP-1 medications promote satiety and weight loss. Patients with certain MC4R mutations may experience different weight loss outcomes when treated with GLP-1 agonists.Â
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A 2020 case report describes how the GLP-1 receptor agonist, liraglutide, effectively helped a woman with severe obesity and type 2 diabetes. This particular patient had two mutated copies of the MC4R allele. After 16 weeks of taking liraglutide at a dose of 3 mg per day, she lost 9.7 kg—a weight loss similar to that seen in people with only one mutated MC4R gene (heterozygous) or common forms of obesity. Additionally, her fasting blood sugar, triglyceride levels, and systolic blood pressure decreased significantly, and her glucose tolerance returned to normal.
Genetic variations can influence:
The field of pharmacogenetics explores how genes affect a person’s response to drugs. By identifying genetic markers associated with better or worse responses to GLP-1 medications, clinicians can personalize treatment plans.
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Research is ongoing to fully elucidate the genetic factors influencing GLP-1 medication response.
Large-scale genome-wide association studies (GWAS) studies are on-going aiming to identify novel genetic variants linked to treatment outcomes. A 2023 GWAS included 4,571 adults with type 2 diabetes and baseline HbA1c levels of 7% or higher, who were treated with GLP-1 receptor agonists across several cohorts and clinical trials. The study found that genetic variations significantly influenced the reduction in HbA1c after six months of treatment. Specifically, the GLP1R variant rs6923761 (Gly168Ser) was associated with a modestly greater HbA1c reduction, while low-frequency variants in the ARRB1 gene, particularly rs140226575 (Thr370Met), were linked to a substantially greater reduction, especially in Hispanic and Native American populations where this variant is more common. The findings suggest that when genotyping is readily available, individuals with certain ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists
Other research directions include combining genetic information with clinical factors to enhance predictive models and designing drugs that can overcome genetic resistance or target alternative pathways.
Genetic variations significantly influence individual responses to GLP-1 medications. Understanding these genetic factors holds the promise of optimizing treatment efficacy, minimizing adverse effects, and advancing the move toward personalized medicine in managing T2DM and obesity. As research progresses, incorporating genetic testing into clinical practice may become a standard approach to tailoring GLP-1-based therapies for optimal patient outcomes.
