Advanced science (Weinheim, Baden-Wurttemberg, Germany)Oct 15, 2026

Removing Intestinal MSTN May Increase GLP-1 Release by Changing SGLT1 Function

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 16, 2026

Abstract

S-palmitoylation is required for stable plasma membrane enrichment of SGLT1, which is essential for GLP-1 secretion.

Intestinal glucagon-like peptide-1 (GLP-1) is secreted in response to glucose levels.
Myostatin (MSTN) is identified as a key regulator of SGLT1 palmitoylation.
Deficiency of MSTN significantly increases SGLT1 palmitoylation and its presence on the plasma membrane.
Enhanced SGLT1 membrane abundance promotes increased secretion of GLP-1 in response to glucose.
Simvastatin was found to upregulate intestinal MSTN, leading to impaired glucose homeostasis.
Blocking SGLT1 palmitoylation reduced its membrane enrichment and suppressed GLP-1 secretion.

Simplified

Intestinal glucagon-like peptide-1 (GLP-1) is secreted by intestinal L cells in a glucose-dependent manner. The localization and surface abundance of glucose-sensing proteins on the cell membrane affect the response to glucose, but the regulatory mechanism remains poorly understood. Here, we show that S-palmitoylation is required for stable plasma membrane enrichment of SGLT1 and for SGLT1-mediated GLP-1 secretion. Notably, myostatin (MSTN) was identified as a key upstream regulator of this modification. Intestinal MSTN deficiency markedly enhanced SGLT1 palmitoylation, increased its plasma membrane abundance, and thereby promoted glucose-stimulated GLP-1 secretion. Importantly, simvastatin induced intestinal MSTN upregulation and impaired glucose homeostasis, whereas MSTN deficiency largely alleviated these effects. Mechanistically, MSTN regulated the expression of the palmitoyl acyltransferase ZDHHC20, which catalyzed SGLT1 S-palmitoylation at Cys301. Blocking SGLT1 palmitoylation attenuated SGLT1 membrane enrichment and markedly suppressed the induction of GLP-1 secretion caused by MSTN deficiency. Collectively, our research results have revealed a new mechanism by which MSTN regulates intestinal endocrine function and S-palmitoylation modification promotes GLP-1 secretion, providing potential targets for regulating endogenous GLP-1 secretion in the intestine and treating metabolic diseases related to glucose imbalance.

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Removing Intestinal MSTN May Increase GLP-1 Release by Changing SGLT1 Function

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