Role of DPP-4 and NPY Family Peptides in Gastrointestinal Symptoms Associated with Obesity and Type 2 Diabetes Mellitus

Abstract

Background and Objectives: Neuropeptide Y (NPY) family peptides and dipeptidyl peptidase-4 (DPP-4) are involved in gastrointestinal regulation and may contribute to obesity and type 2 diabetes mellitus (T2DM) pathophysiology. This study investigates their expression in jejunal muscular tissue and associations with gastrointestinal symptoms in patients with obesity, with (OB+/DM+) and without T2DM (OB+/DM-). Materials and Methods: This cross-sectional study includes forty-four patients undergoing laparoscopic Roux-en-Y gastric bypass divided based on T2DM status. Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, and jejunal tissue samples were analyzed for DPP-4, NPY, peptide YY (PYY), and pancreatic polypeptide (PP) mRNA and protein levels. Results: DPP-4, NPY, PYY, and PP gene expression in jejunal muscular tissue was similar between groups. In the OB+/DM+ group, PP protein was higher, while DPP-4 and PYY were lower compared to the OB+/DM- group. Significant positive correlations between DPP-4 and NPY, PYY, and PP were found in the OB+/DM- group, while only DPP-4 and PYY correlated in the OB+/DM+ group. Gastrointestinal symptoms in the OB+/DM- group showed positive correlations with PP (abdominal pain), DPP-4 (indigestion), and NPY (constipation). Conclusions: The study demonstrates significant differences in DPP-4, PYY, and PP protein expression between patients with obesity, with or without T2DM. Peptide correlations with gastrointestinal symptoms in non-diabetic patients suggest distinct regulatory mechanisms, warranting further research.

Keywords: dipeptidyl peptidase-4; gastrointestinal symptoms; neuropeptide Y; obesity; pancreatic polypeptide; peptide YY; type 2 diabetes.

Figure 1

Overview of DPP-4-mediated cleavage and receptor interactions in intestinal tissue. This figure illustrates the enzymatic activity of DPP-4 in cleaving NPY(1–36), PYY(1–36), and PP, resulting in truncated forms such as NPY(3–36) and PYY(3–36). These truncated peptides shift receptor affinity, losing their binding to Y1R, Y4R, and Y5R and instead becoming agonists of Y2R. PP cleavage by DPP-4 diminishes its affinity for Y4R.

Figure 2

Expression of DPP-4 levels in jejunal muscular tissue. The relative DPP-4 mRNA expression in jejunal muscular tissue for patients with obesity and diabetes (OB+/DM+, n = 17) and patients with obesity and without diabetes (OB+/DM−, n = 25) (a). DPP-4 protein expression in jejunal muscular tissue for patients with obesity and diabetes (OB+/DM+, n = 17) and patients with obesity and without diabetes (OB+/DM−, n = 24) (b). Values are given as mean ± SEM. Significant differences are denoted by * p ≤ 0.05 (Mann–Whitney U test).

Figure 3

Expression of NPY levels in jejunal muscular tissue. The relative NPY mRNA expression in tissue for patients with obesity and diabetes (OB+/DM+, n = 24) and patients with obesity and without diabetes (OB+/DM−, n = 17) (a). NPY protein expression in tissue for patients with obesity and diabetes (OB+/DM+, n = 11) and patients with obesity and without diabetes (OB+/DM−, n = 16) (b).

Figure 4

Expression of PYY levels in jejunal muscular tissue. The relative PYY mRNA expression in tissue for patients with obesity and diabetes (OB+/DM+, n = 17) and patients with obesity and without diabetes (OB+/DM−, n = 26) (a). PYY protein expression in tissue for patients with obesity and diabetes (OB+/DM+, n = 15) and patients with obesity and without diabetes (OB+/DM−, n = 23) (b). Values are given as mean ± SEM. Significant differences are denoted by * p ≤ 0.05 (Mann–Whitney U test).

Figure 5

Expression of PP levels in jejunal tissue. The relative PP mRNA expression in tissue for patients with obesity and diabetes (OB+/DM+, n = 17) and patients with obesity and without diabetes (OB+/DM−, n = 26) (a). PP protein expression in tissue for patients with obesity and diabetes (OB+/DM+, n = 17) and patients with obesity and without diabetes (OB+/DM−, n = 25) (b). Values are given as mean ± SEM. Significant differences are denoted by * p ≤ 0.05 (Mann–Whitney U test).

Figure 6

Correlation of DPP-4 protein and mRNA expression with NPY, PYY, and PP in jejunal muscular tissue in patients with obesity and without diabetes (OB+/DM−). Panels (a–c) show the correlations between DPP-4 (n = 24) protein expression and NPY (n = 16) (a), PYY (n = 23) (b), and PP (n = 25) (c) protein expression. Panels (d–f) illustrate the correlations between DPP-4 (n = 25) mRNA expression and NPY (n = 17) (d), PYY (n = 26) (e), and PP (n = 26) (f) mRNA expression. mRNA values were expressed as log2(2^−ΔΔCt). Spearman’s rank correlation test was applied, and results are reported as correlation coefficients (r) and p-values (p).

Figure 7

Correlation of DPP-4 protein and mRNA expression with NPY, PYY, and PP in jejunal muscular tissue in patients with obesity and diabetes (OB+/DM+). Panels (a–c) show the correlations between DPP-4 (n = 17) protein expression and NPY (n = 11) (a), PYY (n = 15) Panel (b), and PP (n = 17) (c) protein expression. Panels (d–f) illustrate the correlations between DPP-4 (n = 17) mRNA expression and NPY (n = 24) (d), PYY (n = 17) (e), and PP (n = 17) (f) mRNA expression. mRNA values were expressed as log2(2^−ΔΔCt). Spearman’s rank correlation test was applied, and results are reported as correlation coefficients (r) and p-values (p).

Figure 8

Correlation of mRNA and protein expression of NPY, PYY, PP, and DPP-4 with gastrointestinal symptoms in jejunal muscular tissue in patients with obesity and diabetes, and with obesity and without diabetes. Panels (a–c) show correlations in patients with obesity and without diabetes (OB+/DM−): PP (n = 25) protein expression with abdominal pain (a), DPP-4 (n = 24) protein expression with indigestion (b), and NPY (n = 17) mRNA expression with constipation (c). Panels (d–f) represent correlations in patients with obesity and with diabetes (OB+/DM+): NPY (n = 24) mRNA expression with abdominal pain (d), PYY (n = 15) protein expression with indigestion (e), and PP (n = 17) mRNA expression with constipation (f). mRNA values used for correlations were expressed as log2(2^−ΔΔCt). Spearman’s rank correlation test was applied to evaluate relationships, and the results are reported as correlation coefficients (r) and p-values (p).