Catestatin Improves Glucose Control by Modulating Gut Motility: Gut | July 2026

Introduction:

Altered gut motility is increasingly recognized as a contributor to metabolic dysfunction through the gut–brain axis. Enterosynes are gut-derived bioactive molecules that regulate intestinal motility and influence systemic glucose homeostasis. This study investigated whether catestatin, a peptide that inhibits cholinergic signaling, improves glucose metabolism by reducing duodenal hypermotility in obesity-associated diabetes.

Why was this study needed?

Gut dysmotility contributes to impaired glucose regulation in obesity and diabetes.

Most enterosynes improve metabolism by stimulating intestinal nitric oxide (NO), limiting therapeutic diversity.

The metabolic effects of catestatin on gut motility and glucose homeostasis were largely unexplored.

Identifying alternative gut–brain axis mechanisms may lead to novel treatments for metabolic disease.

Results:

In high-fat diet–fed diabetic male mice, acute and short-term oral administration of catestatin significantly reduced duodenal hypermotility, resulting in improved glucose tolerance and lower glucose-stimulated insulin secretion. Unlike previously described enterosynes, these effects occurred without increasing intestinal nitric oxide release, indicating a distinct mechanism of action mediated through inhibition of cholinergic signaling. Catestatin treatment also induced favorable transcriptional changes across multiple metabolic tissues, including the intestine, liver, adipose tissue, muscle, and brain. Longer-term administration further reduced body weight gain, improved glucose tolerance, and significantly decreased hepatic triglyceride accumulation, suggesting sustained metabolic benefits beyond glucose control.

Clinical Impact:

This study identifies catestatin as a novel gut-derived regulator of glucose metabolism that acts by normalizing intestinal motility rather than stimulating nitric oxide pathways. Targeting gut motor function may represent an innovative therapeutic strategy for obesity, type 2 diabetes, and metabolic dysfunction–associated steatotic liver disease, although clinical studies are needed to confirm these findings in humans.

Bottom Line:

Catestatin improves glucose homeostasis by reducing duodenal hypermotility through a nitric oxide–independent mechanism, highlighting gut motility modulation as a promising therapeutic target for metabolic disorders.