physiological regulation of plasma glucose - part i, by professor jens juul holst

7/27/2019 Physiological Regulation of Plasma Glucose - Part I, By Professor Jens Juul Holst

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[MUSIC]Hello.My name is Jens Holst.I'm Professor of Medical Physiology at theUniversity ofCopenhagen and I'm here to talk aboutglucose regulation.

Let us begin by considering the normalconcentrationsof glucose in the circulating body fluids.What should we choose?Blood or plasma?We will choose plasma because theconcentrationin the red blood cells is low.What matters is the amount of glucose,that can diffuse freely,and reach target cells, serving as fuel orexerting regulatory functions.

The concentration in plasma is around fivemillimoles per liter,corresponding to 90 milligrams perdeciliter, and is remarkably constant.In healthy subjects, it rarely falls belowfour millimoles perliter and rarely increases beyond sevenmillimoles per liter.With this tight control one could imaginethat glucosecontrol is important and this is indeedthe case.Numerous tissues depend on glucose for

energy supplyto support vital functions.Particularly the central nervous systemcannotoperate without adequate supplies ofglucose.And the same is true for the red bloodcells.If glucose falls too much, this is what wecall hypoclycemia, we may experienceconfusion, convulsions, loss ofconsciousness

and eventually death.Conversely, acute elevations of plasmaglucose areassociated with impaired neural functions,especially cognitive functions.But the real danger is the damage to alargenumber of proteins caused by a prolongedelevations of plasma glucose.This is what causes the devastatingdiabetic complications.Neuropathy, retinopathy, nephropathy.The so called micro-vascular

complications.Chronic hyperglycemia is also associatedwith macro-vascular damage


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which may lead to myocardial infarction,stroke andamputations. But how is it possible tomaintain this constant glucose level?To answer this question, we must considerthe glucosefluxes inside the body that occur during

daily life.And that will reveal the consumption andproductionare so closely matched, that deviationsfrom fivemillimolar are very rare, in spite of verylarge flux differences depending on thephysiological state.The glucose in plasma is either derivedfrom the diet andabsorbed from the gut into thebloodstream, after digestion of dietary

carbohydrates.Alternatively, it is produced in tissuescapable of producing glucose for export.The amount of glucose from the diet variesof course, but may amount to as much as3000 millimoles or some 5000 grams or aeight to nine kj per 24 hours.Where does all this glucose go?It enters the volume of distribution forglucose.And that is roughly equivalent to theextracellular space.This is because glucose cannot cross the

cell membranes, andenter the cells, unless these are equippedwith special transporters.The extracellular space roughlycorresponds toabout twenty percent of the body weight,that is fourteen liters in a person with abody weight of seventy kilograms.3,000 millimoles in fourteen liters, thiswouldamount to more than 200 millimoles perliter which would be absolutely lethal.But glucose is, of course, also removedfrom the circulation.The brain and the rest of the centralnervous systemneeds a constant supply of some 35millimoles per hour.That's about half of the pool.What is the pool?So it's these 14 liters of extracellularvolume with aconcentration of five millimoles perliter, and that equals 70 millimoles.And then we have the muscles.

During maximal muscular work,the muscles maytake up several hundreds of millimoles per


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hour.Which would off cause rapidly empty thepool.It's clear, that we need very efficientmechanisms to ensure,that the glucose concentration staysnormal in both of these situations.

So what can the body do with the absorbedglucose?There are two possibilities.One is that it can be metabolized in thetissues.But this process is of course limited tothe energy requirements of the tissues.Once these are satisfied, no more glucoseis disposed of in that way.The second is to deposit the glucose.This occurs in several tissues.Them most important ones being the liver

and the skeletal muscular tissues.Here glucose units are combined into largemolecular weight glycogen molecules,facilitated by the glycogen synthasepathway.The glucose stored as glycogen can bemobilized again.The liver can split the glycogen moleculesagain.And actually re-export the individualglucose units.The latter is due to the fact that theliver cells express an enzyme called

glucose-6-phosphatase.Which allows exit of glucose.The muscles can also split glycogen butonly for internal use.They cannot very well export glucose.Once the glycogen deposits are filled theorganism cannot store any more glucose.But may instead convert the glucose intofat.Both the liver and fat cells of theadipose tissue arecapable of synthesizing fatty acidsand eventually triglycerides from glucose.It's well recognized, that storage in thisway is almost unlimited.Can fat be mobilized to bring backglucose to the blood stream.Not readily.The triglycerides may undergo lipolysiswhere by the fatty acids are liberated.The fatty acids may then be exported andtransported.To tissues in need of energy, particularlythe muscles, for combustion.The backbone of the triglycerides, the

glycerolmoiety, may also be exported andtransported


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to the liver where it can serveas substrate for the process designatedgluconeogenesis,whereby new molecules of glucose aresynthesized.Clearly the liver plays a central rolein the regulation of the plasma glucose

concentration.It does so, not only because of itsability to take upconsiderable amounts of glucose but alsoto produce glucose if needed.To summarize, the liver takes up glucoseand storesit as glycogen, in the process namedglycogenesis, but itcan also produce glucose for export tothe circulation,either by mobilizing its stores of

glycogen, so called glycogenolysis,or by production of new glucosefrom various substrates, so-calledgluconeogenesis.We mentioned glycerol as a substrate, butthere are other important substrates.This include lactate, derived fromanaerobicmetabolism of glucose in the tissuesas well as amino acids liberatedfrom peripheral tissues, for instanceduring fasting.It is possible to measure the fluxes

of glucose in humans with minimalinvasion byinfusing at a constant rate isotopicallylabeledglucose, which allows one to follow thefateof the molecules in the body.By measuring the varying dilution of thetracer, the radioactive glucose,in the glucose pool it ispossible to determine boththe formation of glucose in the body, theso-called rate of appearance,and the total glucose disposal,the rate of disappearance.We should mention that also the kidneysarecapable of producing small amounts ofglucose by glyconeogenesis.The kidneys may also help to dispose ofglucose at very high concentrations.The maximum capacity for reabsorption ofglucose in the kidneysis reached at a plasma concentrationaround 10 millimoles per liter.

And at higher concentrations glucose istherefore lost in the urine.Clearly this is not important for healthy


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individuals, butoccurs frequently in diabetes where we talkabout glucosuria.Since the excretion of glucose isaccompanied by a considerable loss ofwater, so-called osmotic diuresis, glucosuriamay lead to

serious loss of fluid and electrolytes,in patients with dysregulated diabetes.Thus, with a person in nutritionalbalance, dietary carbohydrates are eithercombusted or rapidly deposited as glycogenin muscles and liver.In the interdigestive periods when glucoseuptake from thegut has ceased, the liver starts to exportglucose.And is capable of maintaining aconstant plasma glucose concentration for

lengthy periods.In the beginning the predominatingmechanismwill be glycogenolysis, but the liver canonly store glycogen enough to support tobodily needs for about 24 hours.However long before the stores areexhausted,the liver starts to produce glucose bygluconeogenesis.And this pathway is sufficient tomaintain plasma glucose levels for manydays.

As is evident from studies of people subjected tostarvation,which does normally not causehypoglycemia.This situation is obviously extremelydemandingwith respect to supplies of substrates.Which eventually will result in acatabolic state wherethe gluconeogenic substrates is aminoacids from body proteins.The question then arises.Where are the sensors and regulatorymechanism in glucose homeostasis?What makes the liver switch its functionsaccording to the metabolic demands?What makes skeletal muscle switch fromcarbohydrate to fatty acid oxidation?The answer is of course the pancreaticendocrine islets of Langerhans.Albeit several other mechanisms may play arole as well.Our approximately two million pancreaticislets which make up one totwo percent of the pancreatic volume,

contain five endocrine cell type.The two most important ones making up morethan 90% of the cells are the insulin


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producing beta cells and the glucagonproducing alphacells. In total a couple of thousands perislet.The remaining cell types are firstly thesomatostatin producing delta cells,which probably exert important paracrine

regulatory functions within the islets.Secondly, cells producing pancreaticpolypeptidewith no known function.And finally, ghrelin-producing cells, theimportance of which is also unclear.The arrangement of the cells in the isletsvaries somewhat between the species.And appears somewhat irregular in humans.The arrangement is probably very importantfor intra-islet regulatory processes.For example, somatostatin powerfully inhibits

the secretion of both insulin and glucagon,and insulin is thought to inhibitglucagon secretion, while glucagonstimulates insulin secretion.For two such cells lying next to eachother, itis easy to image that they might influenceeach other's functions.But these interrelationships are not verywell worked out.Nevertheless, the main function of theendocrine pancreas is well established.It reacts by increasing insulin secretion,

as the concentration of glucose in theplasmathat perfuses it, rises and with increasingsecretion of glucagon if the glucoseconcentration falls.One way of studying this is to isolatesurgically the pancreas and keepit alive with artificial media for whichone can control glucose concentrations.The mechanism of glucose stimulation ofthe beta cellshas been worked out in considerabledetail.The beta cell is a glucose sensor andcontroller in one.It reacts to changes in plasma glucoseconcentrations by producing appropriateamounts of insulin.So what is the glucose sensor?Like in other cells, glucose cannotdirectlypass into the beta cells.But it is equipped with a glucosetransporter,

a transmembrane protein that facilitatespassage of glucose.This particular transporter is called Glut


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2 and it is characterizedby having a KM close to the normal plasmaglucose concentration.This causes the transporter to operatewith first order kinetics for glucose.And therefore insures that plasma glucosetransport into the

beta cell is proportional to the exterior glucose concentration.Once in the beta cell, the glucose isphosphorylatedby a specific enzyme, glucokinase, with asimilar KM as the transporter, sothat the phosphorylation rate is roughlyproportional to the plasma concentrations.These two molecules, the transporter andtheglucokinase, constitute the glucose sensorof the beta-cells.Since together they allow formation of

glucose-6-phosphateat a rate that is proportionate to plasmaglucose.Phosphorylated glucose then entersglycolysis with ensuing formation of ATP.This cytosolic ATP interacts with acertain ATP-sensitivepotassium channels, in the beta cellmembrane, the K-ATP channels,where increased ATP reduces the openingprobability of the channel.Again, to an extent that is proportional,to plasma glucose.

The reduction diminishes the influx ofpotassium ions from the cell.Since the membrane potential of the betacells to a large extent is generated byefflux of positively charge potassiumions, thismeans that the cell will becomedepolarized.The depolarization in turn will increasethe opening probability.of voltage gated calcium channels, andbecause ofthe steep gradient for calcium, the 10,000times higher concentration,outside compared to inside the cell,calcium will enter the cell.An elevated intracellular level of free ionizedcalcium is exactlywhat is needed to initiate the process ofexocytosis, where byintracellular insulin containing granulesare transported to the cellmembranes where they open and releasetheir contents to the exterior.Clearly any other process that causes

depolarizationor elevated intracellular calcium levelsmay also influence secretion.


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Thus other fuels including lipids and amino acidsmay also generate ATP and influencesecretion.Certain hormone and neurotransmitterreceptors are coupled to intracellularsignalling pathways that may elevateintracellular calcium from intracellular

stores.Some hormones, notably the incretinhormones, which we will talk about later,activate receptors coupled to the membraneassociated adenylate cyclase.Leading to the formation of cAMP,which may both directly and indirectlyinfluence both the KATP channels andexocytosis.Interestingly, the sulfonylurea, among themost widely used anti-diabetic drugs,excert their action by binding to and

blocking the KATPchannels and in this way activating themachinery for insulin release.By acting on the KATP channels they bypassglucose metabolism.And therefore, will cause insulinsecretion regardless ofthe glucose levels, surrounding the thebeta cells.This explains that they may produceinappropriateamounts of insulin and therefore causeunintended hypoglycemia.

The alpha cells share some of thebiochemical features of the beta cells.But react, as mentioned, with decreasingsecretion and response to increasingglucose concentrations,as nicely illustrated in theseexperiments in healthy volunteers,exposed to both high and low plasmaconcentrations of glucose.The mechanisms responsible for this havestill not been completely worked out.Undoubtedly because, pure isolated alphacells are not easy to get hold of.There is good evidence that one of thefunctions ofthe somatostatin-secreting delta cells is toregulate glucagon secretion.As mentioned, the main regulatory mechanisms forthe islets is their ability to react tochanging concentration of glucose inplasma with appropriatealterations in the secretion of insulinand glucagon.But is this enough to keep plasma glucoseconstant?

Indeed the islets will respond to severalother important stimulifor instance what is the role of other


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nutrients? Lipids havelimited effects on both insulin andglucagon secretion but recent evidencesuggests that beta cells are equipt with anumber of receptors,for both long and short chained fattyacids, which

may play a role in it's maintenance ofinsulin secretion.Otherwise the effects of lipids are mostoften discussed into the context oflipotoxicity.Deleterious effects on beta cellsfunction ofhigh lipid levels, as seen in obesity.However, as briefly mentioned, severalamino acids provide apowerful stimulus to both insulin andglucagon secretion.

Indeed, both alpha and beta cell functionmay be evaluated with arginine tests,where arginine is injected intravenouslyand insulin andglucagon responses are measured in plasmashortly after.Protein-rich meals likewise produce astrong stimulus.The combined action on both hormones makessense.The insulin response serves to enhanceperipheral uptake of amino acids andtheir incorporation into tissue proteins

inagreement with insulin's general anabolicactivity.However, if the meal does not contain anequivalent amountof carbohydrate one could fear that theinsulin response might resultin hyperglycemia but this is prevented by thesimultaneous stimulation of glucoconsecretion. That this actually happens,has been demonstrated in simulationexperiments.The presence of cholinergic and otherneurotransmitter receptors on the betaandalpha cells, suggest that the autonomicinnovation of the islets also plays a role.Thus, vagal stimulation provides apowerful stimulus to both insulin andglucagon secretion, suggesting that forinstance meal stimulation, in additionto the effects of absorbed nutrients, alsoengages a neural component.Indeed, there are numerous reports, on theexistence

of a cephalic phase, for insulin secretion.But the sympathetic division of theautonomic


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nervous system may be even more important.Stimulation of the sympathetic nervesupply to the pancreaswill strongly inhibit insulin secretion,and enhance glucagon secretion.This is one of the mechanisms engagedduring muscular work. And as we shall see

later, these changes are essential for themaintenance of plasma glucose levels inthis situation.But are hormones from outside the pancreasalso important for islet function.The answer is yes.In fact it turns out that up to 70% of thepostprandial insulin response iscaused by actions of hormones secretedfrom the gut, the so-called incretinhormones.The amplification of insulin secretion by

gut hormones is called the incretineffect.The incretin effect is normally evaluatedbycomparing the insulin responses to an oralglucoseload and to an intravenous infusion ofglucose adjusted to result in similarglucose concentrations.This is shown in this figure.It is clear that the oral route causesmuch higher insulin secretion.The incretin effect is very important for

keeping down, postprandial glucose levels.Have a look at these experiments inhealthy individuals.Here, glucose in amounts ranging from 25to 100 grams, were given orally.And the resulting excursions were copiedby intravenous infusions.The most surprising observation is thatthe glucose excursions are virtuallyidentical in spite of up to four folddifferences in glucose loads.It is the incretin effect.And the next figure, we see theinsulin responses, to various glucoseloads.And it's clear that insulin secretion, isdramatically anddose dependently increased in response to theincreasing oral loads.In other words, the incretin effect,ensures that plasma glucoseexcursions after carbohydrate loading arekept at a lowand relatively constant level regardlessof the amount of carbohydrate ingested.

Which are the hormones responsible for theincretin effect?The two most important ones are


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glucose-dependent insulinotropicpolypeptide. In short, GIP.And, the glucagon-like peptide-1, GLP-1.Both have remarkable effects on the betacells.The incretin effect is of particularclinical

interest because it is almost completelylostin patients with type two diabetes andthis loss contributes considerablyto the inability of these patients tosecrete sufficient amounts of insulin.Fortunately one of the hormones GLP-1 isneverthelesscapable of stimulating insulin secretionin supraphysiological doses.And because of this, it is possible totreat type two diabetes with GLP-1

agonists.[MUSIC]

physiological regulation of plasma glucose - part i, by professor jens juul holst

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