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Long-term obestatin treatment of mice type 2 diabetes increases insulin sensitivity and improves liver function

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Abstract

Purpose

Obestatin and ghrelin are peptides encoded by the preproghrelin gene. Obestatin inhibits food intake, in addition to regulation of glucose and lipid metabolism. Here, we test the ability of obestatin at improving metabolic control and liver function in type 2 diabetic animals (type 2 diabetes mellitus).

Methods

The effects of chronic obestatin treatment of mice with experimentally induced type 2 diabetes mellitus on serum levels of glucose and lipids, and insulin sensitivity are characterized. In addition, alterations of hepatic lipid and glycogen contents are evaluated.

Results

Obestatin reduced body weight and decreased serum glucose, fructosamine, and β-hydroxybutyrate levels, as well as total and low-density lipoprotein fractions of cholesterol. In addition, obestatin increased high-density lipoproteins cholesterol levels and enhanced insulin sensitivity in mice with type 2 diabetes mellitus. Moreover, obestatin diminished liver mass, hepatic triglycerides and cholesterol contents, while glycogen content was higher in livers of healthy and mice with type 2 diabetes mellitus treated with obestatin. These changes were accompanied by reduction of increased alanine aminotransferase, aspartate aminotransferase, and gamma glutamyl transpeptidase in T2DM mice with type 2 diabetes mellitus. Obestatin increased adiponectin levels and reduced leptin concentration. Obestatin influenced the expression of genes involved in lipid and carbohydrate metabolism by increasing Fabp5 and decreasing G6pc, Pepck, Fgf21 mRNA in the liver. Obestatin increased both, AKT and AMPK phosphorylation, and sirtuin 1 (SIRT1) protein levels as well as mRNA expression in the liver.

Conclusion

Obestatin improves metabolic abnormalities in type 2 diabetes mellitus, restores hepatic lipid contents and decreases hepatic enzymes. Therefore, obestatin could potentially have a therapeutic relevance in treating of insulin resistance and metabolic dysfunctions in type 2 diabetes mellitus.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

AKT:

Protein kinase B

ALT:

Alanine aminostransferase

AMPK:

5′AMP-activated protein kinase

AST:

Aspartate aminostransferase

FABP1:

Fatty acid binding protein 1

FABP4:

Fatty acid binding protein 4

FABP5:

Fatty acid binding protein 5

FAS:

Fatty acids synthase

FGF-21:

Fibroblastic growth factor 21

G6Pc:

Glucose-6-phosphatase catalytic subunit G6Pc

GAPD:

Glyceraldehyde-3-phosphate dehydrogenase

γGT:

Gamma glutamyl transferase

GLP-1R:

Glucagon like peptide-1 receptor

GLUT4:

Glucose transporter 4

GOT:

Glutamic-oxaloacetic transaminase

GPR39:

G-protein-coupled receptor 39

HFD:

High fat diet

IL-6:

interleukin 6

IP:

Intraperitoneally

OBST:

Obestatin

PEPCK:

Phosphoenolpyruvate carboxykinase

STZ:

streptozotocin

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

TG:

Triglycerides

TNF-α:

Tumor necrosis factor alpha

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Acknowledgements

P.A.K. is the recipient of a 2013 fellowship program UE Human Capital. This study forms part of the PhD thesis of P.A.K. This study was partially supported by the National Science Centre, Poland 2015/19/N/NZ4/00572 PRELUDIUM grant. M.Z.S. was supported by the Deutsche Forschungsgemeinschaft and Deutsche Diabetes Stiftung.

Author contributions

P.A.K. designed the study, obtained the data and wrote the manuscript. E.P.O., contributed to the study design, experiment performing, edited, supported and critically revised the manuscript and contributed to the discussion. M.Z.S., K.W.N., contributed to the study design, edited, supported and critically revised the manuscript and contributed to the discussion. All authors have given final approval to the current version to be published.

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Authors and Affiliations

  1. Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska Street 35, 60-637, Poznan, Poland

    Paweł A. Kołodziejski, Ewa Pruszyńska-Oszmałek & Krzysztof W. Nowak

  2. Department of Hepatology and Gastroenterology & the Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, 13353, Berlin, Germany

    Mathias Z. Strowski

  3. Park-Klinik Weissensee, Internal Medicine – Gastroenterology, Berlin, 13086, Germany

    Mathias Z. Strowski

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  1. Paweł A. Kołodziejski
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Correspondence to Paweł A. Kołodziejski.

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Kołodziejski, P.A., Pruszyńska-Oszmałek, E., Strowski, M.Z. et al. Long-term obestatin treatment of mice type 2 diabetes increases insulin sensitivity and improves liver function. Endocrine 56, 538–550 (2017). https://doi.org/10.1007/s12020-017-1309-2

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