Effect of Diabetes on Levels of Lipid Peroxides and Glycolipids in Rat Brain

7/28/2019 Effect of Diabetes on Levels of Lipid Peroxides and Glycolipids in Rat Brain

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Effect of Diabetes on Levels of Lipid Peroxides and Glycolipids in Rat BrainJ.S. Suresh Kumar and Venugopal P. Menon

The effects of diabetes on levels of lipid peroxides and glycolipids in brain were studied in alloxan (18 mg/ 100 g body weight)diabetic rats. Free fatty acid (FFA) and malondialdehyde (MDA) levels were increased in the brains of diabetic animals. On theother hand, activities of the antioxidative enzymes catalase and superoxide dismutase (SOD) were decreased. The study alsoshowed elevated levels of most of the glycolipid fractions except gangliosides, which were found to decrease in diabetic brain.Administration of insulin to diabetic animals results in the restoration of these parameters to normal levels. These changesobserved in diabetic brain may be responsible for the increased frequency of stroke in diabetes.Copyrigh t 0 7993&y W.B. Saunders Company

T E IMPACT OF DIABETES mellitus on the centralnervous system (CNS) has become a field of interestonly recently. 1.2A number of reports are available on thestructural and biochemical abnormalities in the brain indiabetes,3s4 which affects the CNS in several ways.

Epidemiologic studies demonstrate that diabetes melli-tus causes a twofold to sixfold increase in the risk ofthrombotic stroke. Diabetic patients have an increasedfrequency and a poorer outcome of stroke than nondiabeticsubjects.5T6 Diabetes is believed to cause 7% of deaths dueto stroke, and cerebrovascular disease causes 25% of deathsamong diabetic patients.7 Many studies demonstrate al-tered brain energy metabolism during diabetes.8-10 Glucosetransport into the brain of diabetic animals has been foundto decrease as a consequence of hyperglycemia. Diabeteshas also been found to affect neurotransmitter metabolismin the brain.12 Steger and Kienast13 have found decreasednoradrenergic neurotransmission in streptozocin-induceddiabetes.

Lipid peroxidation is a complex process associated with anumber of pathologic phenomena such as increased mem-brane rigidity, atherosclerosis,14 carcinogenesis,ls and myo-cardial infarction.16 Studies in this laboratory and else-where demonstrate that lipid peroxide metabolism is alteredduring diabetes.17,1s Rechthand et all9 have shown thatoxygen free radicals impair the blood-nerve barrier duringdiabetes. Jeremy et al*O ave observed a decreased prostacy-clin synthesis in different brain regions in diabetic rats. Anincreased lipid peroxidation has been reported in red bloodcells (RBCs) of diabetic patients and streptozocin-diabeticrats.Z1,22 t has been suggested that hyperglycemia causesperoxidation of membrane lipids in human RBCs, resultingin changes in properties of RBC membranes.23 Recently,Jain et al24 have demonstrated a decrease in vitamin E leveland an increase in lipofuscin production in RBCs ofdiabetic rats.

Glycolipids are widely distributed in brain. The nervoussystem is characterized by high concentrations of cerebro-sides, sulfatides, and polysialogangliosides. Gangliosidescan interact with monovalent and divalent cations andtherefore interfere with sodium-potassium-dependent aden-osine triphosphatase (ATPase) activity.= Glycolipids areinvolved in a number of processes such as cell membranefunctions, immunologic reactions, and virus cell interac-tions.

Available reports show that although there are changes

Metabol i sm, Vol42, No 11 (November), 1993: pp 1435-1439

in the metabolism of a number of substances in brain duringdiabetes, not much research has been conducted pertainingto the changes taking place in lipid peroxide and glycolipidmetabolism in brain during diabetes. We therefore deter-mined the levels of malondialdehyde (MDA) and glycolip-ids and the activities of superoxide dismutase (SOD) andcatalase in the brain in experimental diabetes mellitus.

MATERIALS AND METHODSSprague-Dawley male albino rats weighing 140 to 160 g were

used for the study; they were fed a normal laboratory diet(Hindustan Lever rat feed, Sigma, St Louis, MO). Diabetes wasinduced by a single subcutaneous injection of 18 mg alloxan/lOO gbody weight. Animals with a blood glucose level of 375 + 20mg/dL were included in the diabetic group. The animals were thengrouped as follows: group I, normal; group II, diabetic; and groupIII, diabetic + insulin.

For the short-term study, insulin (0.9 U/100 g body weight) wasadministered 1 week after the alloxan treatment and continueddaily for 2 weeks. At the end of this period, all animals were killedby decapitation and brain tissue was removed quickly and frozen atliquid nitrogen temperature.

In the case of the long-term study, insulin treatment (daily at theabove dose) started at the end of the 2 months after alloxantreatment. Insulin was administered for 1 month, and at the end ofthe period all of the animals were killed by decapitation. Braintissue was removed immediately and kept at liquid nitrogentemperature.

The concentration of free fatty acids (FFAs) was measured inthe lipid extract according to the method of Falholt et al.26 Lipidextraction was performed according to Folchs* procedure. Forthe determination of MDA levels, tissues were homogenized inTrishydrochloride buffer (0.1 mol/L, pH 7.5); MDA level wasdetermined by the thiobarbituric acid method of Buege and Aust.28

The assay of SOD was performed using the method of Kakkar eta1.29Tissues were extracted with 0.25 mol/L sucrose, and an initialpurification was performed using ammonium sulfate. The ammo-nium sulfate-fractionated SOD preparation was dialyzed over-night against 0.0025 mol/L Tris hydrochloride buffer (pH 7.4)before being used for enzyme assay. The assay system contained 1.2

Fr om the Department of Biochemistry, University of Kerala, Thir u-vananthapuram, India.

Submitted September 5,1992; accepted February I I , 1993.Address r eprint r equests to Venugopal P. Menon, PhD, Reader,

Department of Biochemistty, Uni versity of Kerala, Kari avanom 69.5581, Thir uvananthapuram, India.

Copyrigh t 0 I 993 by W. B. Saunders Company0026-0495/93/4211-0010$03.00/O

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mL sodium pyrophosphate buffer (pH 8.3, 0.025 mol/L), 0.1 mL186 pmol/L phenazine methosulfate, 0.3 mL 300 FmoliL NitroBlue Tetrazolium, 0.2 mL 780 p,mol/L NADH, and approximatelydiluted enzyme preparation and water in a total volume of 3 mL.After incubation at 30C for 90 seconds, the reaction was termi-nated by the addition of 1 mL glacial acetic acid. The reactionmixture was stirred vigorously and shaken with 4 mL n-butanol.The color intensity of the chromogen in the butanol layer wasmeasured at 560 nm against n-butanol.

Catalase activity was determined in the tissue extract preparedusing phosphate buffer (pH 7.0). The activity was measuredaccording to the method of Aebi30 by following the decompositionof hydrogen peroxide at 240 nm.

For estimating brain glycolipid levels, lipid extraction wasperformed according to Folchs27 method. The lipid extract wasshaken with 0.1 mol/L potassium chloride. Upper and lowerphases were washed three times with theoretical lower and upperphases. Combined upper phases were dialyzed against disti lledwater and then lyophilized. The lyophilized material was extractedwith CHC13:CH3OH:H20 (10:5:1), and sialic acid3 was estimatedto quantify gangliosides.

The combined lower phases were reduced to a small volume andpassed through a diethylaminoethyl (DEAE) cellulose column(acetate form, 20 x 1 cm). Glycolipid fractions, namely cerebro-sides, ceramide dihexoside and polyhexoside, monoglycosyl diglyc-eride, and diglycosyl diglyceride, were collected using elutingsolvents containing chloroform/methanol in the ratios 9:1, 7:3.98:2, and 9:1, respectively.3 Total hexose33 and sulfate34 levelswere determined to quantify the various glycolipid fractions.Cerebroside was obtained by subtracting sulfate from total hexosein the first fraction. Protein level was determined by the method ofLowry et al, and statistical analysis was performed using Studentst test.3h

RESULTSA 35% mortality rate was observed after alloxan treat-

ment. Weight change and blood glucose levels are pre-sented in Table 1. Diabetic animals showed significantlyhigh blood glucose levels; administration of insulin restoredblood glucose levels to normal. Diabetic rats lost weight andremained lighter than control rats throughout the durationof the study.

The concentration of FFAs in brain is shown in Table 1.Table 1. Blood Glucose Level, Body Weight Change, and FFA and

MDA Levels in Brain

GroupBlood

GlUCOSe(mgl100 mL)

BodyWeight

(9)

FFA MDA(mgl100 g (mmol~L/lOO gwet tissue) wet tissue)

3 WeeksNormal 80 r 3 170 + IO 12.4 * 0.37 1.04 -c 0.05Diabetic 325 + 21* 120 f 3* 21.6 + 0.9* 1.70 ? 0.06*Diabetic +

insulin 101 + 3t 150 + 5t 10.7 + 0.5t 1.21 lr 0.06t3 Months

Normal 75 z? 2 263 ? 12 10.3 + 0.4 1.15 * 0.05Diabetic 380 + 14* 94 + 5 30.1 r 1.0* 2.0 + 0.08Diabetic +

insulin 83 ? 3 210? 6 9.2 t- 0.5t 1.2 ?I 0.07tNOTE. Values are means ? SEM from six rats.l < .Ol, compared wi th respective normal 9roup.tP < .Ol, compared with respective diabetic 9roup.

Higher levels of FFAs were observed both in the short-termand long-term animal groups. Insulin administration re-stored FFA levels to normal.

As shown in Table 1, both short-term and long-termdiabetic brain registered higher levels of MDA whencompared with normal brain. However, insulin-treatedanimals showed normal levels of MDA.

SOD and catalase activities are shown in Table 2. BothSOD and catalase activities in the brain decreased duringdiabetes; the extent of the decrease was high in the case oflong-term diabetes. On the other hand, animals giveninsulin have a normal activity of these enzymes.

Concentrations of various glycolipid fractions are shownin Table 3. All glycolipid fractions except ganglioside wereincreased significantly during both the early stage and thelater stage of diabetes. Ganglioside levels decreased indiabetic brain compared with normal brain; however, insu-lin treatment of diabetic animals restored glycolipid frac-tions to normal.

DISCUSSIONThese results demonstrate significant alterations in the

metabolism of lipid peroxides and glycolipids in brain ofalloxan-diabetic rats.

The level of FFAs increased in diabetic brain. Thishigher level of FFAs in brain may be due to the extractionof FFAs from the plasma. In this context, an increasedconcentration of FFAs has been observed in the plasma.37This increased FFA level may lead to the accumulation offatty acid metabolites, namely acetyl coenzyme A and acylcarnitine,x both of which have been demonstrated tointerfere with Na+-K+ ATPase activity.38 Recently, it hasbeen shown that Na+-K+ ATPase activity is decreased indiabetic brain. Thus the increased FFA concentrationobserved by us may be in part responsible for decreasedNa+-K+ ATPase activity, which in turn may lead to thedecreased ion permeability observed in diabetes.

The increased levels of MDA (an index of lipid peroxida-tion) observed in the brains of animals with diabetesindicate the activation of the lipid peroxidation system.MDA is the breakdown product of the unsaturated fattyacids containing three methylene-interrupted double bonds.It has been suggested that brain is especially rich in iron.4uMost of this iron is found in enzymes, hemoglobin, myoglo-bin, storage proteins such as ferritin, or transport proteinssuch as transferrin. Brain tissue, due to its high rate ofoxygen consumption and high phospholipid content withpolyunsaturated fatty acids, is particularly susceptible toperoxidative agents, free radical-generating compounds,and lipid peroxidation. Furthermore, it has been demon-strated that brain contains low levels of vitamin E andselenium-dependent glutathione peroxidase activity, andhence the brain is more prone to lipid peroxidation.J

The metal ion-dependent oxidation of adrenaline, nor-adrenaline, and thiol compounds produces superoxideradicals.40 Thomas et a14* have demonstrated that superox-ide can promote the release of iron from ferritin. Thisrelease of iron may cause lipid peroxidation, which may


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Table 2. Activity of Catalase and SOD in BrainCat&Se SOD

Group (x10-3 U/mg protein)* (Uhg protein)3 Weeks

Normal 2.24 ? 0.08 7.5 + 0.30Diabetic 0.96 2 0.05* 2.23 + O.lO*Diabetic + insulin 1.98 -c 0.08t 5.71 + 0.23t

3 MonthsNormal 2.40 ? 0.08 8.50 + 0.30Diabetic 0.89 + 0.05 2.10 + 0.05xDiabetic + insulin 1.91 f 0.07t 6.11 + 0.24t

NOTE. Values are means 2 SEM from six rats.l < .Ol, compared with respective normal group.tP < .Ol, compared with respective diabetic group.*Units = velocity constant per second.One unit is the enzyme concentration required to inhibit the optical

density at 560 nm chromogen production by 50% in 1 minute.

result in the release of still more iron by the reaction of lipidhydroperoxides with cytochromes and the accompanieddestruction of heme and the release of iron. Thus delocal-ization of iron and associated iron-dependent lipid peroxi-dation may be responsible for higher levels of lipid perox-ides in brain. There are also reports that glycosylation ofprotein is increased in diabetic brain.39,43 A number ofstudies suggest that glycosylation of protein is accompaniedby the generation of free radicals.4s45 Therefore, it is alsopossible that the free radicals formed by nonenzymaticglycosylation of proteins activate the lipid peroxidationsystem in diabetic brain. Accumulation of lipid peroxidescauses the loss of membrane fluidity and integrity; lipidperoxides also inactivate receptors. Binding of serotonin toits receptors in rat cortical membrane is decreased by lipidperoxidation. Therefore increased levels of lipid perox-ides may also be responsible for the defective neurotransmis-sion observed in diabetes. Earlier studies in this laboratoryhave demonstrated a defective metabolism of lipid perox-ides in other tissues in diabetic animals. It has been foundthat lipid peroxidation is increased in serum, kidney, andliver, whereas in heart lipid peroxidation is decreased.

Associated with the changes in lipid peroxidation, dia-betic brain showed a decreased activity of two key enzymes,SOD and catalase, which play important roles in scavengingthe toxic intermediates of incomplete oxidation. A decrease

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in the activities of these enzymes can lead to an excessavailability of superoxide (02-) and hydrogen peroxide(H202) in the biological systems, which in turn generatehydroxy radicals, resulting in initiation and propagation oflipid peroxidation. This decreased activity of SOD with aconsequent increase of 02- may be responsible for theaugmented release of iron, leading to iron-dependent lipidperoxidation in brain. This increased lipid peroxidationassociated with a decreased activity of SOD and catalasemay be one of the factors responsible for the inhibition ofNa+-K+ ATPase.39 A decreased activity of catalase andSOD has also been found in other tissues in diabeticanimals.

Glycolipid levels also showed significant alterations indiabetic brain. There were increased levels of cerebrosides,sulfatides, ceramide dihexosides and polyhexosides, andmonoglycosyl and diglycosyl glycerides. On the other hand,ganglioside levels decreased in diabetic brain. Glycolipidsare important features of multiple sclerosis and are in-volved in cell membrane functions, immunologic reactions,and virus cell interactions. Glycosphingolipids are constitu-tive components of the outer leaflet of the lipid bilayerconferring structural rigidity. 46 It is now believed that theformation of the neuromuscular junction is based on ahighly specific recognition process that involves glycosphin-golipids. Sulfatides have been implicated in the binding ofthrombospondin47 and laminin.48 Investigations suggestthat gangliosides act as synaptic calcium storage sites,regulators of growth hormone receptors, and protein ki-nases.49Jo Therefore, any change in glycolipid levels affectsthe property and function of brain tissue. It has been shownthat the structural integrity of myelin depends on thephosphorylation of myelin basic protein: Gangliosideshave been shown to influence the phosphorylation ofmyelin basic protein.51 Therefore, the low levels of ganglio-side observed by us may affect the protein phosphorylationand produce a consequent alteration in the normal struc-ture and function of the myelin sheath. Increased levels ofother glycolipids may result in their deposition in the brain,leading to alterations in the property and function of braintissue. Insulin treatment of diabetic animals restored glyco-lipid levels to normal.

Table 3. Concentration of Glycolipids in Diabetic BrainGroup Cerebroside Sulfatide CDH + CPH MGDG + DGDG Ganglioside

3 WeeksNormal 1,640 ? 50 364 + 8 39 -c 3 36 f 2 12.2 + 0.4Diabetic 3.138 f 78* 1,866 + 43* 158 ? 5 92 * 5= 8.2 + 0.24*Diabetic + insulin 2,015 + 80t 423 + 12.7t 41 f 1.2t 37 2 1.5t 11.0 * 0.44t

3 MonthsNormal 1,694 f 76 439 r 24 49 * 7 43 2 5 10.3 2 0.2Diabetic 3,947 + 108 2,816 ? 70* 300 ? 11* 158 + 4* 6.2 * 0.12*Diabetic + insulin 1,643 ? 65t 501 r 20t 30 * 2t 31 + 1.5t 9.7 2 0.4t

NOTE. Values are means + SEM from six rats and are expressed as mg/lOO g wet tissue.Abbreviations: CDH, ceramide dihexoside; CPH, ceramide polyhexoside; MGDG, monoglycosyl diglyceride; DGDG, diglycosyl diglyceride.l < .Ol, compared with respective normal group.tP < .Ol, compared with respective diabetic group.


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Thus this study demonstrates that diabetes melhtus tions may be responsible for alterations in membraneaffects brain metabolism. Diabetes results in increased lipid property and function, and these changes in the brain mayperoxidation and decreased activity of some antioxidative be responsible for the increased frequency of stroke nor-enzymes. Changes in the levels of various glycolipid frac- mally observed in diabetes.

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Effect of Diabetes on Levels of Lipid Peroxides and Glycolipids in Rat Brain