The effects of synthetic orally administrated insulin nanoparticles in comparison to injectable insulin on the renal function markers of type 1- diabetic rats

Document Type: Original Article

Authors

1 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran

2 Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran

3 Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

4 Department of Chemistry, University of Cincinnati, Cincinnati, OH, United States of America

5 Student Research Committee, Abadan School of Medical Sciences, Abadan, Iran

6 Department of Clinical Biochemistry, Abadan Faculty of Medical Sciences, Abadan, Iran

Abstract

Objective(s): Injectable insulin is the most widely used therapy in patients with type 1 diabetes which has several disadvantages. The present study was aimed to evaluate the efficacy of injectable insulin on diabetes mellitus-related complications in comparison to orally encapsulated insulin nanoparticles.
Materials and Methods: This study involved 42 Wistar rats separated into 5 groups, including control (C), diabetic control (D), diabetic receiving regular insulin (INS), diabetic receiving encapsulated insulin nanoparticle (INP), and diabetic receiving chitosan for two months. Biochemical parameters in serum and urine were measured using spectrophotometric or ELISA methods. mRNA levels of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated using quantitative PCR.
Results: There were no significant differences between the two forms of insulin in controlling the glycemic condition (P-value>0.05), but oral INP was more effective in correcting diabetic dyslipidemia in comparison to injectable insulin (P-value<0.05). Urine volume and creatinine excretion were significantly modulated by insulin and oral INP in diabetic groups (P-value<0.05), although the effects of INP on the modulation of execration of urea, acid uric, and albumin was more dramatic. Oral INP caused a significant decrease in urine concentration of KIM-1 and NGAL as well as expression of KIM-1 in renal tissue (P-value<0.05).
Conclusion: Our results suggested that oral INP is more effective than injectable insulin in modulation of urine and serum diabetic-related parameters.

Keywords


1. Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 2014; 383:1084-1094.
2. Aynalem SB, Zeleke AJ. Prevalence of diabetes mellitus and its risk factors among individuals aged 15 years and above in Mizan-Aman town, Southwest Ethiopia, 2016: a cross sectional study. Int J Endocrinol 2018; 2018:1-7.
3. Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic vascular complications. J Diabetes Investig 2010; 1:77-89.
4. Rask-Madsen C, King GL. Kidney complications: factors that protect the diabetic vasculature. Nat Med 2010; 16:40-41.
5. Cameron JS. The discovery of diabetic nephropathy: From small print to centre stage. J Nephrol 2006; 19:S75-87.
6. Collins AJ, Foley RN, Gilbertson DT, Chen S-C. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl 2015; 5:2-7.
7. Reutens AT. Epidemiology of diabetic kidney disease. Med Clin 2013; 97:1-18.
8. Haller H, Ji L, Stahl K, Bertram A, Menne J. Molecular Mechanisms and treatment strategies in diabetic nephropathy: new avenues for calcium dobesilate—free radical scavenger and growth factor inhibition. Biomed Res Int 2017; 2017.
9. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 1998; 273:4135-4142.
10. Bonventre JV. Kidney injury molecule-1: a translational journey. Trans Am Clin Climatol Assoc 2014; 125:293-299.
11. Anuradha R, Saraswati M, Kumar KG, Rani SH. Apoptosis of beta cells in diabetes mellitus. DNA Cell Biol 2014; 33:743-748.
12. Richardson T, Kerr D. Skin-related complications of insulin therapy. Am J Clin Dermatol 2003; 4:661-667.
13. Fonte P, Araújo F, Reis S, Sarmento B. Oral insulin delivery: how far are we? J Diabetes Sci Technol 2013; 7:520-531.
14. Arbit E, Kidron M. Oral insulin: the rationale for this approach and current developments. J Diabetes Sci Technol 2009; 3:562-567.
15. Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov 2003; 2:289.
16. Elsayed AM. Oral delivery of insulin: novel approaches. Recent Advances in Novel Drug Carrier Systems: IntechOpen; 2012.
17. Sonia TA, Sharma CP. An overview of natural polymers for oral insulin delivery. Drug Discov Today 2012; 17:784-792.
18. Chaturvedi K, Ganguly K, Nadagouda MN, Aminabhavi TM. Polymeric hydrogels for oral insulin delivery. J Control Release 2013; 165:129-138.
19. Cano-Cebrian MJ, Zornoza T, Granero L, Polache A. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery. Curr Drug Deliv 2005; 2:9-22.
20. Montomoli E, Piccirella S, Khadang B, Mennitto E, Camerini R, De Rosa A. Current adjuvants and new perspectives in vaccine formulation. Expert Rev Vaccines 2011; 10:1053-1061.
21. Ding F, Deng H, Du Y, Shi X, Wang Q. Emerging chitin and chitosan nanofibrous materials for biomedical applications. Nanoscale 2014; 6:9477-9493.
22. Kas HS. Chitosan: properties, preparations and application to microparticulate systems. J Microencapsul 1997; 14:689-711.
23. Mahjub R, Dorkoosh FA, Amini M, Khoshayand MR, Rafiee-Tehrani M. Preparation, statistical optimization, and in vitro characterization of insulin nanoparticles composed of quaternized aromatic derivatives of chitosan. AAPS PharmSciTech 2011; 12:1407-1419.
24. Mahjub R, Radmehr M, Dorkoosh FA, Ostad SN, Rafiee-Tehrani M. Lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: in vitro, ex vivo and in vivo characterizations. Drug Dev Ind Pharm 2014; 40:1645-1659
25. Gupta SC, Patchva S, Koh W, Aggarwal BB. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 2012; 39:283-299.
26. Kota N, Panpatil VV, Kaleb R, Varanasi B, Polasa K. Dose-dependent effect in the inhibition of oxidative stress and anticlastogenic potential of ginger in STZ induced diabetic rats. Food Chem 2012; 135:2954-2959.
27. Samadder A, Das J, Das S, De A, Saha SK, Bhattacharyya SS, et al. Poly (lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: some novel findings. Toxicol Appl Pharmacol 2013; 267:57-73.
28. Heidarisasan S, Ziamajidi N, Karimi J, Abbasalipourkabir R. Effects of insulin-loaded chitosan-alginate nanoparticles on RAGE expression and oxidative stress status in the kidney tissue of rats with type 1 diabetes. Iran J Basic Med Sci 2018; 21:1035-1042.
29. Jamshidi M, Ziamajidi N, Khodadadi I, Dehghan A, Kalantarian G, Abbasalipourkabir R. The effect of insulin-loaded trimethylchitosan nanoparticles on rats with diabetes type I. Biomed Pharmacother 2018; 97:729-735.
30. Mahjub R, Radmehr M, Dorkoosh FA, Ostad SN, Rafiee-Tehrani M. Lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: in vitro, ex vivo and in vivo characterizations. Drug Dev Ind Pharm 2014; 40:1645-1659.
31. Mukhopadhyay P, Mishra R, Rana D, Kundu PP. Strategies for effective oral insulin delivery with modified chitosan nanoparticles: A review. Prog Polym Sci 2012; 37:1457-1475.
32. Ramudu SK, Korivi M, Kesireddy N, Lee L-C, Cheng I-S, Kuo C-H, et al. Nephro-protective effects of a ginger extract on cytosolic and mitochondrial enzymes against streptozotocin (STZ)-induced diabetic complications in rats. Chin J Physiol 2011; 54:79-86.
33. Manley S, Stratton I, Cull C, Frighi V, Eeley E, Matthews D, et al. Effects of three months’ diet after diagnosis of Type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45). Diabet Med 2000; 17:518-523.
34. Mukhopadhyay P, Chakraborty S, Bhattacharya S, Mishra R, Kundu P. pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery. Int J Biol Macromol 2015; 72:640-648.
35. Kuhad A, Chopra K. Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci 2009; 84:296-301.
36. Green M, Miller LL. Protein catabolism and protein synthesis in perfused livers of normal and alloxan-diabetic rats. J Biol Chem 1960; 235:3202-3208.
37. Sugimoto Ki, Tsuruoka S, Fujimura A. Effect of enalapril on diabetic nephropathy in oletf rats: the role of an anti‐oxidative action in its protective properties. Clin Exp Pharmacol Physiol 2001; 28:826-830.
38. Modan M, Halkin H, Karasik A, Lusky A. Elevated serum uric acid—a facet of hyperinsulinaemia. Diabetologia 1987; 30:713-718.
39. Morakinyo A, Akindele A, Ahmed Z. Modulation of antioxidant enzymes and inflammatory cytokines: possible mechanism of anti-diabetic effect of ginger extracts. Afr J Biomed Res 2011; 14:195-202.
40. Palsamy P, Subramanian S. Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomed Pharmacother 2008; 62:598-605.
41. Yan LJ. Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res 2014; 2014.
42. Jefferson J, Shankland S, Pichler R. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 2008; 74:22-36.
43. Nielsen S, Schjoedt K, Astrup A, Tarnow L, Lajer M, Hansen P, et al. Neutrophil gelatinase‐associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1) in patients with diabetic nephropathy: a cross‐sectional study and the effects of lisinopril. Diabet Med 2010; 27:1144-1150.
44. Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2004; 15:3073-3082.
45. Alter ML, Kretschmer A, Von Websky K, Tsuprykov G, Reichetzeder C, Simon A, et al. Early urinary and plasma biomarkers for experimental diabetic nephropathy. Clin Lab 2012; 58:659-671.
46. Ghasemi H, Einollahi B, Hosseini-Zijoud SR, Farhadiannezhad M. Protective effects of curcumin on diabetic nephropathy via attenuation of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) expression and alleviation of oxidative stress in rats with type 1 diabetes. Iran J Basic Med Sci 2019; 22: 376-383.
47. Paolisso G, D’Amore A, Galzerano D, Balbi V, Giugliano D, Varricchio M, et al. Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients. Diabetes Care 1993; 16:1433-1437.
48. Arellano-Buendía AS, García-Arroyo FE, Cristóbal-García M, Loredo-Mendoza ML, Tapia-Rodríguez E, Sánchez-Lozada LG, et al. Urinary excretion of neutrophil gelatinase-associated lipocalin in diabetic rats. Oxid Med Cell Longev 2014; 2014.