Site author Richard Steane
The BioTopics website gives access to interactive resource material, developed to support the
learning and teaching of Biology at a variety of levels.
Control of blood glucose concentration
On the right side of the page are several links to interactive 3-dimensional molecule files on this website
Glucose is fuel - so it must not run out
Glucose is the body's main respiratory substrate. It is dissolved in the blood plasma and tissue fluid which bathes all the cells of the body. It is often called blood sugar. Cells absorb and use glucose throughout the daily cycle, so the concentration of glucose in the plasma falls gradually.
The concentration of glucose in the blood plasma is increased when (carbohydrate-containing) food is eaten and digested, and the body needs to convert surplus glucose into other compounds which it can store.
And of course at a later stage the body needs to break down these stored compounds and possibly other compounds to provide glucose.
The regulation of glucose concentration in the body is usually controlled by hormones which circulate within the blood and interact with cells of the body with specific receptors on their surface.
There are three main hormones involved, each dealing with a different aspect of control of blood glucose concentration.
Inside the cells, different enzyme systems are then activated to cause certain biochemical reactions to occur.
It is important to stress the role of activation of enzymes between the hormones and the processes they initiate.
The maintenance of a stable concentration of glucose in the blood is an important aspect of homeostasis.
Glucose is constantly needed to produce ATP and provide energy within cells, and it also contributes to the osmolarity of blood and body fluids on the outside of the cells. In order to control the water potential of blood, the glucose concentration must be kept within limits.
Any departures from the normal composition of blood will affect the metabolism of cells, as well as causing cells to gain or lose water and so vary in size due to osmosis as a result of variations in the water potential of blood.
Several G words
I make no apology for transplanting this bit from my unit on Skeletal Muscle (and adding two more)
Glyco- means sugar, and more specifically glucose and its derivatives.
-gen and -genesis mean producer and production
so glycogen produces glucose when broken down
-lysis means the process of breaking down
-neo- means new
Glycogen is a polysaccharide consisting of a variable number of glucose units - up to 30,000.
The process of glycogen synthesis is called glycogenesis. Glucose molecules are added to the free ends of the radiating polysaccharide chains of glycogen for storage.
Glycogenolysis is the breakdown of glycogen, removing glucose units at the tips of polysaccharide branches linked by alpha 1-4 glycosidic bonds and producing glucose 1-phosphate (and a slightly smaller glycogen molecule). This is done by substitution of a phosphoryl group for the α 1-4 linkage.
Gluconeogenesis is the formation of glucose from other (non carbohydrate) compounds, such as glycerol and amino acids, but also pyruvate and lactate formed in different stages of respiration.
Glycolysis is the breakdown of glucose (by several stages) into pyruvate, releasing energy by the production of 2 molecules of ATP, and it can lead to other compounds via anaerobi or aerobic respiration.
Not a process, not a carbohydrate, but a hormone:
Glucagon - named from 'glucose agonist' — initiating a physiological response leading to the release of glucose.
Measuring the concentration of glucose in blood
It is best not to refer to glucose 'level'
Glucose concentration in blood may be expressed either as (milli)molarity - units mmol/L - or as (milli)grams per 100 millilitres - units mg/dL.
1 mmol/L of glucose is equivalent to 18 mg/dL.
The normal range of blood glucose is between 4.0 to 5.9 mmol/L (72 to 106 mg/dL) before meals or 4.0 to 5.4 mmol/L (72 to 97 mg/dL) when fasting (after at least 8 hours of fasting - usually taken in the morning).
After a meal it may rise - perhaps up to 7.8 mmol/L (140 mg/dL) 2 hours after eating.
People who suffer from diabetes (type 1 or 2) may have higher blood glucose concentrations - up to 9 or 8.5 mmol/L (153-162 mg/dL) after meals. See below
Deviations from the normal range have a number of consequences for health.
is blood glucose concentration below 3.9 mmol/L (70 mg/dL).
is blood glucose concentration above 10 mmol/L (180 mg/dL).
is normal blood glucose concentration.
But how much glucose is that in the body?
From the concentration mentioned above, a simple calculation reveals the interesting fact that the average human has only 4-5 grams of glucose dissolved in the blood circulating around the body.
For comparison, a standard serving of breakfast cereal is about 25 grams of carbohydrate.
The body normally has backup stores of glucose in the form of the polysaccharide glycogen: typically 100g in the liver, and 400g in muscles.
Obviously this will be reduced when the body undergoes exercise, and increased slightly after meals.
Over a 24-hour cycle there is clearly quite a dynamic interchange of glucose between various organs of the body, and blood functions to transport and transfer it.
The brain requires 120 g of glucose per day, which is 60% of the whole body's glucose utilisation when at rest.
Another dietary comparison: Guideline Daily Amounts for carbohydrates are 230-300 g.
Storage of surplus glucose
We do not normally ingest glucose directly. However most meals contain a component which is mainly starch: a polymer of glucose. Examples include rice, bread, and potatoes.
Starch is digested by amylase to give maltose and then the action of maltase results in glucose which is absorbed into the bloodstream.
Other sugars: sucrose, fructose etc in fruits and sweetened drinks are also converted into glucose by hydrolysis and isomerisation.
A small section of a starch molecule
This is a model of amylopectin, a branching molecule which makes up much of starch.
This section is made up from 84 glucose units (see right
) although in reality a single starch molecule may consist of 100,000 - 200,000 glucose residues
The body's blood glucose concentration is effectively monitored by the cells of the islets of Langerhans in the pancreas.
When this rises, beta cells in the islets release insulin into the blood stream. If the blood glucose concentration continues to rise, more insulin is released.
Insulin in the blood affects (target) cells whose membrane contains insulin receptor molecules. This happens in a number of organs of the body, notably the liver, and muscle. It also occurs in adipose tissue (fat) and brain tissue as well as bone cells - osteoblasts.
Insulin increases the uptake of glucose from the blood and into the target cells. This is achieved by stimulating the inclusion of channel proteins ( such as the glucose transporter channel protein GLUT 4) in the cell membrane, so that glucose enters the cells by facilitated diffusion.
Attachment of insulin to receptors on the cell surface activates several enzyme systems inside the cell.
When it has entered the cells, glucose is converted by kinase enzymes (hexokinase in most cells or glucokinase in liver cells) into a phosphorylated form: glucose 6-phosphate, taking phosphate groups from ATP.
This conversion creates a concentration gradient which causes glucose to diffuse into the cell. Glucose phosphate cannot pass through the cell membrane so it stays within the cell.
All at sea in the pancreas
In 1869 German pathological anatomist Paul Langerhans identified distinct patches of different tissue
within the pancreas.
He called them islets
and later the term insulin (from the Latin insula
- an island) was coined in 1921 to describe the substance they produce.
In the liver and muscles glucose is converted into glycogen, which is effectively a polymer of glucose. This process is called glycogenesis. In ordinary cells glucose phosphate enters the glycolysis pathway and is used in respiration for the release of energy.
Together with action inside the liver, this has the effect of lowering the blood glucose concentration (and this affects the beta cells in the Islets of Langerhans which respond by reducing the production of insulin).
Consequently when insulin receptors are no longer occupied, the glucose transporters are removed from the plasma membranes and recycled back into vesicles in the cytoplasm (ready for reuse).
More molecular detail
Glycogen is a variable molecule: a large polymer with a branching 3-dimensional structure.
A small section of a glycogen molecule
This shows 40 glucose units, forming a gentle helical structure, with 2 branches
Click here to interact with this 3-D model of
The Glycogen molecule
In fact glucose is not simply turned into glycogen, but really it is added to the ends of strands of glucose residues within glycogen that is already present.
Several enzymes are involved: glycogenin
, glycogen synthase
and a glycogen branching enzyme
Schematic two-dimensional cross-sectional view of glycogen
In the centre is a core protein of glycogenin, surrounded by branches of glucose units.
The entire globular granule may contain around 30,000 glucose units or more.
By Mikael Häggström, used with permission
Getting more glucose back into the bloodstream
Do not confuse glucagon with glycogen
The body's blood glucose concentration is monitored continuously by the cells of the islets of Langerhans in the pancreas. When this falls below normal, alpha cells
within the islets release the hormone glucagon
into the blood stream. This has the opposite effect to insulin.
The blood glucose concentration can be raised or topped up by one or two processes, each of which is controlled by enzymes which are activated as a result of the binding of glucagon with receptors on target cell membranes - mostly liver cells. This binding brings about a chain of reactions inside the cells. This interaction is called the second messenger model
Glucagon is a polypeptide hormone
Glucagon consists of 29 amino acids, and forms a simple alpha helix
Click here for more information about the
3-dimensional structure of Glucagon
The main process involves the release of glucose from its storage product, glycogen, in liver and muscles.
This process is called glycogenolysis.
Alteratively, glucose can be synthesised from non-carbohydrate sources. This process - gluconeogenesis - may take glycerol or amino acids and feed them and products derived from them into reaction pathways within the cell - effectively reversing the Krebs cycle and glycolysis - and so producing glucose.
As a result of the action of glucagon, glucose is exported from the cell and into the bloodstream, restoring the blood glucose concentration to normal.
More details, more enzymes
In the second messenger model (more details below), the enzyme protein kinase A is activated and this in turn activates other enzyme systems.
The principal enzyme involved in glycogenolysis is glycogen phosphorylase which is itself activated by being phosphorylated.
This breaks the bond linking a terminal glucose residue to a glycogen branch.
It does this by splitting the α(1→4) linkage, substituting it with a phosphoryl group and producing glucose 1-phosphate, which can be converted by another enzyme phosphoglucomutase into glucose 6-phosphate.
In muscle cells this can quickly enter the glycolysis pathway causing the release of ATP to power muscle contraction. In aerobic conditions this can lead to the Krebs cycle which produces more ATP.
In liver cells glucose 6-phosphate is converted into glucose by the enzyme glucose-6-phosphatase, and it leaves the cell by facilitated diffusion via GLUT2 channels.
Gluconeogenesis is stimulated by activation of the enzyme PEP carboxykinase
which converts oxaloacetate into phosphoenolpyruvate and carbon dioxide, turning a 4-carbon compound into a 3-carbon compound (decarboxylation). By the reverse of glycolysis, PEP can be built up into glucose.
Summary of activity of insulin and glucagon
Both of these hormones act as control mechanisms for blood glucose concentration. Each operates a negative feedback loop which opposes any departure from the normal concentration of glucose in the blood, thus bringing it back to the original value.
It is called negative feedback
because a departure from the normal blood glucose concentration (i.e. it moving up or down) results in an action which has the opposite effect, i.e. reversing any change.
Here it can be seen that there are two separate mechanisms, each involving negative feedback controlling departures in different directions from the original state, giving a degree of control.
Insulin and Glucagon Degradation
Insulin normally has a half-life of 4-6 minutes in the blood system, meaning that it is quite quickly removed from circulation, by binding with cell surface receptors as described above.
After activation of enzymes which cause glucose uptake and glycogenesis, insulin may be released back into the circulation, or it may be taken into the cells (together with the insulin receptor) and incorporated into vesicles called endosomes where it is broken down by enzyme action.
Insulin degrading enzyme (IDE) is particularly active in liver and kidney cells.
Glucagon also has a short half life in the blood : 5-6 minutes. It is degraded by the enzyme dipeptidyl peptidase in the kidneys. This removes 2 amino acids from the amino end of the molecule, leaving a 27- and then a 25-amino acid polypeptide which are less active than glucagon.
Greater activity needs more glucose
If an animal is suddenly exposed to an unexpected situation, it needs to respond quickly.
The term fight or flight
is often used to describe the response in these situations.
Many parts of the body are involved and several chemical substances are used to control them.
The location of the adrenal glands
Image source U.S. Department of Health and Human Services
The principal compound is the hormone adrenalin(e)
, produced in the adrenal medulla.
Like glucagon, adrenaline binds with receptors on target cell membranes, mostly liver cells, bringing about a chain of reactions inside the cells resulting in glycogenolysis and releasing glucose. This interaction also involves a second messenger
Two or more naming systems
Adrenaline - an
amino acid-derived hormone
The adrenaline molecule is smaller than the other examples.
Click here for the interactive 3D structure of the adrenaline molecule
Adrenaline is a catecholamine
. It is derived from tyrosine and tryptophan.
The name adrenaline has Latin roots: ad
means nearby, and rena
means kidney - so the this gives the name to the adrenal glands situated on top of the kidneys. Adrenal glands have an outer cortex layer
and an inner medulla. Adrenaline is produced by cells within the medulla, and it passes out in to the blood circulation so that it quickly has effects on most of the body.
Adrenaline has an alternative name: epinephrine - based on Greek roots: epi
means above and nephros
In the UK the term adrenaline is more commonplace; in the USA epinephine is used more.
There is another related compound noradrenaline - norepinephine
- which functions as a neurotransmitter. Synapses responding to this are generally decribed as adrenergic.
EpiPens contain adrenaline for use in anaphylaxis
Some people carry these automatic injectors for use if they suffer an allergic reaction such as to food ingredients, possibly peanuts and other snack ingredients.
[This action is not related to control of blood sugar]
The second messenger model
The hormones glucagon and adrenaline bind to (different) receptors on the surface membrane of target cells. Each of these hormones acts as a first messenger
, causing the cell to carry out the processes of glycogenolysis and/or gluconeogenesis.
Within the cell a number of changes take place, leading to the enzyme adenylate cyclase
converting ATP into cyclic AMP (cAMP)
which is the second messenger
and this activates the enzyme protein kinase.
This causes a cascade of reactions activating enzymes controlling the required processes within the cells.
The first messenger hormone does not need to enter the cell
to do this.
One P thing leads to another
The glucagon receptor, in the plasma membrane, is a 'G protein-coupled' receptor. This is so called because it can have the nucleoside phosphates GDP or GTP - (the equivalent of ADP and ATP in energy/phosphate group transfer) - attached to one of its subunits.
Binding of glucagon - the first messenger - with the receptor on the outside of the target cell membrane causes the G protein to change conformation and release its α subunit with attached GTP, which moves within the phospholipid bilayer of the plasma membrane and then activates the enzyme adenylate cyclase which is also in the plasma membrane, but facing inwards.
Adenylate cyclase acts on ATP to produce cyclic AMP, which acts a second messenger and moves into the cytoplasm where it activates protein kinase A (cAMP-dependent protein kinase).
This activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b, turning it into the active a form which causes the release of glucose-1-phosphate from the tips of glycosidic chains projecting out from glycogen.
If the blood glucose concentration is not controlled by hormones as described above, a condition known as diabetes mellitus
is usually the cause.
- excessive urination
- weight loss
- blurred vision
- poor healing to everyday wounds
- repeated thrush infections
(Long Term) Effects on the body
The main effects of elevated blood glucose are on the circulatory system.
Endothelial (lining) cells are adversely affected.
Blood flow may be reduced due to atherosclerosis - 'hardening of the arteries' - caused by plaque formation from cholesterol and other lipids, which over time reduces arterial diameter.
Excess glucose also causes reduced production of nitric oxide which is involved in vasodilation, so raised blood pressure may result.
This may especially affect the cells at the back of the eye (retinopathy) causing impairment of vision, possibly leading to blindness.
It may also affect the kidneys (nephropathy) leading to end-stage renal failure and nerves, especially in the extremities (peripheral neuropathy).
It is also implicated in coronary artery disease causing angina and possibly heart attacks.
There are actually two fairly distinct forms of diabetes mellitus: type 1 and type 2.
When blood sugar concentration is higher than normal, the body (wastefully) excretes excess glucose in the urine. There is normally no glucose in urine, so testing for the presence of glucose in the urine serves as a simple test to diagnose diabetes.
(See the 'required practical' material at the bottom of the web references below.
These are specific for glucose, unlike other chemical tests e.g. Benedict's which test for reducing sugars.
Originally released in 1956, this 'dip-and-read' test strip uses two enzymes: glucose oxidase
, dried onto the paper pad at the end of the stick.
Glucose oxidase oxidises only glucose (and no other sugar) to yield gluconic acid and hydrogen peroxide. Peroxidase, together with a coloured dye (chromagen) gives a colour change which can be compared with a chart, or a label.
There is yet another (fairly uncommon) condition causing excessive production of urine and consequently thirst, but it is not associated with carbohydrate metabolism. This condition - diabetes insipidus - is caused by a failure in osmoregulation.
Normally the hormone ADH - antidiuretic hormone - also known as (arginine) vasopressin - AVP - is produced in the hypothalamus and released from the posterior pituitary gland in response to a decrease in the water potential of blood plasma. This circulates in the blood and it affects cells in the epithelium of the collecting ducts and distal convoluted tubules in the kidney. These respond by incorporating the channel protein aquaporin into the cell membrane, increasing the reuptake of water into the blood by osmosis.
However if the production of ADH fails or if there is an absence of ADH receptors in the tubules, water will not be reabsorbed, and a much greater than normal amount of urine (perhaps 20 litres per day) is produced.
Type 1 diabetes
In type 1 diabetes the body does not produce enough insulin in response to increases in glucose concentration after a meal (or sugary sweets).
As a result, the blood glucose concentration may quickly become too high, then when the excess glucose has been used by the body it may fall to too low, and continue to fall quite quickly.
This is because the liver has not not been able to store the surplus (and remove it from the circulation), so there is no reserve to call on later when the glucose concentration falls.
It can be controlled by regular injections of insulin. This must be accompanied by regular testing of blood glucose concentration in order to vary the timing and dosage of insulin.
Treatment also focuses on managing diet and lifestyle to prevent complications.
Type 1 diabetes is caused by destruction of pancreatic β-cells by the body's own immune system (an autoimmune disease).
It is sometimes known as juvenile onset diabetes because it usually appears during childhood or adolescence, but it can develop in adults.
It afflicts 10 million people worldwide.
Blood testing - instant results
Diabetics can test their blood glucose concentration fairly conveniently using a small meter and test strips.
They must get a drop of blood using a small sharp lancet and put that on a plastic strip that is then plugged into the meter.
Again this uses the enzyme glucose oxidase but the electronics detect the concentration of gluconic acid, not hydrogen peroxide.
They generally give a direct digital readout of results.
Oral glucose tolerance test
This test is used to determine whether a person has difficulty metabolising glucose.
They must fast for 8-12 hours before the test.
At the clinic, a small blood sample is taken and tested to give an initial reading for glucose concentration.
They are asked to take a (rather strong) glucose drink containing 75 grams of glucose and their blood glucose is measured again at intervals.
The 2-hour reading is the most useful.
| At 2 hours
Values between these are generally taken to indicate impaired glucose tolerance (IGT) which is associated with insulin resistance and it may precede type 2 diabetes mellitus.
Type 2 diabetes
In type 2 diabetes the insulin receptors become unresponsive
It may be called insulin-resistant or adult-onset diabetes. It is especially associated with obesity, and is more prominent in certain racial groups.
It can be controlled by manipulating the diet - particularly reducing the intake of sweet and starchy foods, and 'portion control'.
There are about 9 times as many sufferers from type 2 diabetes compared to type 1.
Not just hype
Sufferers of type 1 diabetes may have hypoglycaemia (low blood sugar) from time to time, and experience an event called a 'hypo'.
Most common symptoms:
- trembling and feeling shaky
- being anxious or irritable
- going pale
- palpitations and a fast pulse
- lips feeling tingly
- blurred sight
- being hungry
- feeling tearful
- having a headache
- lack of concentration.
This may be caused by taking too much insulin (or other diabetic medications), missing a meal or reducing carbohydrate intake and even indulging in extra exercise.
If caught early, it can be quickly reversed by taking sugary snacks or drinks. If the sufferer becomes unconscious or very drowsy glucagon may be administered (by injection).
Hyperglycaemia (high blood sugar concentration) is a common problem for people with diabetes - both type 1 diabetes and type 2 diabetes.
Symptoms are as listed above, and are generally dealt with by changes in diet, exercise and adjustment to dosage of insulin.
More serious consequences
With type 1 diabetes, lack of insulin can lead to diabetic ketoacidosis (DKA) which may cause critical events such as a diabetic coma.
This is caused by the body needing to break down fat as a source of energy, and producing ketones. This frequently causes breath to smell fruity, like pear drop sweets or nail varnish - acetone (propanone). Ketones can be tested for in blood or urine.
Hyperosmolar hyperglycaemic state (HHS) is a potentially life-threatening emergency that may occur in people with Type 2 diabetes
as a result of stopping diabetes medication (during illness?) or as an effect of other hormones.
Blood testing - the long term picture
Direct blood testing only produces a snapshot of the glucose concentration at one point in time. Prolonged exposure to excess glucose causes problems in the body so it is sometimes useful to monitor blood glucose concentration over a longer time scale.
The HbA1c test
Haemoglobin is an oxygen-carrying protein carried around the blood system inside red blood cells, which have a 'lifetime' of about 120 days. Haemoglobin reacts with glucose, and becomes 'glycated
'. This can therefore be used to give an estimate of the body's exposure to elevated glucose concentrations over the last 2-3 months. This is especially important with type 2 diabetes.
A blood sample is sent to a laboratory where the level of glycation can be measured, usually by high-performance liquid chromatography. Results are expressed in terms of the ratio of glycated to unglycated haemoglobin, so the units are sometimes given as mmol/mol. Alternatively there is a DCCT
scale expressed as a percentage.
HbA1c values below 48 mmol/mol (6.5 DCCT %) are generally recommended
Type 2 Diabetes control
In the treatment of type 2 diabetes, elevated concentrations of glucose in the blood can be avoided by the administration of drugs which prevent the reabsorption of glucose in the kidneys.
As a result, glucose passes into the urine and is excreted, rather than passing back into the blood.
[Curiously, (type 1) diabetes used to be detected on the basis of glucose in the urine!]
This molecule clearly consists of glucose combined with some bulky aromatic rings, which presumably block the SGLT2 sodium (ion) glucose cotransport channel in the primary convoluted tubules of the kidney.
It does not affect the SGLT1 cotransport channel which is responsible for the absorption of glucose in the ileum.
The impact of type 2 diabetes on healthcare
According to the NHS, around 3.5 million people in England now have Type 2 diabetes. It can cause personal suffering through its complications - it is a leading cause of sight loss and lower limb amputation, and can contribute to kidney failure, heart attack and stroke. Diabetes and its complications cost over £6 billion every year to treat and one in six patients in hospital now has diabetes.
The impact of the food industry on type 2 diabetes
The food industry clearly exists to produce and market food, especially processed food which is by and large acceptable to the majority of the public.
The amount produced by a number of retail chains is substantial and manufacturers are looking to extend their sales into developing countries.
There has been considerable concern about the ingredients used in a variety of food products and there are a number of pressure groups who recommend reductions in salt, sugar and saturated fat content and portion sizes of processed foods, with a view to reducing the trend towards obesity which inevitably leads to Type 2 diabetes. Some manufacturers have responded by creating 'lower calorie' versions and there has also been a call for more informative labelling of processed foods, e.g the 'traffic light system'.
Other related topics on this site
(also accessible from the drop-down menu above)
Control of blood water potential When glucose levels vary there are consequences for blood water potential: Scroll down to 'Reabsorption of glucose'
Interactive 3-D molecular graphic models on this site
(also accessible from the drop-down menu above)
Showing levels of protein structure
Natural and unnatural products compared
The salbutamol, terbutamine, adrenaline and triamcinolone molecules - rotatable in 3 dimensions
Metabolic patterns of body organs
'Each Organ Has a Unique Metabolic Profile' - Section 30.2 of
Biochemistry. 5th edition.(Berg JM, Tymoczko JL, Stryer L. New York: W H Freeman; 2002)
Physiologic Effects of Insulin
Functions of Cell Surface Receptors
Glycogenolysis and glycogenesis from Diapedia - an open-access, peer-reviewed, unbiased and up-to-date knowledge base about all aspects of Diabetes Mellitus
"Where name and image meet" - the argument for "adrenaline"
BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7233.506 (Published 19 February 2000) Those familiar with HTML will note that somehow the ampersand has been omitted from about 8 instances on the page
Blood Sugar Level Ranges from National Institute for Clinical Excellence (NICE) guidelines
Four grams of glucose
David H. Wasserman
Type 1 diabetes Everything you need to know, from the NHS
Type 2 diabetes from the Mayo Clinic
Type 2 diabetes and the importance of prevention NHS blog
Britons tell food manufacturers to cut fat, salt and sugar from their products from Diabetes UK
Preventing type 2 diabetes: Changing the food industry
Insulin Degradation: Progress and Potential
Dipeptidyl Peptidase IV (DPIV/CD26) Degradation of Glucagon
What is HbA1c?
Production of a dilution series of a glucose solution and use of colorimetric techniques to produce a calibration curve with which to identify the concentration of glucose in an unknown 'urine' sample.
One of the Biology practicals apparatus set-up guides produced by examination board AQA