Altered gastrointestinal function and neurotensin signaling in experimental type 2 diabetes

Type 2 diabetes (T2D) often leads to diabetic gastroenteropathy characterized by gastrointestinal motility disorders, mucosal damage, and oxidative stress. Neurotensin (NT), a gastrointestinal peptide, modulates mucosal healing and metabolic regulation, but its role in diabetic GI dysfunction remains unclear.

A streptozotocin (STZ) + nicotinamide (NAD) rat model was used to induce a non-obese T2D phenotype. Male Sprague Dawley rats were assigned to four groups (n = 8/group): Control, STZ, STZ + NT, and STZ + NT + SR-48692 (NTR1 antagonist). Systemic metabolic parameters, serum biochemical markers, gastric and ileal histopathology, oxidative stress markers (MDA, GSH, MPO, luminol and lucigenin chemiluminescence), and neurotransmitter levels (dopamine, serotonin, norepinephrine) were evaluated. Gastrointestinal function was assessed by intestinal transit, visceromotor reflex responses, and isolated organ bath analysis of gastric and ileal smooth muscle contractility.

Diabetes induction caused significant hyperglycemia, dyslipidemia, hepatic and renal dysfunction, accompanied by marked gastric and ileal structural injury, including mucosal disruption, reduced glycoprotein content, and altered NT immunoreactivity. These changes were associated with increased oxidative stress, inflammatory activity, and disturbances in monoaminergic signaling. Functionally, diabetic rats exhibited impaired intestinal transit, reduced visceral sensory responses, and diminished cholinergic contractility in gastric and ileal smooth muscle. NT treatment significantly attenuated hyperglycemia, improved serum metabolic abnormalities, restored mucosal architecture, reduced oxidative stress, and improved gastrointestinal motility and contractile function. Most protective effects were abolished by SR-48692 co-administration, supporting a predominantly NTR1-dependent mechanism.

NT ameliorates diabetes-induced GI dysfunction and systemic metabolic disturbances primarily via NTR1 signaling, suggesting the NT/NTR1 axis as a potential therapeutic target for diabetic gastroenteropathy.