Effects of GLP-1 and GIP on Cholinergic-induced Contractility in Isolated Jejunal Muscle from Obese Patients with and without Type 2 Diabetes Mellitus

Mantas Malinauskas^1*Darius Stukas²Kristina Rysevaite-Kyguoliene³Rita Gudaityte⁴Limas Kupčinskas²Anna Casselbrant⁵Lina Jankauskaite, MD, PhD¹Almantas Maleckas⁴

• ¹Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, Kaunas, Lithuania
• ²Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
• ³Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania
• ⁴Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania
• ⁵Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Background: Intestinal dysmotility in type 2 diabetes mellitus (T2DM) may involve impaired cholinergic and incretin-mediated regulation. This study compared cholinergic-induced jejunal contractility and evaluated the effects of Glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP) in relation to the expression of these peptides, their receptors, and Dipeptidyl peptidase 4 (DPP-4) in jejunal muscle of obese patients with and without T2DM. Methods: Jejunal samples were collected from 32 obese patients undergoing bariatric surgery (14 with and 18 without T2DM). Jejunal muscular tissue was examined for expression of GLP-1, GIP, and for expression and localization of DPP-4 and incretin receptors (GLP-1R and GIPR). In addition, DPP-4 enzymatic activity was quantitatively assessed. Contractility of circular and longitudinal muscle strips was assessed in vitro following bethanechol stimulation, with or without GLP-1 or GIP. Results: GLP-1 receptors were detected in smooth muscle nuclei and enteric ganglia, while GIP receptors localized to both muscle layers. DPP-4 was present in neural and muscular compartments. In T2DM, GIPR and DPP-4 expression and activity were increased, while GIP protein was reduced. GLP-1 protein levels tended to be higher. Longitudinal muscle contractility independent of neural input was reduced in T2DM. GLP-1 selectively inhibited circular muscle contractions in both groups, whereas GIP had no effect. Conclusions: This study demonstrates that reduced cholinergic activity in longitudinal muscle, lower GIP, and increased GLP-1 in T2DM indicate a shifted local incretin environment that may collectively suppress jejunal contractility.