2 Neil Bulleid The brain is the most critical organ in our body. It needs a constant supply of glucose to function correctly, This requirement for glucose lasts long after any nutrients absorbed from a meal have been exhausted. In this article we explore how the body maintains this vital supply of glucose. all kos dhe feeling of fatigue when we haven’ eaten for a while. Our brain stops working efcienty — we lose concentra tion easly and feel lethargic. This poor brain function Is caused by a drop in blood glucose concentration and is our body’s way of telling us is time to eat or rest Lucklly most of us ca adjust eur blond glucose concentration by a numberof diferent imechanisis to ensure that, even daring periods of starvation, our brain can sil function adequately. Where does our blood glucose come from? Glucose is supplied to the blood in several ways. I can be absorbed dieclly into the blood after 1 meal. can come fom the breakdown of the storage molecule glycogen ort can be synthesised from laqtate by the ver. To explain bow a fay constant supply of glucose tothe brain matitained we wil consider what happens during and after a meal Just affer a meal our blood glucose concentration Increases as carbohydrates are digested and glucose, along with other nutrients s absorbed from our ites tines and sransported around the body. During this period our blood ghucose level is high, so the body either uses the absorbed glucose directly to release ‘energy oF ores iby converting tint glycogen or fas Releasing energy from glucose {cose is broken dovm to pyruvate via several steps in a metabolic pathway called glycolysis. Glyeoysis ultimately results in the production of adenosinetriphosphate, ATP (sce Box 1 and Figure 1). The fs ‘Sep s the phosphorylation of glucose to form glucose fcphosphate. This step is required to trap glicose in the cell Glicose can be transported across the plasma membrane via special sransporers bat glucose 6-pnosphate cannot, Thus plucose ean ener the cel but -sglucose 6plshate it cannot exit he cell because the negative changes on the (highly hydrophilic phosphate ‘r0up prevent it passing through the (highly hydro: hb) phospholipid Iyer of dhe plasma membrane The conversion of glucose Gsphomphate to pysuvate ‘occurs inthe cytoplasin — and no oxygen Is required For glycolysis to continue under anaerobic cond tions the reduced NAD produced during the pathway needs to be recycled back to NAD, a process that ‘occurs when pyruvate Is converied to lactate, Under anaerobic conditions. such a in muscle undergoing heavy exercise. glycolysis isthe main source f ener. Under aerobic conultions, pyruvate is transported into ritochondsia where {ti nally converted to acetyl CoA belore entering Krebs yee. Much more energy is released when ghicose is broken devin under aerobic conditions, Following 2 meal our blood glucose level i well in ‘excess of what we need immediately. The body stores the excess glucose as eter glycogen off Glucose storage in times of plenty “The main organ that synthesises and stores glycogen the liver though glycogen s als stored in eur muscles. Glucose Is transported across the plasina mentbrane iro cells through specialised protein channels called shucose transporters The fist step in glycogen synthesis is the formation of ghicose 6-phosphate molecules ‘These can then be joined to each other to form a polymer of ghicose, which is called glycogen. The polymer slong and branched. Ir forms lage, insoluble ‘deposits — glycogen gramules — which cam be seen in microscopic views of liver cells (se Figure 2). The livers partcwany suited forthe syns of glycogen. Ic contains a specialised enzyme called glucokina which can eontinue to phosphorylate ghicose even ‘when the concentration of gtucse 6 phosphate i high. 1 sightly diferent form of the enzyme (hexokinase) is present in ote tues, bt tis nied at ih _hicose phosphate concentration to prevent glucose metabolism hy the glycolytic pathway Dietary sugars inchiding ghucose can also be ‘onverted to fats because the acetyl Go formed from pyruvate breakdown sa ulin Block for fatty aids ‘whieh can then be converted 0 fas What happens when we run out of dietary glucose? ‘The glucose from a meal is nomnally used up ater 3-4 hous. During the day we usualy feet hungry and have ‘our next meal However at nighttime, oif we skip a meal, thee follows a peviod sehen we must maimain blood glucose concentration oF our brain function BOX 1 ctucose breakcown and synthesis The conversion of guoose to pyruvate fs called glycols, end the reverse pathway s cated gluconecgenesis (see Figure 1), Not that acetyl CoA an enter Krebs cyl or be Uses as. stating metabolite fr ft syne Fats can be converted to acetyl CoA to promde energy for glaconecgen- ess bul hey cannot be converte fo glucose. Ptceins, onthe ether han, fan be broken down to amine acids, some of which can be converted 10 pyrurate end therefore to ghicose: Under zerobic conditions, NADH ‘and ubicuinel fuel the mitochon eecten transport chain to produce [AT®. Under anaerobic conditions, NADH needs to be reconverted to NAD, curing the conversion of pyruvate to aca, to allow Ryobi to continue ucese [ Hevtnase Glucose 6 phosphate Fructose 1,-sphsphote ee icc heer ¥ Poteins > Amina aids —> Prutate Leta ‘luconcogersis yea ; Ree Cod Fats AP <—Ubiquio! arr NADH ATP Figure 2 Colosed tansmisioneectanmirozraph of et cal rossi, Uhongen arteles cn te sen 8 th ak elecon opaque mata S000 2BOX 2 source of biood glucose following @ meal Following 2 meal, mostof the hicose tues is tom the get Aer 4 hours of lucess aver the nant 16ers Pours 's gycogen. This is slonly ceplaces by luce syhisisx curing sluconec- genesis. Once the glycogen s used Up, the only source e glucose fom liconeogenesis. after prolonged Slaneton there is less sluceneogen 5 (see Figue 3) ond feeding nt resumed, ceath nil ow. Suncyneionteome 9 i eovlewih diate have to monte lod aos wil be affected. To do dis we need 19 mobilise stored Figure 3). Mobilisation of glucose from stored glycogen occas first. The ver contains the main store of the glycogen reserves fal so the synthesis of increases. Glucose is made from lactate oF other metabolites that can be convereed to pyruvate — such as amino acids formed by the breakdown of proteins {lacose synthesis from pyruvate Is called slaconee: seness and requires energy, Most of the energy for this pathway comes from the breakdown of fats, which releases acetyl CoA to enter Krebs cycle (ee Figure 1). I's important to note thar mammals cannot convert fats 10 glucose, so during prolonged siava tion, when glycogen and lactate diminish, the only = protein way of making glicose is to use the Hence to cope with an inconsistent supply fom out erratic mealtimes, the body has evolved mechanisms Figue 3 Cures tte sours of bas gues afters sine eal flawed 2 prbged pod of ast, Dita eco ease ‘lucoraogenesis Pigen mwa Days to store glucose in times of plemy and to synthesise slucose during tes of starvation. Controlling glucose breakdown, storage and synthesis To ensue that the various metabulic pathways are coordinated, a complex st of mechanisms tums them ‘on or off, as requited. When blood glucose concen: tation high. the hormone isan i released to Blood, Insulin stimulates glucose storage by increasing gycogen and fat symthesis and by inhibiting their breakdown. 1 also stimulates glucose upiake into muscle ad fat-produing cells by creasing the ‘mimber of transporters on the cell surface. When flcose level is low, another hormone, glucagon, i Ng secreted. Glucagon simulates glucose symesis and ycagen breakdown, This hormone also inhibits glyco lisis by blocking the enzyme phosphotnucokinase- 5 which rests in an increased concentration of ghicose Gephosphate, In adlition, glicagon stimulates the breakdown of fats to provide energy for glicom Losing control For individls with diabetes, controling blood ghacose concentration ia major problem. People with type 1 abeces cannot produce any insulin, The cel the immune system. The condition can be treated by injecting insulin into the blocdsteam, This treatment can be tricky as the dose of insulin has to be carefully regulated. too much is given, the blood glucose caemia). This results in insutficient blo slucose 10 maintain bain fancton, causing individuals to become ‘comatose if they do not quickly aie thet Hood glacose level by eating a sugary snack People with iy I diabetes secrete insulin but the body's cells seem to have become insensitive toi and cannot respond properly. Even sehen their blood thicose concentration is high, their body behaves asthough starved. Glucose still produced by the Hver but ins underused by oxher assoes because they canoe take up the glucose propery. The result high Mood _hicose level (hyperglycaemia), which causes a raging thirst because the kidneys excrete the excess glucose ‘This glucose excretion represents the loss of a valuable ‘energy source but the glucose mast be removed from the blood because ofthe strong osmoti elect it exer Te this is caused ecause the kidneys need water to remove the ghicose Inboth types of diabetes there i progresive damage tw a wide range of tissues — peripheral nerves. the redina and capillanes for example Iuis remarkable o think tha, given the various fates ‘ofblood glucose, the body can maintain blood glucose ‘concentration within quite a narrow range afer several days or even weeks of iarvation, While our bodies are ‘capable of changing our metabolism drastically over those extreme periods of starvation (ee Fguze 2), the problem nowadays is usually surplus glucose in our ‘et. There fs nly a finite amount of glycogen that cat estore and any excess ghtose rst then be Sore 3 fa, The consequence of our ilestye and the excessive amount of sugars and fats in oe diet is that there as boon a huge increase in obesity among the population in developed countes, Obesity i a major factor i the “development of type M diabetes. 1s sobering o think that years of evolution have enabled our bodies to function through tines of shortage by stoxing sucose fora period of starvation, yet these same adaprations are now causing major health problems forthe affivent ‘counties of the word Points for discussion > What effets do you think diets such a lw cabo hnydrate tut bigh protem and fat have om on body's ‘metabolism? P Why is kidney function impaired when blood lacose concentration is high? ¥ could you recognise the eatly signs of hypo- slycaemia ether in yourself or someone el? Nei ule 2 Prfossor Cal Bick atthe University of Glasgow andar editor of Sova. 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