Differential Effects of Liraglutide Naltrexone/bupropion, and Caloric Restriction on Metabolic Parameters and Beta-cell Regeneration in Type 2 Diabetic Rat Model: Role of Beta Arrestin 1

Overview

Journal J Mol Histol

Specialty Biochemistry

Date 2024 Dec 20

PMID 39704859

Authors

Dina H Merzeban

Amani M El Amin Ali

Reem O Hammad

Mohamed H Elmahdi

Marwa A Sofi

Rania H Mahmoud

Sayed M Metwally

Ahmed M El Ebiary

Affiliations

Soon will be listed here.

Abstract

Traditional antidiabetic treatments often carry the risk of beta-cell exhaustion, highlighting the need for therapies that promote beta-cell regeneration. This study investigates the comparative effects of Liraglutide, naltrexone/bupropion (NTX + BUP), and caloric restriction on metabolic control and beta-cell regeneration in a rat model of obese type 2 diabetes. Fifty male albino rats were randomized into five groups: normal control, diabetic control, diabetic + caloric restriction (50%), diabetic + NTX + BUP (4 mg/45 mg /kg/day orally), and diabetic + liraglutide (0.3 mg/kg/day, S.C). Body weight, BMI, serum glucose, insulin, lipid profile, atherogenic indices, beta-arrestin-1 levels, pancreatic histopathology, and immunohistochemical staining for insulin and Ki67 were assessed. All interventions significantly improved body weight, BMI, glycemic control, lipid profiles (except HDL), and atherogenic indices compared to the diabetic control group. NTX + BUP and caloric restriction resulted in greater weight loss compared to liraglutide. Of note, liraglutide significantly decreased β-arrestin-1 levels compared to both NTX + BUP and caloric restriction. Furthermore, liraglutide and caloric restriction significantly increased anti-insulin antibodies and Ki67 indicating beta-cell regeneration, while NTX + BUP showed insignificant effects. Thus we can conclude that, while NTX + BUP demonstrates efficacy in improving metabolic parameters in obese type 2 diabetic rats, it shows limitations in promoting beta-cell regeneration compared to liraglutide and caloric restriction.

References

Abunasef S, Amin H, Abdel-Hamid G . A histological and immunohistochemical study of beta cells in streptozotocin diabetic rats treated with caffeine. Folia Histochem Cytobiol. 2014; 52(1):42-50. DOI: 10.5603/FHC.2014.0005. View

Katano A, Takahashi W, Yamashita H, Yamamoto K, Ando M, Yoshida M . The impact of elevated C-reactive protein level on the prognosis for oro-hypopharynx cancer patients treated with radiotherapy. Sci Rep. 2017; 7(1):17805. PMC: 5736698. DOI: 10.1038/s41598-017-18233-w. View

Apple D, Mahesula S, Fonseca R, Zhu C, Kokovay E . Calorie restriction protects neural stem cells from age-related deficits in the subventricular zone. Aging (Albany NY). 2019; 11(1):115-126. PMC: 6339798. DOI: 10.18632/aging.101731. View

Ard J, Fitch A, Fruh S, Herman L . Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists. Adv Ther. 2021; 38(6):2821-2839. PMC: 8189979. DOI: 10.1007/s12325-021-01710-0. View

Billes S, Greenway F . Combination therapy with naltrexone and bupropion for obesity. Expert Opin Pharmacother. 2011; 12(11):1813-26. DOI: 10.1517/14656566.2011.591382. View

Buteau J, El-Assaad W, Rhodes C, Rosenberg L, Joly E, Prentki M . Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia. 2004; 47(5):806-15. DOI: 10.1007/s00125-004-1379-6. View

Rocha V, Claudio E, da Silva V, Cordeiro J, Domingos L, da Cunha M . High-Fat Diet-Induced Obesity Model Does Not Promote Endothelial Dysfunction via Increasing Leptin/Akt/eNOS Signaling. Front Physiol. 2019; 10:268. PMC: 6435481. DOI: 10.3389/fphys.2019.00268. View

Fletcher M, Halls M, Christopoulos A, Sexton P, Wootten D . The complexity of signalling mediated by the glucagon-like peptide-1 receptor. Biochem Soc Trans. 2016; 44(2):582-8. DOI: 10.1042/BST20150244. View

Gerber P, Rutter G . The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus. Antioxid Redox Signal. 2016; 26(10):501-518. PMC: 5372767. DOI: 10.1089/ars.2016.6755. View

10.

Golan M, Schreiber G, Avissar S . Antidepressant-induced differential ubiquitination of β-arrestins 1 and 2 in mononuclear leucocytes of patients with depression. Int J Neuropsychopharmacol. 2013; 16(8):1745-54. DOI: 10.1017/S1461145713000291. View

11.

Halban P, Polonsky K, Bowden D, Hawkins M, Ling C, Mather K . β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. J Clin Endocrinol Metab. 2014; 99(6):1983-92. PMC: 5393482. DOI: 10.1210/jc.2014-1425. View

12.

Iorga R, Bacalbasa N, Carsote M, Bratu O, Stanescu A, Bungau S . Metabolic and cardiovascular benefits of GLP-1 agonists, besides the hypoglycemic effect (Review). Exp Ther Med. 2020; 20(3):2396-2400. PMC: 7401476. DOI: 10.3892/etm.2020.8714. View

13.

Johnson M, Distelmaier K, Lanza I, Irving B, Robinson M, Konopka A . Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults. Diabetes. 2015; 65(1):74-84. PMC: 4686951. DOI: 10.2337/db15-0675. View

14.

Kanda Y, Hashiramoto M, Shimoda M, Hamamoto S, Tawaramoto K, Kimura T . Dietary restriction preserves the mass and function of pancreatic β cells via cell kinetic regulation and suppression of oxidative/ER stress in diabetic mice. J Nutr Biochem. 2014; 26(3):219-26. DOI: 10.1016/j.jnutbio.2014.10.007. View

15.

Kawamori D, Shirakawa J, Liew C, Hu J, Morioka T, Duttaroy A . GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice. Diabetologia. 2017; 60(8):1442-1453. PMC: 5508991. DOI: 10.1007/s00125-017-4303-6. View

16.

Kornelius E, Li H, Peng C, Yang Y, Chen W, Chang Y . Liraglutide protects against glucolipotoxicity-induced RIN-m5F β-cell apoptosis through restoration of PDX1 expression. J Cell Mol Med. 2018; 23(1):619-629. PMC: 6307795. DOI: 10.1111/jcmm.13967. View

17.

Lee S, Lee N, Kim S, Kim K, Kim Y . Effect of liraglutide 3.0mg treatment on weight reduction in obese antipsychotic-treated patients. Psychiatry Res. 2021; 299:113830. DOI: 10.1016/j.psychres.2021.113830. View

18.

Levy A, Daniels S, Hudson R, Horman T, Flynn A, Zhou Y . Bupropion and naltrexone combination alters high fructose corn syrup self-administration and gene expression in rats. Neuropharmacology. 2018; 135:547-554. DOI: 10.1016/j.neuropharm.2018.01.035. View

19.

Makowski C, Gwinn K, Hurren K . Naltrexone/bupropion: an investigational combination for weight loss and maintenance. Obes Facts. 2012; 4(6):489-94. PMC: 6444555. DOI: 10.1159/000335352. View

20.

Moin A, Nandakumar M, Diane A, Dehbi M, Butler A . The Role of Heat Shock Proteins in Type 1 Diabetes. Front Immunol. 2021; 11:612584. PMC: 7873876. DOI: 10.3389/fimmu.2020.612584. View