A subphenotype of obesity with reduced enteroendocrine GLP-1 synthesis and enhanced tirzepatide response.
Tirzepatide just got a plot twist. Researchers at Mayo Clinic say they’ve found a specific subgroup of people with obesity who respond way better to tirzepatide than others. The difference? Their bodies make less GLP-1 in the gut, and their stomachs empty food faster.
Gastroenterology
by Ticho AL, McRae AN, Cifuentes L et al.
“A subphenotype of obesity with reduced enteroendocrine GLP-1 synthesis and enhanced tirzepatide response. Ticho AL(1), McRae AN(1), Cifuentes L(1), Fredrick T(1), Anazco D(1), Espinosa MA(1), Garcia Cordova JM(1), Romanos M(1), Villamarin J(1), Johnson S(2), Lennon R(2), Hurtado Andrade MD(3), Chen J(2), Camilleri M(1), Acosta AJ(4). Author information: (1)Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine. (2)Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota. (3)Division of Endocrinology, Department of Medicine, Mayo Clinic, Jacksonville, Florida. (4)Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine. Electronic address: acosta.andres@mayo.edu. BACKGROUND & AIMS: Obesity is a heterogeneous disease characterized by different pathophysiological and behavioral traits that influence response to GLP-1-based therapies. We previously identified an obesity phenotype characterized by fast gastric emptying and increased postprandial hunger. We aimed to elucidate pathophysiologic mechanisms in this phenotype by evaluating plasma enteroendocrine hormones and mucosal gene expression, and to evaluate treatment response to tirzepatide across subphenotypes. METHODS: 483 adults with obesity underwent solid meal gastric emptying (SGE) by scintigraphy, postprandial appetite assessment using visual analog scale (VAS), and plasma enteroendocrine hormone profiling. Gaussian mixed modeling identified phenotypic clusters. Associations with plasma short-chain fatty acids (SCFAs) and fecal metagenomics were explored. A separate cohort (n=31) underwent colonic mucosal biopsies with quantification of GCG (GLP-1) and PYY mRNA. Retrospective evaluation of weight loss in participants treated with tirzepatide among each cluster was performed (n=61). RESULTS: Three clusters were identified based on SGE and GLP-1. One cluster demonstrated fast SGE, increased postprandial hunger, and discordantly low postprandial GLP-1 (termed dc-GE/GLP-1; n=130, 26.9%), as well as lower plasma PYY and CCK. dc-GE/GLP-1 showed higher plasma SCFA levels, without significant differences in fecal microbial composition. Compared with concordant clusters (c-GE/GLP-1; n=353, 73.1%), dc-GE/GLP-1 had decreased mucosal mRNA expression of GCG (GLP-1) and PYY. At 6-months of tirzepatide, dc-GE/GLP-1 was associated with greater weight loss compared with c-GE/GLP-1 (21.5% vs 11.7%). CONCLUSIONS: We identified a subphenotype of obesity with fast gastric emptying and discordantly low GLP-1 plasma levels, reduced mucosal hormone synthesis, and enhanced weight loss to tirzepatide. Further studies are needed to identify mechanisms contributing to GLP-1 deficiency in this subphenotype of obesity. Copyright © 2026. Published by Elsevier Inc.”
Here’s what went down: Scientists tested over 480 adults with obesity. They measured how fast their food left the stomach, checked hormone levels after eating, and even looked at gene activity from gut biopsies. Using machine learning, they found three main clusters based on gastric emptying speed and GLP-1 levels.
One group—about 27% of participants—stood out. These folks had:
Fast gastric emptying (food leaves the stomach quickly)
Low GLP-1 after meals (the hormone usually spikes to curb appetite)
Even lower levels of other appetite hormones like PYY and CCK
They also had higher blood short-chain fatty acids, but their gut microbes looked similar to the rest. The kicker: this low-GLP-1 group lost almost twice as much weight on tirzepatide at six months compared to the other groups (21.5% vs 11.7%).
Why does this matter? Not everyone with obesity is the same at the molecular level. Some make less GLP-1, which could explain why they’re hungrier and why certain research peptides, like tirzepatide, work especially well for them. It’s a big deal for researchers designing future studies or looking for precision approaches.
Key takeaway: If you’re studying tirzepatide, phenotype matters. The field is moving closer to matching the right peptide to the right subject. For those sourcing quality material for trials, check our vendor directory.
Personalized peptide research is heating up. This study shows there’s more under the hood than weight and BMI.
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