Inflammation and Oxidative Stress: The Molecular Connectivity Between Insulin Resistance, Obesity, and Alzheimer's Disease

Overview

Journal Mediators Inflamm

Publisher Wiley

Specialties Biochemistry
Pathology

Date 2015 Dec 23

PMID 26693205

Citations 171

Authors

Giuseppe Verdile

Kevin N Keane

Vinicius F Cruzat

Sandra Medic

Miheer Sabale

Joanne Rowles

Nadeeja Wijesekara

Ralph N Martins

Paul E Fraser

Philip Newsholme

Affiliations

Soon will be listed here.

Abstract

Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.

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References

Kurz G, Wiesinger H, Hamprecht B . Purification of cytosolic malic enzyme from bovine brain, generation of monoclonal antibodies, and immunocytochemical localization of the enzyme in glial cells of neural primary cultures. J Neurochem. 1993; 60(4):1467-74. DOI: 10.1111/j.1471-4159.1993.tb03309.x. View

Konner A, Janoschek R, Plum L, Jordan S, Rother E, Ma X . Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 2007; 5(6):438-49. DOI: 10.1016/j.cmet.2007.05.004. View

Rosenstraus M, Chasin L . Isolation of mammalian cell mutants deficient in glucose-6-phosphate dehydrogenase activity: linkage to hypoxanthine phosphoribosyl transferase. Proc Natl Acad Sci U S A. 1975; 72(2):493-7. PMC: 432338. DOI: 10.1073/pnas.72.2.493. View

Taniguchi C, Emanuelli B, Kahn C . Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7(2):85-96. DOI: 10.1038/nrm1837. View

Jacobson J, Duchen M . Interplay between mitochondria and cellular calcium signalling. Mol Cell Biochem. 2004; 256-257(1-2):209-18. DOI: 10.1023/b:mcbi.0000009869.29827.df. View

Zhao W, De Felice F, Fernandez S, Chen H, Lambert M, Quon M . Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2007; 22(1):246-60. DOI: 10.1096/fj.06-7703com. View

Bourne K, Ferrari D, Lange-Dohna C, Rossner S, Wood T, Perez-Polo J . Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J Neurosci Res. 2007; 85(6):1194-204. DOI: 10.1002/jnr.21252. View

Wu L, Rowley J, Mohades S, Leuzy A, Dauar M, Shin M . Dissociation between brain amyloid deposition and metabolism in early mild cognitive impairment. PLoS One. 2012; 7(10):e47905. PMC: 3480449. DOI: 10.1371/journal.pone.0047905. View

Hoyer S, Nitsch R . Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J Neural Transm. 1989; 75(3):227-32. DOI: 10.1007/BF01258634. View

10.

Thambisetty M, Metter E, Yang A, Dolan H, Marano C, Zonderman A . Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol. 2013; 70(9):1167-72. PMC: 3934653. DOI: 10.1001/jamaneurol.2013.284. View

11.

Hotamisligil G, Shargill N, Spiegelman B . Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259(5091):87-91. DOI: 10.1126/science.7678183. View

12.

Doble B, Woodgett J . GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003; 116(Pt 7):1175-86. PMC: 3006448. DOI: 10.1242/jcs.00384. View

13.

Piroli G, Grillo C, Reznikov L, Adams S, McEwen B, Charron M . Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus. Neuroendocrinology. 2007; 85(2):71-80. DOI: 10.1159/000101694. View

14.

Martini G, Ursini M . A new lease of life for an old enzyme. Bioessays. 1996; 18(8):631-7. DOI: 10.1002/bies.950180806. View

15.

Correia S, Santos R, Santos M, Casadesus G, LaManna J, Perry G . Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer's disease. Curr Alzheimer Res. 2012; 10(4):406-19. DOI: 10.2174/1567205011310040006. View

16.

Bonnet M, Weil R, Dam E, Hovanessian A, Meurs E . PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Mol Cell Biol. 2000; 20(13):4532-42. PMC: 85837. DOI: 10.1128/MCB.20.13.4532-4542.2000. View

17.

Krause M, Keane K, Rodrigues-Krause J, Crognale D, Egan B, De Vito G . Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro. Clin Sci (Lond). 2013; 126(10):739-52. DOI: 10.1042/CS20130678. View

18.

Hsu Y, Chen C, Wu S, Jong Y, Lo Y . Berberine activates Nrf2 nuclear translocation and protects against oxidative damage via a phosphatidylinositol 3-kinase/Akt-dependent mechanism in NSC34 motor neuron-like cells. Eur J Pharm Sci. 2012; 46(5):415-25. DOI: 10.1016/j.ejps.2012.03.004. View

19.

Garvey W, Olefsky J, Marshall S . Insulin induces progressive insulin resistance in cultured rat adipocytes. Sequential effects at receptor and multiple postreceptor sites. Diabetes. 1986; 35(3):258-67. DOI: 10.2337/diab.35.3.258. View

20.

Chiu S, Chen C, Cline H . Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008; 58(5):708-19. PMC: 3057650. DOI: 10.1016/j.neuron.2008.04.014. View