Tissue and systemic dipeptidyl peptidase 4 and glucose homeostatic responses in a dietinduced prediabetic rat model.

Abstract

Background Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycaemia, resulting from impaired insulin action, insulin secretion, or both. Type-2-diabetes mellitus (T2DM) is the most common occurring form of DM accounting for 90% of all cases. Various enzymes including dipeptidyl peptidase-4 (DPP-4), an enzyme found in various tissues including plasma (sDPP-4) that primarily degrades incretin hormones such as GLP-1 and GIP that stimulate insulin secretion and inhibit glucagon release and are dysregulated during T2DM. The onset of T2DM is often preceded by a condition called prediabetes whereby blood glucose levels are elevated but not high enough to be diagnosed as T2DM. However, there is a lack of studies that have documented DPP-4 expression in tissues as well as sDPP-4 concentrations during the prediabetic state and how these may influence glucose homeostasis. Therefore, this study investigated the changes in tissue and plasma DPP-4 expression in a diet-induced prediabetic rat model and examined how these changes influence glucose homeostasis. Materials and Methods Twelve male Sprague Dawley rats were randomly allocated into two equal groups (n=6 each). Experimental prediabetes was induced in the animals using a previously reported protocol. The first group (A) was fed a standard rat chow and supplied with tap water. The second group (B), group was fed high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose for 20 weeks to induce prediabetes. At the end of the 20-week induction period, the American Diabetes Association (ADA) criteria were used to confirm prediabetes. At the end of the induction period, the animals were then sacrificed, and ELISA was used to measure plasma sDPP-4, insulin, GLP-1, ghrelin and leptin in both groups. Furthermore, quantitative PCR was used to measure DPP-4 gene expression in tissues including the kidney, lungs and liver. Fold change in gene expression was calculated using the 2-ΔΔCt method. Results and Discussion The induction of prediabetes in the HFHC-diet fed group resulted in increased blood glucose and HbA1c levels by comparison to the non-prediabetic group. This was accompanied by increased plasma sDPP-4, insulin, ghrelin and leptin levels in the PD group by comparison to the NPD group. There was also decreased plasma GLP-1 in the PD group by comparison to the NPD group. The increased insulin, glucose and HbA1c levels reflect insulin resistance and disrupted glucose regulation. The elevated sDPP-4 and decreased plasma GLP-1 levels indicate impaired incretin signalling. Additionally, the rise in ghrelin and leptin suggest hormonal imbalance contributing to metabolic dysregulation. Furthermore, the results showed increased DPP-4 expression in the kidney, whereas reduced expression was observed in the liver and lungs. These findings suggest that DPP-4 is regulated in a tissue-specific manner during the prediabetic state. The upregulation in the kidney may indicate a compensatory or pathological role in renal glucose handling or inflammation, while the downregulation in the liver and lungs could reflect altered metabolic or immune responses. Overall, this differential expression pattern points to a complex, tissue-dependent role of DPP-4 in the early stages of metabolic dysregulation. Conclusion Taken together, the results of the present study suggest a complex disruption of glucose homeostasis and hormonal signalling. The reduced plasma GLP-1 levels in the presence of elevated sDPP-4 suggest enhanced incretin degradation, which may impair insulin secretion and contribute to hyperglycaemia. Furthermore, the results suggest that DPP-4 expression varies between tissues and is differently regulated during the prediabetic state. Increased expression in the kidney, along with decreased levels in the liver and lungs, indicates that DPP-4 may have distinct, tissue-dependent roles in metabolic regulation and disease development. The observed metabolic and hormonal disturbances highlight the role of DPP-4 in impairing glucose homeostasis during the prediabetic state.