1. Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells.
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Nag, Snehasish, Mandal, Samanwita, Mukherjee, Oindrila, Majumdar, Tanmay, Mukhopadhyay, Satinath, and Kundu, Rakesh
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PANCREATIC beta cells , *INSULIN , *GLUCAGON-like peptide 1 , *LIPIDS , *CD26 antigen , *ISLANDS of Langerhans - 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. [Display omitted] • Vildagliptin downregulates DPP-4 and fetuin-A expression in MIN6 and palmitate treated pancreatic islets • DPP-4 inhibition in MIN6 cell line suppresses TLR4-NFkB activation • Vildagliptin lowers high fat and fetuin-A mediated lipid accumulation and improves insulin secretion in pancreatic beta cells [ABSTRACT FROM AUTHOR]
- Published
- 2024
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