Cargando…

Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice

In the preceding study, we delineated that high-fat diet (HFD) consumption in mice increases the circulatory level of pancreastatin (PST), which additionally enhances the free fatty acid (FFA) concentration in circulation. Consequently, the aggravated FFA activates Fetuin-A, which facilitates hepati...

Descripción completa

Detalles Bibliográficos
Autores principales: Singh, Pragati, Garg, Richa, Goand, Umesh K., Riyazuddin, Mohammed, Reza, Mohammad Irshad, Syed, Anees A., Gupta, Anand P., Husain, Athar, Gayen, Jiaur R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533370/
https://www.ncbi.nlm.nih.gov/pubmed/33033766
http://dx.doi.org/10.1016/j.heliyon.2020.e05133
_version_ 1783590118075924480
author Singh, Pragati
Garg, Richa
Goand, Umesh K.
Riyazuddin, Mohammed
Reza, Mohammad Irshad
Syed, Anees A.
Gupta, Anand P.
Husain, Athar
Gayen, Jiaur R.
author_facet Singh, Pragati
Garg, Richa
Goand, Umesh K.
Riyazuddin, Mohammed
Reza, Mohammad Irshad
Syed, Anees A.
Gupta, Anand P.
Husain, Athar
Gayen, Jiaur R.
author_sort Singh, Pragati
collection PubMed
description In the preceding study, we delineated that high-fat diet (HFD) consumption in mice increases the circulatory level of pancreastatin (PST), which additionally enhances the free fatty acid (FFA) concentration in circulation. Consequently, the aggravated FFA activates Fetuin-A, which facilitates hepatic lipid accumulation, insulin resistance (IR), and culminates in type 2 diabetes (T2D). Metformin (Met) is a widely known first-line drug for the treatment of T2D. We previously unveiled PSTi8, an inhibitor of PST, comprising antidiabetic property. Hence, we hypothesized that combination therapy of Met and PSTi8, at reduced therapeutic doses, would mitigate HFD-induced IR by inhibiting hepatic Fetuin-A in mice model of T2D. C57BL/6 mice were fed HFD for 12 weeks, followed by treatment with Met, PSTi8, and its combination for 10 days. Glucose and insulin tolerance tests were conducted. Circulatory levels of PST, Fetuin-A, and lipid markers were determined. Also, the mRNA and protein expression of Fetuin-A was assessed by qPCR, western blotting, and immunofluorescence. Moreover, the energy expenditure was measured by comprehensive laboratory animal monitoring system (CLAMS). Combination therapy displayed improved PST, Fetuin-A, and lipid profile in plasma. We also found reduced hepatic Fetuin-A, which reduced inhibitory phosphorylation of IRS and increased phosphorylation of AKT. Consequently, ameliorated hepatic lipogenesis, gluconeogenesis, and inflammation. Also, combination treatment attenuated Fetuin-A expression, lipid accumulation, and glucose production in palmitate-induced HepG2 cells. Altogether current study promulgates the beneficial effect of combination therapy of Met and PSTi8 (comparable to alone higher therapeutic doses) to ameliorate Fetuin-A activation, hepatic lipid accumulation, insulin resistance, and associated progressive pathophysiological alterations in T2D.
format Online
Article
Text
id pubmed-7533370
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-75333702020-10-07 Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice Singh, Pragati Garg, Richa Goand, Umesh K. Riyazuddin, Mohammed Reza, Mohammad Irshad Syed, Anees A. Gupta, Anand P. Husain, Athar Gayen, Jiaur R. Heliyon Research Article In the preceding study, we delineated that high-fat diet (HFD) consumption in mice increases the circulatory level of pancreastatin (PST), which additionally enhances the free fatty acid (FFA) concentration in circulation. Consequently, the aggravated FFA activates Fetuin-A, which facilitates hepatic lipid accumulation, insulin resistance (IR), and culminates in type 2 diabetes (T2D). Metformin (Met) is a widely known first-line drug for the treatment of T2D. We previously unveiled PSTi8, an inhibitor of PST, comprising antidiabetic property. Hence, we hypothesized that combination therapy of Met and PSTi8, at reduced therapeutic doses, would mitigate HFD-induced IR by inhibiting hepatic Fetuin-A in mice model of T2D. C57BL/6 mice were fed HFD for 12 weeks, followed by treatment with Met, PSTi8, and its combination for 10 days. Glucose and insulin tolerance tests were conducted. Circulatory levels of PST, Fetuin-A, and lipid markers were determined. Also, the mRNA and protein expression of Fetuin-A was assessed by qPCR, western blotting, and immunofluorescence. Moreover, the energy expenditure was measured by comprehensive laboratory animal monitoring system (CLAMS). Combination therapy displayed improved PST, Fetuin-A, and lipid profile in plasma. We also found reduced hepatic Fetuin-A, which reduced inhibitory phosphorylation of IRS and increased phosphorylation of AKT. Consequently, ameliorated hepatic lipogenesis, gluconeogenesis, and inflammation. Also, combination treatment attenuated Fetuin-A expression, lipid accumulation, and glucose production in palmitate-induced HepG2 cells. Altogether current study promulgates the beneficial effect of combination therapy of Met and PSTi8 (comparable to alone higher therapeutic doses) to ameliorate Fetuin-A activation, hepatic lipid accumulation, insulin resistance, and associated progressive pathophysiological alterations in T2D. Elsevier 2020-10-03 /pmc/articles/PMC7533370/ /pubmed/33033766 http://dx.doi.org/10.1016/j.heliyon.2020.e05133 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Singh, Pragati
Garg, Richa
Goand, Umesh K.
Riyazuddin, Mohammed
Reza, Mohammad Irshad
Syed, Anees A.
Gupta, Anand P.
Husain, Athar
Gayen, Jiaur R.
Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice
title Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice
title_full Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice
title_fullStr Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice
title_full_unstemmed Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice
title_short Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice
title_sort combination of pancreastatin inhibitor psti8 with metformin inhibits fetuin-a in type 2 diabetic mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533370/
https://www.ncbi.nlm.nih.gov/pubmed/33033766
http://dx.doi.org/10.1016/j.heliyon.2020.e05133
work_keys_str_mv AT singhpragati combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT gargricha combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT goandumeshk combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT riyazuddinmohammed combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT rezamohammadirshad combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT syedaneesa combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT guptaanandp combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT husainathar combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice
AT gayenjiaurr combinationofpancreastatininhibitorpsti8withmetformininhibitsfetuinaintype2diabeticmice