Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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provides glucose-6-phosphate to meet the liver’s

requirements for glycolysis.

0037 An isoenzyme with a high K

(also known as glu-

cokinase) which only has significant activity as the

concentration of glucose coming from the small

intestine in the hepatic portal vein rises to above

10–15 mmol l

1

. In the fed state this isoenzyme

produces glucose-6-phosphate considerably in

excess of the liver’s requirement for glycolysis; it

is used for glycogen synthesis.

0038As shown in Figure 5, glycogen synthesis involves

the intermediate formation of uridine diphosphate

(UDP) glucose by reaction between glucose-

1-phosphate and uridine triphosphate (UTP). As

each glucose unit is added to the growing glycogen

chain, so UDP is released, and must be rephosphory-

lated to UTP by reaction with ATP. There is thus a

significant cost of ATP for the synthesis of glycogen:

2 mol of ATP are converted to ADP þ phosphate for

each glucose unit added, and overall the energy cost

HC O

HO CH

NADP

NADPH

NADP

NADPH

COOH

HO CH

CHHO

Xylulose-5-phosphate

Glyceraldehyde-3-phosphate

Sedoheptulose-7-phosphate

Fructose-6-phosphateFructose-6-phosphate

Erythrose-4-phosphate

Ribose-5-phosphate

HC OH

HC O

HC OH

HO CH

HC OH

HC O

HC OH

HO CH

HC OH

HO CH

Glucose-6-phosphate 6-phosphogluconate

Ribulose-5-phosphate

Ribulose-phosphate

epimerase

Transketolase

Transaldolase

Transketolase

Phosphoribose

isomerase

Glucose-6-phosphate

dehydrogenase

Phosphogluconate

dehydrogenase

fig0003 Figure 3 The pentose phosphate pathway. Glucose-6-phosphate dehydrogenase EC 1.1.1.49, phosphogluconate dehydrogenase EC

1.1.1.44, ribulose phosphate epimerase EC 5.1.3.1, phosphoribose isomerase EC 5.3.1.6, transketolase EC 2.2.1.1, transaldolase EC

2.2.1.2.

2908 GLUCOSE/Function and Metabolism

Lipoamide

NADH

NAD

Dihydrolipoamide

dehydrogenase

Acetyl lipoamide

SH SH

SSH

Hydroxyethyl thiamin diphosphate

Thiamin diphosphate

Enzyme-bound

thiamin diphosphate

α-Keto-acid

dehydrogenase

COOH

Pyruvate

CHOH

Reduced lipoamide

Dihydrolipoamide

acyltransferase

SCoA

Acetyl CoA

CoASH

fig0004 Figure 4 The reaction sequence of the pyruvate dehydrogenase multienzyme complex (EC 1.2.4.1).

Glucose-1-phosphate Glucose-6-phosphate Glucose

OHP

UTP

pyrophosphate

O UDP

UDP

ADP

ATP

Isomerase

Uridyl transferase

Glycogen synthase

Hexokinase

fig0005 Figure 5 The synthesis of glycogen. Hexokinase EC 2.7.1.1, uridyl transferase EC 2.7.7.9. glycogen synthase EC 2.4.1.11. ADP,

adenosine diphosphate; ATP, adenosine triphosphate.

GLUCOSE/Function and Metabolism 2909

of glycogen synthesis may account for 5% of the

energy yield of the carbohydrate stored.

0039 Glycogen synthetase forms only the a1!4 links

that form the straight chains of glycogen. The branch

points are introduced by the transfer of 6–10 glucose

units in a chain from carbon-4 to carbon-6 of the

glucose unit at the branch point.

0040 In the fasting state, glycogen is broken down by

the removal of glucose units one at a time from

the many ends of the molecule, in response to stimu-

lation by the hormone glucagon. The reaction is a

phosphorolysis – cleavage of the glycoside link be-

tween two glucose molecules by the introduction of

phosphate. The product is glucose-1-phosphate,

which is then isomerized to glucose-6-phosphate.

In the liver, glucose-6-phosphatase catalyzes the

hydrolysis of glucose-6-phosphate to free glucose,

which is exported for use by the brain and red

blood cells.

0041 Muscle cannot release free glucose from the

breakdown of glycogen, since it lacks glucose-

6-phosphatase. However, muscle glycogen can be an

indirect source of blood glucose in the fasting state.

Glucose-6-phosphate from muscle glycogen under-

goes glycolysis to pyruvate (Figure 1), which is then

transaminated to alanine. Alanine is exported from

muscle, and taken up by the liver for use as a substrate

for gluconeogenesis.

0042 Glycogen phosphorylase stops cleaving a1 !4

links four glucose residues from a branch point, and

a debranching enzyme catalyzes the transfer of a

three-glucosyl unit from one chain to the free end of

another chain. The a1 !6 link is hydrolyzed by a

glucosidase, releasing glucose.

0043 The branched structure of glycogen means that

there are many points at which glycogen phosphoryl-

ase can act; in response to stimulation by epinephrine

(adrenaline) there can be a rapid release of glucose-1-

phosphate from glycogen.

0044 Endurance athletes require a slow release of

glucose-1-phosphate from glycogen over a period of

hours, rather than a rapid release. There is some

evidence that this is achieved better from glycogen

that is less branched, and therefore has fewer points

at which glycogen phosphorylase can act. The forma-

tion of branch points in glycogen synthesis is slower

than the formation of a1 !4 links, and this has been

exploited in the process of ‘carbohydrate loading’ in

preparation for endurance athletic events. The athlete

exercises to exhaustion, when muscle glycogen is

more or less completely depleted, then consumes a

high-carbohydrate meal, which stimulates rapid

synthesis of glycogen, with fewer branch points

than normal. There is little evidence to show

whether this improves endurance performance or

not; the improvement that has been reported may be

the result of knowing that one has made an effort to

improve performance rather than any real metabolic

effect.

Gluconeogenesis – The Synthesis of

Glucose from Noncarbohydrate

Precursors

0045Because the brain is largely dependent on glucose as

its metabolic fuel (and red blood cells are entirely so)

there is a need to maintain the blood concentration of

glucose between about 3 and 5 mmol l

1

in the fasting

state. If the plasma concentration of glucose falls

below about 2 mmol l

1

there is a loss of conscious-

ness – hypoglycemic coma.

0046In short-term fasting the plasma concentration of

glucose is maintained by the use of glycogen, and by

releasing free fatty acids from adipose tissues, which

are preferentially used by muscle, sparing such glu-

cose as is available for use by the brain and red blood

cells.

0047However, the total body content of glycogen

would be exhausted within 12–18 h of fasting if

there were no other source of glucose. Gluconeogen-

esis is the synthesis of glucose from noncarbohydrate

precursors: amino acids from the breakdown of

protein, and the glycerol of triacylglycerols. It is

important to note that, although acetyl CoA, and

hence fatty acids, can be synthesized from pyruvate

(and therefore from carbohydrates), the decarboxyla-

tion of pyruvate to acetyl CoA (Figure 2) cannot be

reversed, and pyruvate cannot be formed from

acetyl CoA. Since two molecules of carbon dioxide

are formed for each 2-carbon acetate unit metabol-

ized in the citric acid cycle, there can be no net

formation of oxaloacetate from acetate. It is not

possible to synthesize glucose from acetyl CoA,

and fatty acids and ketone bodies cannot serve

as substrates for gluconeogenesis under any circum-

stances.

0048The pathway of gluconeogenesis is essentially

the reverse of the pathway of glycolysis, shown in

Figure 1. However, at three steps there are separate

enzymes involved in the breakdown of glucose (gly-

colysis) and gluconeogenesis. The reactions of pyru-

vate kinase, phosphofructokinase, and hexokinase

cannot readily be reversed (i.e., they have equilibria

which are strongly in the direction of glycolysis and

the formation of pyruvate, fructose bisphosphate,

and glucose-6-phosphate, respectively).

0049There are separate enzymes, under distinct meta-

bolic control, for the reverse of each of these reactions

in gluconeogenesis:

2910 GLUCOSE/Function and Metabolism

.0050 Pyruvate is converted to phosphoenolpyruvate for

glucose synthesis by a two-step reaction, with the

intermediate formation of oxaloacetate, as shown

in Figure 6. Pyruvate is carboxylated to oxalo-

acetate in an ATP-dependent reaction in which

the vitamin biotin is the coenzyme. Oxaloacetate

then undergoes a phosphorylation reaction, in

which it also loses carbon dioxide, to form phos-

phoenolpyruvate.

0051 Fructose bisphosphate is hydrolyzed to fructose-

6-phosphate by a hydrolysis reaction catalyzed by

the enzyme fructose bisphosphatase;

0052 Glucose-6-phosphate is hydrolyzed to free glucose

and phosphate by the action of glucose-6-phos-

phatase.

0053 The other reactions of glycolysis are readily revers-

ible, and the overall direction of metabolism, either

glycolysis or gluconeogenesis, depends mainly on

the relative activities of phosphofructokinase and

fructose bisphosphatase.

0054 Many of the products of amino acid metabolism

can also be used for gluconeogenesis, since they are

sources of either pyruvate or one of the intermediates

in the citric acid cycle, and hence give rise to oxalo-

acetate. The requirement for gluconeogenesis from

amino acids in order to maintain a supply of glucose

explains why there is often a considerable loss of

muscle in prolonged fasting or starvation, even if

there are apparently adequate reserves of adipose

tissue to meet energy needs.

See also: Energy Metabolism; Thiamin: Physiology

Further Reading

Bender DA (2002) Introduction to Nutrition and Metabol-

ism, 3rd edn. London: Taylor & Francis.

Bender DA and Bender AE (1997) Nutrition: A Reference

Handbook. Oxford: Oxford University Press.

Murray RK, Granner DK, Mayes PA and Rodwell VW

(2000) Harper’s Biochemistry, 25th edn. New York:

McGraw-Hill.

Maintenance of Blood Glucose

Level

V Marks, Haslemere, UK

Glucose

0001Glucose is almost the only simple sugar found in most

body fluids in anything more than trace amounts and

for all practical purposes is confined to extracellular

water. Lactose and fructose are the major sugars in

milk and semen, respectively. This article reviews

the major factors determining the concentrations

of glucose in blood under everyday physiological

and pathological conditions.

Body Glucose Pool

0002The body of an adult subject seldom contains less

than 8 g, or more than 28 g, of glucose at any one

time (corresponding to blood glucose concentrations

of 3.5–10 mmol l

1

) despite enormous fluctuations in

demand and supply. This quantity of glucose can be

looked upon as constituting a hypothetical body pool

(Figure 1) confined within a glucose space equal in

volume to the combined water in blood and the

interstitial fluid, i.e., some 35% of total body water.

0003Glucose enters the cells by facilitated transport

utilizing one or more of the genetically determined

glucose transporter proteins that have been identified,

depending on the tissue. Upon entering a cell, it

is immediately phosphorylated and consequently

removed from the glucose pool.

0004Although its subsequent conversion into carbon

dioxide and water or other metabolites (most notably

glycerol, fatty acids and the glycomoieties of muco-

polysaccharides and glycoproteins) is the only way

that glucose can ordinarily leave the glucose pool,

its loss in the urine may become a major factor in

diabetes mellitus.

ATP

ADP, P

COOH

Pyruvate

Pyruvate carboxylase

COP

COOH

Phosphoenolpyruvate

COOH

Oxaloacetate

COOH

GDP

GTP

Phosphoenolpyruvate

carboxykinase

fig0006 Figure 6 Reactions in the reversal of the pyruvate kinase reaction in gluconeogenesis. Pyruvate carboxylase EC 6.4.1.1, phospho-

enolpyruvate carboxykinase EC 4.1.1.32. ATP, adenosine triphosphate; ADP, adenosine diphosphate; P

, inorganic phosphate; GTP,

guanosine triphosphate; GDP, guanosine diphosphate.

GLUCOSE/Maintenance of Blood Glucose Level 2911

0005 Glucose enters the glucose pool from food via the

hepatic vein or, in the postabsorptive subject, by

release of glucose from preformed glycogen or

molecules newly synthesized by liver cells – also into

the hepatic vein.

Glucose Space

0006 The glucose space is constant in any individual, and

consequently, the amount of glucose in the pool is

directly proportional to its concentration in the

blood (see below). It is this concentration that is

homeostatically controlled through a series of rather

complicated control mechanisms, the most important

of which involve individual pancreatic islets of

Langerhans that function semiautonomously.

0007 When pool size increases above a threshold, corres-

ponding to a concentration in blood of about

10 mmol l

1

, glucose filtered at the glomeruli exceeds

the tubular capacity to reabsorb it, and consequently,

glucose spills over into the urine. Although temporary

increases in glucose pool size (hyperglycemia) are

not immediately harmful, decreases in glucose pool

size (hypoglycemia) are. Indeed, they are potentially

so dangerous that many defense mechanisms have

evolved to prevent or overcome it (see below).

Blood Glucose

0008The brain is the only important drain on the glucose

pool in the fasting subject when plasma insulin levels

are minimal. It consumes glucose at the rate of about

78 mg per gram of tissue per day. This amounts, in an

adult man, to about 110 g per day or 75 g per day in a

1-year-old child. A much smaller loss is into the ery-

thron, which consists mainly of the bone marrow and

red blood cells. Estimates of glucose turnover suggest

that about 9 g of glucose enter and leave the glucose

pool every hour in the average overnight fasting

healthy subject.

0009The concentrations of glucose in venous and arterial

blood are similar in the fasting subject because periph-

eral tissues such as muscle, skin, and connective tissue

Glucagon

Insulin

Overflow to

urine

Islets

Blood

glucose

concentration

Insulin-

sensitive

valve

Glucose

Glucose precursors

Glycogen

Brain

RBC

Muscle

Adipose tissue

Fibrous tissue, etc.

Glucose

precursors

from tissues

Liver

Glucose from gut

via portal vein

fig0001 Figure 1 Schematic representation of blood glucose concentration and its relationship to the body glucose pool. The central system

represents the hypothetical glucose pool, the actual size of which is represented by the horizontal axis, i.e., volume of distribution

multiplied by blood (and extracellular fluid) glucose concentration. The postulated homeostatic switch is the cells of the endocrine

pancreas that respond to blood glucose concentration modulated by hormonal and neural factors, themselves controlled by messages

received from the gut (enteroinsular axis) and the autonomic nervous system. RBC, red blood cells.

2912 GLUCOSE/Maintenance of Blood Glucose Level

do not extract significant amounts of glucose from the

blood under these circumstances. In the recently fed

subject, however, glucose uptake by peripheral tissues

increases markedly under the influence of insulin re-

leased in response to the ingestion of a meal. This can

produce a difference in arterial and venous blood glu-

cose concentrations of 2 mmol l

1

or more.

0010 This fact, known for more than 80 years, is still

often forgotten or ignored by both experimentalists

and clinicians. It not only has implications as regards

our understanding of the physiology of glucose

homeostasis, but sometimes has unfortunate conse-

quences for patients who may, if only venous blood is

sampled, be misdiagnosed as suffering from hypogly-

cemia (i.e., blood glucose < 3.0 mmol l

1

) when it is

not really present. It is, after all, arterial, and not

venous blood glucose, that is homeostatically con-

trolled and relevant to brain physiology.

0011 Venous blood is much easier to obtain than arterial

blood and explains why, despite its theoretical and

practical disadvantages, it is so often used in studies

of glucose homeostasis and clinical practice. Finger-

prick or earlobe-capillary blood accurately reflects ar-

terial blood glucose levels under most circumstances

but is more difficult to obtain in more than small

amounts. So-called arterialized venous blood collected

from heat-distended veins on the back of the hands can

often be used in studies of glucose homeostasis when

collection of arterial blood would not be ethical.

0012 Blood glucose concentrations generally lie within the

range 3.5–6.0 mmol l

1

in healthy fasting adult sub-

jects and seldom rise above 11 mmol l

1

in arterial, or

10 mmol l

1

in venous blood, even after a large carbo-

hydrate-rich meal. Glucose and other simple sugars

given in solution produce greater rises in blood glucose

than equal or larger amounts of glucose-yielding carbo-

hydrate taken as part of a solid mixed meal. Con-

versely, prolonged starvation for as long as several

weeks rarely causes the blood glucose concentration

to fall below 3 mmol l

1

, except in children and adults

with impaired gluconeogenesis.

0013 The remarkable ability of the body to regulate the

size of the glucose pool under such widely diverse

conditions depends mainly upon two organs – the

liver and the pancreas – although during prolonged

starvation, the kidneys become important generators

of new glucose molecules.

Effects of Feeding on Blood Glucose

Glucose

0014 Glucose and the two lesser dietary monosaccharides –

fructose and galactose – enter the circulation through

the intestinal mucosa. The speed with which they can

be absorbed is limited by the rate of transfer from the

intestine but rarely exceeds 50 g (0.28 mol) of carbo-

hydrate, as glucose, per hour. This comparatively

massive influx of glucose into a pool of *20 g ordin-

arily produces a remarkably small perturbation in

blood glucose, as the rate of removal from the glucose

pool rises to match glucose input.

0015In healthy people, arterial blood glucose concen-

trations generally return to fasting levels within 2 h of

eating a carbohydrate-rich meal. This remarkable feat

of homeostasis is achieved through the prompt, but

appropriate, release of insulin into the circulation.

This is a consequence of stimulation of pancreatic

B cells (the source of insulin) by a rising arterial

blood glucose concentration augmented by nervous

impulses originating in the brain (cephalic phase),

mouth, gut wall, and portal vein, as well as the

insulinotropic hormones, GIP and GLP-1, released

by endocrine cells in the intestinal mucosa.

0016Under the influence of the insulinemia so produced,

hyperglycemia resulting from glucose inflow from

the gut and a reduction in glucagon secretion, the

liver reduces its rate of glucose input into the pool

and starts extracting it. Peripheral insulin-sensitive

tissues, such as connective tissue, skin, fat, and

especially striatal muscle start removing glucose.

As a result, the arterial blood glucose concentration

falls, and the stimulus to insulin secretion declines.

0017Ordinarily, the rates of change of glucose inflow

from the gut into the glucose pool and the outflow of

glucose into the tissues are so well aligned that arter-

ial blood glucose levels rarely fall below fasting levels

after a meal, and then only temporarily. Under the

somewhat unnatural conditions resulting from inges-

tion of large amounts of sugar in solution on an

empty stomach a ‘reactive hypoglycemia’ may result

from persistence of insulin action after plasma insulin

has fallen to basal levels and all of the glucose has

been absorbed from the gut. It may be, but usually is

not, sufficiently severe to produce (neuroglycopenic)

symptoms, even in perfectly healthy individuals.

Disposal of an Oral Glucose Load

0018The exact disposition of glucose absorbed from the

gut after a carbohydrate-rich meal by healthy subjects

varies widely from individual to individual, and

depends on the size, composition, and physical nature

of the meal.

0019All in all, some 70% of a 70-g oral glucose load is

taken up by the peripheral tissues, where most of it is

used, within 4 h of ingestion, to generate energy by

oxidation to carbon dioxide and water. The remaining

30% is removed by the liver during its passage from

the gut to the periphery and converted into glycogen,

triglycerides, or other metabolites.

GLUCOSE/Maintenance of Blood Glucose Level 2913

0020 Volunteers given a meal consisting of glucose

(1 gram per kilogram of bodyweight) as a 45% solu-

tion on an empty stomach reduced their normal basal

release of glucose from preformed glycogen in the

liver from 9 g h

1

to about 2.2 g h

1

, i.e., by about

75%. This persisted for a period (*3 h), during

which glucose was being absorbed from the gut. In

other words, although there is a small net uptake of

glucose by the liver following a carbohydrate-rich

meal, the liberation of glucose from preformed

glycogen does not cease completely. Put differently,

glycogenolysis and gluconeogenesis take place simul-

taneously though at different rates, depending on

whether glucose is or is not being absorbed, as well

as on the amount and nature of the hormones released

by the pancreas and intestine in response to the

presence of food.

Fructose and Galactose

0021 Galactose and fructose are absorbed from the gut by

different mechanisms from one another: galactose

shares a transporter mechanism with glucose, whereas

fructose has a less efficient one of its own. Once in the

portal circulation, both sugars are rapidly taken up by

the liver and largely converted into glycogen. This,

together with glycogen formed from glucose, provides

a small store of carbohydrate that is released as glucose

into the body pool during the period when absorption

from the gut is no longer occurring, and gluconeogen-

esis has not yet become fully reestablished.

0022 Starches and their hydrolytic products are con-

verted enzymatically into glucose in the gut lumen

and brush border of the mucosa at a rate dependent

upon their exact composition. Some starches are

absorbed as rapidly as performed glucose, whereas

others are absorbed much more slowly. Sucrose is

cleaved into glucose and fructose, and lactose into

glucose and galactose, before absorption into the

body. Intraluminal hydrolysis is rarely a factor in

limiting the rate of absorption of simple sugars.

Each moiety is dealt with separately.

Postabsorptive Stage

0023 The exact duration of the absorptive phase that follows

ingestion of a meal depends on many factors. These

include the rate of gastric emptying as well as the size,

composition and physical nature of the food. It is un-

likely, however, that an average adult eating three

meals a day is truly postabsorptive, i.e., absorbing no

glucose at all through the intestinal mucosa, for more

than a few hours in any 24-h period, and this is mainly

between 02.00 and 08.00. During this brief fasting

period, glucose lost from the glucose pool by a constant

drain into the brain and erythron is replaced by glucose

from the liver. This is derived either from reserves of

glycogen built up during the absorptive phase of a meal

or from new glucose molecules formed from glucose

precursors such as lactate, pyruvate, glycerol, and ala-

nine, brought to it in the blood from peripheral tissues.

Gluconeogenesis increases under the influence of rising

levels of glucagon and fatty acids, both of which are a

consequence of falling plasma insulin levels.

0024The amount of glycogen in the liver varies with

the nature of the diet, the size and composition of

the last meal, and its timing. The average amount of

glycogen in the liver after an overnight fast is about

44 g (range 15–80 g) and does not increase very much

after a meal; in other words, gluconeogenesis is al-

ready well under way within 12 h of eating the last

meal. Nevertheless, after 36 h without food, liver

glycogen stores may fall to as low as 4–8 g. Paradox-

ically, more prolonged fasting has little additional

effect: indeed, hepatic glycogen stores may actually

be replenished as the brain shifts from using glucose

to b-hydroxybutyrate as its main source of energy.

0025Glycogen probably never disappears from the liver

completely except in extremis, and there is evidence

that it may be an intermediary in the production of

glucose by the gluconeogenic pathway. Striatal

muscles lack glucose-6 phosphatase, and conse-

quently, although they contain substantial amounts

of glycogen, they cannot convert and release it into

the blood as glucose. They can, however, release its

main breakdown product, lactate, into the blood for

reconversion into glucose in the liver.

Gluconeogenesis

0026The mechanism whereby the liver and, to a smaller

but significant extent, the kidneys make new glucose

molecules from chemically simpler compounds is

referred to as ‘gluconeogenesis.’ Much attention has

been paid to the role of specific hormones, such as

glucagon and cortisol, and the enzymes they affect, in

determining the rate of gluconeogenesis. The supply

of glucose precursors is also important. In humans,

lactate is probably the most important precursor,

especially during exercise. Others, in descending

order of importance, are alanine, pyruvate, glycerol,

and, finally, some glucogenic amino acids, including

glutamate. The last named is especially important

in gluconeogenesis in the kidney. Fatty acids, apart

from propionate, do not serve as glucose precursors

to any significant degree.

0027The contribution made by alanine to gluconeogen-

esis may have been exaggerated in the past, though it

does have a role in transporting three-carbon skel-

etons derived from muscle glycogen to the liver

2914 GLUCOSE/Maintenance of Blood Glucose Level

during fasting for conversion into glucose. It is also

formed from amino acids released by proteolysis of

nonstructural muscle proteins during periods of pro-

longed fasting and starvation.

0028 Gluconegenesis is inhibited by eating, mainly

through an increase in insulin, and a decrease in

glucagon, action. It is enhanced by fasting, probably

by the reverse procedure. Alcohol specifically inhibits

gluconeogenesis, from lactate but not alanine, by ad-

versely changing the redox potential within the hepa-

tocytes and reducing the availability of nicotinamide

adenine dinucleotide (NAD), which is an essential

component in the formation of glucose from lactate

but not, for example, from other sugars. The inhib-

ition of gluconeogenesis by modest amounts of alco-

hol can be so profound that severe hypoglycemia may

develop in fasting subjects, especially children, who

are totally dependent upon gluconeogenesis for

glucose needed by their brain and erythron.

Hormones and Glucose Homeostasis

0029 Insulin is the only major hormone capable of

lowering blood glucose levels. It does so by inhibiting

glycogen breakdown in the liver and inhibiting gluco-

neogenesis and by encouraging glucose to leave the

glucose pool by entering peripheral tissues. It achieves

this mainly by activating the glucose transporter

protein GLUT 4: an action that is enhanced by exer-

cise and hyperglycemia. Consequently, insulin lowers

blood glucose by two independent mechanisms.

Which of the two actions predominates depends

upon the circumstances: one of the most important

is the concentration of insulin in the blood; another is

whether it is of exogenous or endogenous (pancreatic)

origin. Exogenous insulin reaches peripheral tissues

at a concentration in blood greater than in blood

perfusing the liver and is unaccompanied by C-

peptide. Endogenous insulin, however, reaches the

liver at a higher concentration than peripheral tissues

and is accompanied by C-peptide, for which there is

increasing evidence of synergism with insulin action.

0030 Insulin released into the portal circulation is par-

tially or completely removed by the liver. Insulin

injected into skin, muscle, or a vein reaches insulin-

sensitive tissues in the periphery at a concentration

equal to, or greater than, the liver. Not all tissues on

which insulin acts are equally sensitive to its actions:

fat cells, for example, are more sensitive to its anti-

lipolytic actions than muscle cells are to its glucose

uptake-stimulating properties.

0031 At the concentration at which insulin normally

circulates in the peripheral blood of fasting subjects

(*30 pmol l

1

), it depresses, but does not completely

suppress, the unbridled release of fatty acids from

lipocytes. At this concentration, insulin does not

encourage glucose uptake by striatal muscle – which

falls almost to zero. At insulin concentrations seen in

peripheral blood in the absorptive phase of a meal

(*150–600 pmol l

1

), its effect on peripheral glucose

uptake is pronounced and responsible for the marked

arteriovenous glucose difference observed at this

time. Similar plasma insulin levels are achieved

during insulin therapy for diabetes.

0032The release of insulin from the B cells of the pan-

creatic islets is highly dependent upon the concentra-

tion of glucose in the blood perfusing them. At blood

glucose levels below about 3.5–4.0 mmol l

1

, insulin

secretion is minimal. This means that as the arterial

blood glucose falls towards its basal level in the post-

absorptive state, plasma insulin levels also fall. They

never fall low enough, however, in the nondiabetic

subject to permit uncontrolled liberation of glucose

by the liver or fatty acids by adipocytes. This does of

course happen when the B cells are destroyed and

results in gross hyperglycemia and ketosis, which

are the hallmark of insulin-dependent diabetes.

0033During prolonged starvation (20 days or more

without food), small amounts of insulin reach the

liver. The amounts reaching the adipocytes are,

however, insufficient to prevent seemingly un-

controlled lipolysis leading to hyperketonemia com-

parable with that seen in diabetic keto-acidosis

(*10–20 mmol l

1

). The situation differs, however,

from that obtained in diabetes, in that the restraining

effect of insulin on hepatic gluconeogenesis and

glycogenolysis remains. Consequently, blood glucose

levels are normal rather than grossly elevated as in

insulin deficiency resulting from B cell malfunction.

0034A consequence of the reduction of insulin release as

blood glucose levels fall after absorption of a meal is

liberation of the A cells, which are ‘downstream’ of

B cells in the islet, from the suppressive effect of

(endogenous) insulin on their own release of gluca-

gon. On reaching its target organ, glucagon promotes

glycogenolysis and gluconeogenesis in the liver, in

effect reversing the effect of insulin during the absorp-

tive phase. In other words, each islet functions as a

miniature homeostat.

Counterregulatory Hormones

0035Whilst it is possible to explain the control of blood

glucose largely by means of the servoregulatory

control of insulin and glucagon secretion described

above, the body also has many neural and hormonal

mechanisms at its disposal to correct or overcome any

fall in blood glucose to below the critical level neces-

sary for the maintenance of normal brain function.

The sensors for this regulatory function are located in

at least two anatomically distinct sites within the

brain and in the portal vein itself.

GLUCOSE/Maintenance of Blood Glucose Level 2915

0036 The most important mechanisms involved are:

0037 stimulation of the sympathetic and parasympa-

thetic nervous systems, which in turn lead, respect-

ively, to release of adrenaline from the adrenal

medula and noradrenaline from nerve terminals in

the liver, and glucagon from the pancreas;

0038 secretion of vasopressin by the posterior pituitary

gland; adrenocorticotrophic hormone (ACTH),

growth hormone, and prolactin by the anterior

pituitary gland; and cortisol by the adrenal

cortex.

0039 None of these hormones, apart from cortisol,

appears to be absolutely essential individually for

the maintenance of normal glucose homeostasis, but

all are brought into play under adverse conditions.

They produce their hyperglycemic effects in a variety

of ways that can be summarized as follows:

0040 Increasing the liberation of glucose by the break-

down of preformed glycogen in the liver, e.g.,

glucagon, adrenaline, noradrenaline, vasopressin.

0041 Increasing gluconeogenesis in the liver, e.g., gluca-

gon, cortisol.

0042 Decreasing peripheral glucose utilization by

peripheral tissues, e.g., growth hormone, cortisol,

and prolactin.

Glycosuria

0043 Upwards of 100 g of glucose are normally filtered

from the blood at the glomeruli of the kidneys each

day, more than 99% of which is reabsorbed by the

kidney tubules. As a result, healthy people lose less

than 150 mg of glucose in their urine each day, an

amount too small to be detected by most simple

screening procedures for glycosuria. When, for any

reason, the amount of glucose filtered at a glomerulus

is more than can be reabsorbed by the tubules,

glucose appears in the urine at a concentration

many times greater than it occurs in blood.

0044 The commonest cause of significant glucosuria,

i.e., the presence of glucose in the urine at a concen-

tration greater than 0.15 g l

1

(0.8 mmol l

1

)isa

blood glucose concentration of 10 mmol l

1

or more.

At or above this concentration, the amount of glucose

filtered at the glomerulus is more than its associated

kidney tubule can transport back into the circulation.

Once this reabsorptive threshold has been exceeded,

any increase in filtered glucose load is reflected by a

large increase in the amount of glucose eliminated in

the urine. The osmotic diuresis so produced is associ-

ated with an increased excretion of water, sodium,

chloride, and potassium and is often the first clue to

the existence of hyperglycemia, the characteristic

hallmark of diabetes.

0045Glycosuria can occur at normal blood glucose

levels when, for example, blood flow through the

glomerulus is increased, such as during pregnancy or

when, owing to either an inherited or acquired defect

of renal tubular glucose transport, even the normal

amount of glucose filtered at the glomerulus cannot be

reabsorbed. Conversely, in people in whom blood flow

through the glomeruli is reduced or in whom glomeru-

lar filtration is impaired, but in whom normal tubular

glucose reabsorption is retained, even gross hypergly-

cemia may not be accompanied by glycosuria.

0046Fructose and galactose do not normally appear in

urine since their concentration in blood is never suffi-

ciently high – except in disease – for them to do so.

See also: Carbohydrates: Metabolism of Sugars;

Diabetes Mellitus: Etiology; Chemical Pathology;

Fructose; Galactose; Glucose: Properties and Analysis;

Function and Metabolism; Maintenance of Blood Glucose

Level; Glucose Tolerance and the Glycemic (Glycaemic)

Index; Glycogen