https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1518 Mon, 27 Apr 2026 15:59:15 GMT 2026-04-27T15:59:15Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1560 Title: Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells Authors: Nag, Snehasish; Mandal, Samanwita; Mukherjee, Oindrila; Majumdar, Tanmay; Mukhopadhyay, Satinath; Kundu, Rakesh Abstract: Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia. Mon, 01 Jan 2024 00:00:00 GMT https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1560 2024-01-01T00:00:00Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1558 Title: Targeting DPP4-RBD interactions by sitagliptin and linagliptin delivers a potential host-directed therapy against pan-SARS-CoV-2 infections Authors: Mani, Shailendra; Kaur, Anupamjeet; Jakhar, Kamini; Kumari, Geetika; Sonar, Sudipta; Kumar, Amit; Das, Sudesna; Kumar, Santosh; Kumar, Vijay; Kundu, Rakesh; Pandey, Anil Kumar; Singh, Umesh Prasad; Majumdar, Tanmay Abstract: Highly mutated SARS-CoV-2 is known aetiological factor for COVID-19. Here, we have demonstrated that the receptor binding domain (RBD) of the spike protein can interact with human dipeptidyl peptidase 4 (DPP4) to facilitate virus entry, in addition to the usual route of ACE2-RBD binding. Significant number of residues of RBD makes hydrogen bonds and hydrophobic interactions with α/β-hydrolase domain of DPP4. With this observation, we created a strategy to combat COVID-19 by circumventing the catalytic activity of DPP4 using its inhibitors. Sitagliptin, linagliptin or in combination disavowed RBD to establish a heterodimer complex with both DPP4 and ACE2 which is requisite strategy for virus entry into the cells. Both gliptins not only impede DPP4 activity, but also prevent ACE2-RBD interaction, crucial for virus growth. Sitagliptin, and linagliptin alone or in combination have avidity to impede the growth of pan-SARS-CoV-2 variants including original SARS-CoV-2, alpha, beta, delta, and kappa in a dose dependent manner. However, these drugs were unable to alter enzymatic activity of PLpro and Mpro. We conclude that viruses hijack DPP4 for cell invasion via RBD binding. Impeding RBD interaction with both DPP4 and ACE2 selectively by sitagliptin and linagliptin is an potential strategy for efficiently preventing viral replication. Sun, 01 Jan 2023 00:00:00 GMT https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1558 2023-01-01T00:00:00Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1519 Title: FFA-Fetuin-A regulates DPP-IV expression in pancreatic beta cells through TLR4-NFkB pathway Authors: Majumdar, Tanmay; Mandal, Samanwita; Kundu, Rakesh; Mukhopadhyay, Satinath; Nag, Snehasish Abstract: Dipeptidyl peptidase 4 (DPP-IV) is a ubiquitous proteolytic enzyme that cleaves incretin hormones, such as glucagon-like peptide 1 (GLP1) and gastric inhibitory protein (GIP), leading to reduced glucose stimulated insulin secretion from the pancreatic beta cells. The functionally active enzyme is present in a membrane bound form in several cell types as well as in a soluble form in the circulation. The present report deals with DPP-IV expression and its regulation in the pancreatic beta cells in presence of free fatty acids (FFAs) and Fetuin-A, a circulatory glycoprotein associated with insulin resistance in humans and animals. FFA and Fetuin-A individually or in combination trigger DPP-IV expression in MIN6 cells. Islets isolated from high fat diet fed (HFD) mice (16 weeks) showed higher levels of DPP-IV expression than standard diet (SD) fed mice. Fetuin-A increased DPP-IV expression in HFD mice (4 weeks). Inhibition of TLR4 or NFkB prevented palmitate-Fetuin-A mediated DPP-IV expression in MIN6. It has been seen that Fetuin-A alone also could trigger DPP-IV expression in MIN6 cells via NFkB. Additionally, palmitate treatment exhibited reduced level of soluble DPP-IV in the media of MIN6 culture, which corroborated with the expression pattern of its protease, KLK5 that cleaves and releases the membrane bound DPP-IV into the secretion. Our results demonstrate that FFA-Fetuin-A upregulates DPP-IV expression in the pancreatic beta cells through the TLR4-NFkB pathway. Sun, 01 Jan 2023 00:00:00 GMT https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1519 2023-01-01T00:00:00Z