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Combination of APD668, a G protein-coupled receptor 119 agonist with linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in a murine model of non-alcoholic steatohepatitis with diabetes

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Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, and hepatocyte injury with or without fibrosis. In this study, we explored the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor, on the progression of steatohepatitis in a murine model of NASH with diabetes. A novel NASH model with diabetes was generated by administration of streptozotocin injection to neonatal C57BL/6 mice (2–3 days old) combined with a high-fat diet feeding from the age of 4 weeks. The plasma biochemical parameters, oxidative stress, inflammation and histopathological changes were assessed. APD668 alone showed reduction in plasma glucose (− 39%, P < 0.05) and triglyceride level (− 26%) whereas a combined treatment of APD668 with linagliptin resulted in a more pronounced reduction in plasma glucose (− 52%, P < 0.001) and triglyceride (− 50%, P < 0.05) in NASH mice. In addition, co-administration of APD668 with linagliptin demonstrated a significant decrease in hepatic triglyceride, NAS score, hepatic TBARS and hepatic TNF-α in NASH mice with diabetes. These findings suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of NASH.

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Abbreviations

NASH:

Non-alcoholic steatohepatitis

NAFLD:

Non-alcoholic fatty liver disease

GLP-1:

Glucagon-like peptide-1

GIP:

Gastric inhibitory peptide

DPPIV:

Dipeptidyl peptidase IV

HFD/STZ:

High-fat diet/streptozotocin

CDAA:

Choline-deficient, l-amino acid-defined

KO:

Knockout

AMPK:

AMP-activated protein kinase

SREBP-1c:

Sterol regulatory element binding protein-1c

SCD-1:

Stearoyl-CoA desaturase

FAS:

Fatty acid synthase

SOCS3:

Suppressor of cytokine signaling 3

ALT:

Alanine aminotransferase

HTF:

High trans-fat

TG:

Triglyceride

TC:

Total cholesterol

TBARS:

Thiobarbituric acid reactants

NAS:

NAFLD activity score

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Acknowledgements

This work was supported and funded by Lupin Limited (Research Park), India. We express our sincere thanks to Mr. Vikram Jadhav, Mr. Shyam Sundar for technical assistance, Mr. Kiran Powale, Mr. Gururaj Vishwase and Dr. Sharad Sharma for their contribution in histopathology analysis.

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Authors and Affiliations

  1. Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited (Research Park), 46A/47A, Village Nande, Taluka Mulshi, Pune, Maharashtra, 412115, India

    Umakant Ashok Bahirat, Rashmi Talwar, Kumar V. S. Nemmani & Rajan Naresh Goel

  2. Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

    Rekha Raghuveer Shenoy

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  1. Umakant Ashok Bahirat
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  2. Rashmi Talwar
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  3. Rekha Raghuveer Shenoy
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  4. Kumar V. S. Nemmani
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  5. Rajan Naresh Goel
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Correspondence to Umakant Ashok Bahirat.

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Bahirat, U.A., Talwar, R., Shenoy, R.R. et al. Combination of APD668, a G protein-coupled receptor 119 agonist with linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in a murine model of non-alcoholic steatohepatitis with diabetes. Med Mol Morphol 52, 36–43 (2019). https://doi.org/10.1007/s00795-018-0200-4

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  • DOI: https://doi.org/10.1007/s00795-018-0200-4

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