A Subphenotype of Obesity With Reduced Enteroendocrine Glucagon-Like Peptide 1 Synthesis and Enhanced Tirzepatide Response.

In 483 adults with obesity, a dc-GE/GLP-1 subphenotype (n = 130; 26.9%) shows fast gastric emptying with discordantly low postprandial GLP-1 and greater tirzepatide weight loss.

• Why it matters: GLP-1-based therapies vary in effectiveness, and prior work linked a fast gastric emptying phenotype to hunger; mechanisms and treatment responsiveness across subtypes were unclear.
• What they did: Using solid meal gastric emptying by scintigraphy, visual analogue appetite ratings, and plasma enteroendocrine hormone profiling, Gaussian mixed modeling defined clusters; a separate biopsy cohort (n = 31) quantified mucosal GCG and PYY messenger RNA.
• The result: At 6 months, dc-GE/GLP-1 was associated with greater weight loss than c-GE/GLP-1 (21.5% vs 11.7%), alongside reduced mucosal GCG (GLP-1) and PYY expression.

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