Beneficial effects of Insulin and Rivastigmine in Type-3 Diabetes mellitus in rats

Abhilasha Ahlawat Vaibhav Walia Munish Garg   

Open Access   

Published:  Feb 25, 2023

DOI: 10.7324/JAPS.2023.112670

Type-3 diabetes mellitus (T3D) is a pathological condition that possesses the characteristics of both Diabetes and Alzheimer’s disease, considered as brain diabetes. Treatment of T3D is still a challenging task for clinical practitioners. In this regard, this study was carried out to explore the effect of Insulin and Rivastigmine in the experimental rats. T3D was induced by administering streptozotocin (STZ; 35 mg/kg, i.p., single dose) followed by daily administration of aluminum chloride (AlCl3) (12.5 mg/kg, i.p. × 28 days). The Insulin (1 IU s.c. daily × 28 days) and Rivastigmine (1 mg/kg, i.p. × 28 days) treatment was given 30 minutes prior to administration of AlCl3. After 28 days of treatment, the rats were subjected to the estimation of various behavioral parameters using elevated plus maze (EPM) and Morris water maze (MWM) test and biochemical parameters including Insulin, glucose, malondialdehyde (MDA), nitrite, and amyloid beta (Aβ) levels. The results obtained revealed that the Insulin administration increased the square crossings in the open field, and reduced the transfer latency of T3D rats in the closed arm of EPM at day 2 and the frequency of platform crossing in the MWM test in T3D rats. The administration of Insulin and Rivastigmine reduced the blood glucose level and Aβ levels in the brain of T3D rats. Furthermore, Rivastigmine treatment also reduced the brain Insulin level of T3D rats. These studies indicate toward the beneficial effects of Insulin and Rivastigmine that open newer opportunities in the management protocol of T3D.

Keyword:     Diabetes mellitus hyperinsulinemia cognitive deficits amyloid beta Insulin Rivastigmine


Ahlawat A, Walia V, Garg M. Beneficial effects of Insulin and Rivastigmine in Type-3 Diabetes mellitus in rats. J Appl Pharm Sci, 2023.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abbott MA, Wells DG, Fallon JR. The Insulin receptor tyrosine kinase substrate p58/53 and the Insulin receptor are components of CNS synapses. J Neurosci, 1999; 19:7300-8.

Abdel-Aal RA, Assi AAA, Kostandy BB. Rivastigmine reverses aluminum-induced behavioural changes in rats. Eur J Pharmacol, 2011; 659(2-3):169-76.

Adzovic L, Lynn AE, D'Angelo HM, Crockett AM, Kaercher RM, Royer SE, Hopp SC, Wenk GL. Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains. J Neuroinflammation, 2015; 12:63.

Alam MA, Bansal G. Effects of Insulin against aluminium induced Neurotoxicity in Wistar rats. Pharmacol Clin Pharm Res, 2020; 5(2):62-71.

Andrade EF, Silva VO, Moura NO, Foureaux RC, Orlando DR, Moura RF, Pereira LJ. Physical exercise improves glycemic and inflammatory profile and attenuates progression of periodontitis in diabetic rats (HFD/STZ). Nutrients, 2018; 10(11):1702.

Ashraf GM, Greig NH, Khan TA, Hassan I, Tabrez S, Shakil S, Sheikh IA, Zaidi SK, Akram M, Jabir NR, Firoz CK, Naeem A, Alhazza IM, Damanhouri GA, Kamal MA. Protein misfolding and aggregation in Alzheimer's disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets, 2014; 13(7):1280-93.

Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol, 2011; 68(1):51-7.

Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC. Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat Neurosci, 2000; 3:1291-300.

Caberlotto L, Nguyen TP, Lauria M, Priami C, Rimondini R, Maioli S, Cedazo-Minguez A, Sita G, Morroni F, Corsi M, Carboni L. Cross-disease analysis of Alzheimer's disease and type-2 diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases. Sci Rep, 2019; 9:3965.

Chen X, Zhang M, Ahmed M, Surapaneni KM, Veeraraghavan VP, Arulselvan P. Neuroprotective effects of ononin against the aluminium chloride-induced Alzheimer's disease in rats. Saudi J Biol Sci, 2021; 28(8):4232-9.

Cooper GJ, Day AJ, Willis AC, Roberts AN, Reid KB, Leighton B. Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. Biochim Biophys Acta Mol Cell Res BBA Mol Cell Res, 1989; 1014(3):247-58.

Das UN. Acetylcholinesterase and butyrylcholinesterase as possible markers of low-grade systemic inflammation. Med Sci Monit, 2007; 13:RA214-21.

Delikkaya B, Moriel N, Tong M, Gallucci G, de la Monte SM. Altered expression of Insulin-degrading enzyme and regulator of calcineurin in the rat intracerebral streptozotocin model and human apolipoprotein E-ε4-associated Alzheimer's disease, Alzheimer's and dementia: diagnosis. Assess Dis Monit, 2019; 11:392-404.

Den HeijerT, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MMB. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia, 2003; 46:1604-10.

Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ. Insulin receptor signaling in long-term memory consolidation following spatial learning. Learn Mem, 2005; 12:646-55.

Dulla BS, Bindhu S. A Study on the effect of valeric acid in Alzheimer's induced rats by the estimation of Aβ 1-42 biomarker. J Health Allied Sci NU, 2022; 12(02):134-8.

Ferreira LSS, Fernandes CS, Vieira MNN, de Felice FG. Insulin resistance in Alzheimer's disease. Front Neurosci, 2018; 12:830.

Garwood CJ, Ratcliffe LE, Morgan SV, Simpson JE, Owens H, Vazquez-Villaseñor I, Heath PR, Romero IA, Ince PG, Wharton SB. Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol Brain, 2015; 8:51.

Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci, 2001; 21:2561-70.

Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem, 1982; 126(1):131-8.

Guo Z, Chen Y, Mao YF, Zheng T, Jiang Y, Yan Y, Yin X, Zhang B. Long-term treatment with intranasal Insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer's rat model. Sci Rep, 2017; 7:45971.

Hak AE, Pols HA, Stehouwer CD, Meijer J, Kiliaan AJ, Hofman A, Breteler MMB, Witteman JCM. Markers of inflammation and cellular adhesion molecules in relation to Insulin resistance in nondiabetic elderly: the Rotterdam study. J Clin Endocrinol Metab, 2001; 86:4398-405.

Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science, 1992; 256(5054):184-6.

Hira S, Saleem U, Anwar F, Raza Z, Rehman AU, Ahmad B. In silico study and pharmacological evaluation of eplerinone as an anti- Alzheimer's drug in STZ-induced Alzheimer's disease model. ACS Omega, 2020; 5(23):13973-83.

Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A. Diet-induced Insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J, 2004; 18:902-4.

Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of Insulin resistance. Nature, 2006; 440:944-8.

Hoyer S. Glucose metabolism and Insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol, 2004; 490:115-25.

Huang CC, You JL, Lee CC, Hsu KS. Insulin induces a novel form of postsynaptic mossy fiber long-term depression in the hippocampus. Mol Cell Neurosci, 2003; 24:831-41.

Isik AT, Bozoglu E, Eker D. aChE and BuChE inhibition by rivastigmin have no effect on peripheral Insulin resistance in elderly patients with Alzheimer disease. J Nutr Health Aging, 2012; 16(2):139-41.

Ismail MF, Elmeshad AN, Salem NA. Potential therapeutic effect of nanobased formulation of Rivastigmine on rat model of Alzheimer's disease. Int J Nanomed, 2013; 8:393-406.

Jamshidnejad-Tosaramandani T, Kashanian S, Babaei M, Al- Sabri MH, Schiöth HB. The potential effect of Insulin on AChE and its interactions with Rivastigmine in vitro. Pharmaceuticals (Basel). 2021; 14(11):1136.

John J, Nampoothiri M, Kumar N, Mudgal J, Nampurath GK, Chamallamudi MR. Sesamol, a lipid lowering agent, ameliorates aluminium chloride induced behavioural and biochemical alterations in rats. Pharmacogn Mag, 2015; 11(42):327-36.

Khan KA, Kumar N, Nayak PG, Nampoothiri M, Shenoy RR, Krishnadas N, Rao CM, Mudgal J. Impact of caffeic acid on aluminium chloride-induced dementia in rats. J Pharm Pharmacol, 2013; 65(12):1745- 52.

Kroner Z. The Relationship between Alzheimer's disease and diabetes: Type 3 diabetes. Altern Med Rev, 2009; 14(4):373-9.

Kulkarni SK. Hand book of experimental pharmacology. 4th edition, Vallabh Prakashan, Delhi, India, pp 146-8, 2012.

Kumar AY, Nandakumar K, Handral M, Talwar S, Dhayabaran D. Hypoglycaemic and anti-diabetic activity of stem bark extracts Erythrina indica in normal and alloxan-induced diabetic rats. Saudi Pharm J, 2011; 19(1):35-42.

Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery JM, Götz J. Aβ and human amylin share a common toxicity pathway via mitochondrial dysfunction. Proteomics, 2010; 10(8):1621-33.

Lin JW, Ju W, Foster K, Lee SH, Ahmadian G, Wyszynski M, Wang YT, Sheng M. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat Neurosci, 2000; 3:1282-90.

Liu KF, Niu CS, Tsai JC, Yang CL, Peng WH, Niu HS. Comparison of area under the curve in various models of diabetic rats receiving chronic medication. Arch Med Sci, 2020; 18(4):1078-87. Lv H, Tang L, Guo C, Jiang Y, Gao C, Wang Y, Jian C. Intranasal Insulin administration may be highly effective in improving cognitive function in mice with cognitive dysfunction by reversing brain Insulin resistance. Cogn Neurodyn, 2020; 14(3):323-38.

Ma XH, Zhong P, Gu Z, Feng J, Yan Z. Muscarinic potentiation of GABA(A) receptor currents is gated by Insulin signaling in the prefrontal cortex. J Neurosci, 2003; 23:1159-68.

McGeer PL, McGeerEG. Inflammation and the degenerative diseases of aging. Ann NY Acad Sci, 2004; 1035:104-16.

Meehan S, Berry Y, Luisi B, Dobson CM, Carver JA, MacPhee CM. Amyloid fibril formation by lens crystallin proteins and its implications for cataract formation. J Biol Chem, 2004; 279:3413-9.

Mielke JG, Taghibiglou C, Wang YT. Endogenous Insulin signaling protects cultured neurons from oxygen-glucose deprivation-induced cell death. Neuroscience, 2006; 143:165-73.

Mittal K, Mani RJ, Katare DP. Type 3 diabetes: cross talk between differentially regulated proteins of type 2 diabetes mellitus and Alzheimer's disease. Scientific Rep, 2016; 6(1):1-8.

Mohamed LA, Keller JN, Kaddoumi A. Role of P-glycoprotein in mediating Rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer's disease mouse model. Biochimica et biophysica Acta, 2016; 1862(4):778-87.

Moloney AM, Griffin RJ, Timmons S, O'Connor R, Ravid R, O'Neill C. Defects in IGF-1 receptor, Insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and Insulin signalling. Neurobiol Aging, 2010; 31(2):224-43.

Morris R. Development of water maze procedure for studying spatial learning in the rat. J Neurosci Meth, 1984; 11:47-60.

Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, McClain DA. Functionally distinct Insulin receptors generated by tissue-specific alternative splicing. EMBO J, 1990; 9:2409-13.

Muller T. Rivastigmine in the treatment of patients with Alzheimer's disease. Neuropsychiatr Dis Treat, 2007; 3:211-8.

Neumann KF, Rojo L, Navarrete LP, Farías G, ReyesP, Maccioni RB. Insulin resistance and Alzheimer's disease: molecular links & clinical implications. Curr Alzheimer Res, 2008; 5(5):438-47.

Nguyen TT, Ta QTH, Nguyen TKO, Nguyen TTD, Giau VV. Type 3 diabetes and its role implications in Alzheimer's Disease. Int J Mol Sci, 2020; 21(9):3165.

Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association between Insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol, 2018; 17:122.

Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitus and dementia. Diabetes Metab, 2006; 32(5 Pt 1):403-14.

Passafaro M, Piech V, Sheng M. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat Neurosci, 2001; 4:917-26.

Qinna NA, Badwan AA. Impact of streptozotocin on altering normal glucose homeostasis during Insulin testing in diabetic rats compared to normoglycemic rats. Drug Des Devel Ther, 2015; 9:2515-25.

RajaSankar S, Manivasagam T, Surendran S. Ashwagandha leaf extract: a potential agent in treating oxidative damage and physiological abnormalities seen in a mouse model of Parkinson's disease. Neurosci Lett, 2009; 454(1):11-5.

Randell EW, Mathews MS, Zhang H, Seraj JS, Sun G. Relationship between serum butyrylcholinesterase and the metabolic syndrome. Clin Biochem, 2005 ;38(9):799-805.

Ray B, Maloney B, Sambamurti K, Karnati HK, Nelson PT, Greig NH, Lahiri DK. Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease. Transl Psychiatry, 2020; 10(1):47.

Reyes AE, Chacón MA, Dinamarca MC, Cerpa W, Morgan C, Inestrosa NC. Acetylcholinesterase-abeta complexes are more toxic than Abeta fibrils in rat hippocampus: effect on rat beta-amyloid aggregation, laminin expression, reactive astrocytosis, and neuronal cell loss. Am J Pathol, 2004; 164:2163-74.

Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and Insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis, 2005; 8(3):247-68.

Rorbach-Dolata A, Piwowar A. Neurometabolic evidence supporting the hypothesis of increased incidence of type 3 diabetes mellitus in the 21st century. BioMed Res Int, 2019; 1435276.

Sato T, Shimogaito N, Wu X, Kikuchi S, Yamagishi S, Takeuchi M. Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. Am J Alzheimers Dis Other Demen, 2006; 21(3):197-208.

Sharma P, Senthilkumar RD, Brahmachari V, Sundaramoorthy E, Mahajan A, Sharma A, Sengupta S. Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids Health Dis, 2006; 5:1.

Skeberdis VA, Lan J, Zheng X, Zukin RS, Bennett MV. Insulin promotes rapid delivery of N-methyl-D-aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci USA, 2001; 98:3561-66.

Soto M, Cai W, Konishi M, Kahn CR. Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci, 2019; 116(13):6379-84.

Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SMJR. Impaired Insulin and Insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes? J Alzheimers Dis, 2005; 7:63-80.

Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H, Akaike A. Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacol, 2006; 51(3):474-86.

Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Arnold SE. Demonstrated brain Insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest, 2012; 122(4):1316-38.

Táyebati SK, Di Tullio MA, Amenta F. Effect of treatment with the cholinesterase inhibitor Rivastigmine on vesicular acetylcholine transporter and choline acetyltransferase in rat brain. Clin Exp Hypertens, 2004; 26:363-73.

Temitayo GI, Olawande B, Emmanuel YO, Timothy AT, Kehinde O, Susan LF, Ezra L, Joseph OO. Inhibitory potentials of Cymbopogon citratus oil against aluminium-induced behavioural deficits and neuropathology in rats. Anat Cell Biol, 2020; 53(3):342-54.

Thippeswamy AH, Rafiq M, Viswantha GL, Kavya KJ, Anturlikar SD, Patki PS. Evaluation of bacopa monniera for its synergistic activity with Rivastigmine in reversing aluminum-induced memory loss and learning deficit in rats. Acupunct Meridian Stud, 2013; 6(4):208-13.

Valenciano AI, Corrochano S, de Pablo F, de la Villa P, de la Rosa EJ. Proinsulin/insulin is synthesized locally and prevents caspase-and cathepsin-mediated cell death in the embryonic mouse retina. J Neurochem, 2006; 99:524-36.

Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature, 1997; 388:686-90.

Weinstein G, Davis-Plourde KL, Conner S, Himali JJ, Beiser AS, Lee A, Rawlings AM, Sedaghat S, Ding J, Moshier E, van Duijn CM, Beeri MS, Selvin E, Ikram MA, Launer LJ, Haan MN, Seshadri S. Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer's disease: pooled analysis from 5 cohorts. PLoS One, 2019; 14:e0212293.

Wickelgren I. Tracking insulin to the mind. Science, 1998; 280:517-9.

Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging, 2004; 21:453-78.

Wills E. Mechanisms of lipid peroxide formation in animal tissues. Biochem J, 1966; 99(3):667.

Wills S, inventor. Glycemic control, diabetes treatment, and other treatments with acetyl cholinesterase inhibitors. US; 2009/0081314 A1, 2009. Xie L, Helmerhorst E, Taddei K, Plewright B, van Bronswijk W, Martins R. Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. J. Neurosci, 2002; 22:RC221.

Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem, 1999; 274:34893- 902.

Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol, 2001; 177:125-34.

Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol, 2004; 490(1-3):71-81.

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