Biology › Hormonal communication, plant responses and homeostasis › Blood glucose: two hormones, one liver, and two different diabetes
Blood glucose: two hormones, one liver, and two different diabetes
You have about a teaspoon of glucose dissolved in your whole blood volume, and you keep it within a factor of two of that all day, through meals, fasting and exercise. Two hormones from the same gland, pulling in opposite directions, are what hold it there.
Before this Negative feedback and antagonistic effectors · Adrenaline, cyclic AMP and the second messenger model
Before you start
Insulin converts glucose into glycogen. It is the sentence most students write, and every word of it is defensible except the verb. Insulin is a small protein circulating at picomolar concentrations; it never touches a glucose molecule. What it does is bind to receptors on liver, muscle and fat cells and change what those cells are doing — putting more glucose transporters into their membranes, activating the enzymes that build glycogen, and raising the rate of respiration. The conversion is done by enzymes inside the cell, and insulin is the signal that switches them on. Get the verb right and questions about insulin resistance, about injected insulin and about why type 2 diabetes exists at all become straightforward.
What you should be able to do
- State the normal blood glucose concentration and name the three places glucose in the blood comes from.
- Describe the effects of insulin and of glucagon, naming the cells that secrete each.
- Use glycogenesis, glycogenolysis and gluconeogenesis correctly.
- Describe how a beta cell secretes insulin, from glucose entering to vesicles fusing.
- Distinguish type 1 from type 2 diabetes by cause, and say how each is managed.
- Read a glucose tolerance test curve and justify a diagnosis from it.
What is being controlled, and why so tightly
Blood glucose sits at about 90 mg per 100 cm3, which is roughly 5 mmol per dm3, and a healthy person stays between about 4 and 6 between meals. Glucose reaches the blood by three routes: absorption from the gut after a meal, glycogenolysis in the liver, and gluconeogenesis, the making of glucose from non-carbohydrate sources such as amino acids, lactate and glycerol.
Both directions of error are dangerous, and for different reasons. Too low, and the brain is in trouble within minutes: nervous tissue respires glucose almost exclusively and stores none, so confusion, unconsciousness and death follow quickly. Too high, and the blood's water potential falls, water leaves cells by osmosis, and glucose appears in the urine because the kidney's carrier proteins are saturated — dragging water out with it and causing the thirst and constant urination that give diabetes its name.
Three words are used throughout this topic and they are easy to mix up. Learn them as a set, and notice that the middle syllables tell you which is which.
- Glycogenesis
- The synthesis of glycogen from glucose, in liver and muscle cells. Promoted by insulin.
- Glycogenolysis
- The hydrolysis of glycogen to glucose. Promoted by glucagon and by adrenaline.
- Gluconeogenesis
- The production of glucose from non-carbohydrate sources such as amino acids and glycerol, in the liver. Promoted by glucagon.
Two cell types in the same tissue
The islets of Langerhans are patches of endocrine tissue scattered through the pancreas, and each contains two kinds of cell that matter here. Beta cells, the larger group and mostly central in the islet, detect a rise in blood glucose and secrete insulin. Alpha cells, fewer and towards the edge, detect a fall and secrete glucagon. Both hormones go straight into the blood, and both find their main target in the liver.
Insulin lowers blood glucose in several ways at once. It binds to receptors on liver, muscle and adipose cells, and vesicles carrying glucose transporter proteins fuse with the cell surface membrane, so more glucose can enter by facilitated diffusion. It activates the enzymes of glycogenesis, so glucose entering the liver and muscle is stored as glycogen. It raises the rate of respiration of glucose, and it promotes the conversion of glucose into fat. At the same time it inhibits the alpha cells, so the opposing signal is switched off.
Glucagon raises blood glucose, and it acts on the liver alone. Binding to receptors on hepatocytes triggers the cyclic AMP cascade from the last lesson, glycogen phosphorylase is activated and glycogenolysis releases glucose, and the enzymes of gluconeogenesis are activated as well. Adrenaline produces the same two effects by the same second messenger, for a different reason.
Muscle glycogen is worth one sentence of its own. Muscle stores plenty of it, but a muscle cell cannot release free glucose back into the blood, so its glycogen is a private fuel supply for that muscle. When a question asks which organ raises blood glucose, the answer is the liver.
How a beta cell counts glucose
A beta cell has to convert a concentration in the blood outside it into a quantity of hormone released, and the mechanism it uses is unusually satisfying because every step is one you have met before. OCR A and CAIE both examine it directly; AQA asks for less detail, but the sequence is the clearest way to see why insulin release tracks glucose rather than switching on and off.
At rest, potassium channels in the beta cell membrane are open and potassium ions diffuse out, holding the inside at about −70 mV. When blood glucose rises, more glucose enters the cell through its transporter, is phosphorylated and respired, and the concentration of ATP in the cytoplasm rises.
ATP binds to the potassium channel and closes it. Potassium can no longer leave, so positive charge builds up inside and the membrane depolarises. The depolarisation opens voltage-gated calcium channels, calcium ions diffuse in, and — exactly as at a synapse — the calcium causes vesicles of insulin to fuse with the cell surface membrane and release their contents by exocytosis.
The elegance is in the middle. Because ATP is produced in proportion to how much glucose the cell is respiring, the amount of insulin secreted is graded to the concentration outside. The cell is not detecting glucose with a receptor at all; it is metabolising it and reading the answer off its own ATP.
Two diseases with one name
Diabetes mellitus is a persistently raised blood glucose concentration, and the two common forms have almost nothing in common except that symptom. Distinguish them by cause. Age is a tendency, not a definition, and answers that separate them as 'childhood' and 'adult' lose the mark now that type 2 is regularly diagnosed in teenagers and type 1 can begin at fifty.
| Type 1 | Type 2 | |
|---|---|---|
| Cause | Beta cells destroyed by the body's own immune system | Cells respond poorly to insulin; secretion may also fall |
| Insulin present? | Little or none produced | Produced, sometimes in excess, but the receptors respond weakly |
| Onset | Usually rapid, often in childhood or adolescence | Usually gradual, more often later in life |
| Risk factors | Genetic susceptibility; some viral triggers proposed | Obesity, especially around the abdomen; inactivity; diet; age; family history |
| Management | Insulin injections matched to meals and exercise | Diet, weight loss and exercise first; drugs; sometimes insulin |
| Diet alone? | Never sufficient | Often sufficient at first |
Two points about treatment are worth having ready. Insulin has to be injected because it is a protein, and a protein swallowed is hydrolysed by proteases in the stomach and small intestine into amino acids that do nothing. And an injection is a blunt instrument next to a pancreas: a beta cell adjusts its secretion second by second, while an injection commits to a dose in advance, which is why matching insulin to meals and exercise takes so much of a diabetic person's attention.
Type 2 is where the misconception in the opening does real damage. If insulin converted glucose into glycogen directly, insulin resistance would make no sense. Because insulin is a signal, a cell can have plenty of the hormone around it and still fail to respond — the receptors are fewer or less responsive, the transporters are not brought to the membrane, and glucose stays in the blood while the pancreas secretes ever more insulin into a system that is not listening.
Reading a glucose tolerance test
The test is standardised so that curves can be compared. The person fasts overnight, a fasting blood glucose is measured, they drink a solution containing 75 g of glucose, and blood glucose is measured at intervals for two hours. Diagnosis rests on two numbers: a fasting concentration of 7.0 mmol per dm3 or more, or a two-hour concentration of 11.1 mmol per dm3 or more.
Reading the curves without falling for the rate
Between 60 and 120 minutes the person without diabetes falls from 6.4 to 5.0 mmol per dm3, and the person with diabetes falls from 14.2 to 12.4. A student concludes that the diabetic pancreas is clearing glucose faster. Calculate both rates, and say what is wrong with the conclusion.
For the person without diabetes: a fall of 6.4 − 5.0 = 1.4 mmol per dm3 in 60 minutes, so the rate is 1.4 ÷ 60 = 0.023 mmol per dm3 per minute.
For the person with diabetes: 14.2 − 12.4 = 1.8 mmol per dm3 in 60 minutes, so the rate is 1.8 ÷ 60 = 0.030 mmol per dm3 per minute. The arithmetic supports the student: that is the faster fall.
The conclusion is still wrong, because rate of fall is not what the test measures. Some of the loss is glucose leaving in the urine rather than being taken into cells, and a concentration that starts at 14.2 has further to fall. What matters is where the curve ends up: at 120 minutes the diabetic value is 12.4, above the 11.1 threshold, while the other has returned to its fasting value.
The general habit to take away is to answer the question the graph is drawn to answer. A tolerance test asks whether the concentration is brought back under control within two hours, so quote the two-hour value and compare it with the threshold.
TRY IT — Explaining a symptom from first principles
An untreated person with type 1 diabetes produces large volumes of urine containing glucose, feels constantly thirsty and loses weight despite eating normally. Explain all three observations.
Check your answer
Glucose in the urine comes from saturation of the reabsorption mechanism. Glucose is filtered at the glomerulus and normally reabsorbed completely at the proximal convoluted tubule by carrier proteins. When the filtrate contains far more glucose than usual, every carrier is occupied, and the glucose that cannot be reabsorbed passes on into the urine.
The large volume follows from that glucose. Glucose left in the tubule lowers the water potential of the filtrate, so less water is reabsorbed by osmosis along the tubule and collecting duct, and a greater volume of dilute urine is produced.
The thirst is the consequence of losing that water. Blood water potential falls, osmoreceptors in the hypothalamus detect it, and thirst is triggered — while ADH release also rises, which is why the urine is not as dilute as the volume alone would suggest.
The weight loss comes from the cells being unable to use the glucose. With little or no insulin, glucose transporters are not brought into the membranes of muscle and fat cells, so glucose cannot be taken up and respired despite being abundant outside. The body respires fat and protein instead, and mass is lost — which is why untreated type 1 diabetes causes wasting in the middle of plenty.
In the exam
- Name the cells, not just the pancreas. Beta cells secrete insulin, alpha cells secrete glucagon, and both are in the islets of Langerhans.
- Insulin does not convert glucose to glycogen. It binds to receptors and activates the enzymes that do, and it increases the number of glucose transporters in the membrane.
- Spell the three 'glyco' words carefully and use them in the right direction. Examiners will not award a mark for glycogenesis where glycogenolysis was meant.
- Glucagon acts on the liver. Answers saying it acts on muscle to raise blood glucose lose the mark, because muscle cannot release glucose into the blood.
- Separate the two diabetes types by cause, not by age: destroyed beta cells against a poor response to insulin.
- In a tolerance test question, quote figures from the graph with their units, and give the two-hour value against the 11.1 mmol per dm3 threshold rather than describing the shape of the line.
Check yourself
A person has a fasting blood glucose concentration of 8.2 mmol per dm3 and a two-hour value of 13.5 in a glucose tolerance test. Their blood contains a higher concentration of insulin than a person without diabetes. Which type of diabetes do they have? Justify your answer from both pieces of evidence, and explain why their pancreas is secreting more insulin than normal.
Answer
Both test values are diagnostic. A fasting concentration of 8.2 is above the 7.0 threshold, and a two-hour value of 13.5 is above 11.1, so the person has diabetes.
The high insulin concentration identifies it as type 2. In type 1 the beta cells have been destroyed by the immune system, so there would be little or no insulin in the blood. Insulin is present here in more than the usual amount, so the beta cells are working.
The cause is therefore a poor response to insulin rather than a shortage of it. The target cells have fewer receptors, or receptors that respond weakly, so fewer glucose transporters are moved into their membranes and less glucose is taken up and stored, and the concentration in the blood stays high.
That persistently high concentration is what drives the extra secretion. Beta cells respond to the glucose around them: more glucose entering means more ATP, the potassium channels stay shut, the cell stays depolarised and more insulin is secreted. The negative feedback loop is intact at the pancreas and broken at the target cell, which is why the correction never arrives.
Questions
Question 15 marks
Describe how a rise in blood glucose concentration causes a beta cell in an islet of Langerhans to secrete insulin.
Mark scheme
- B1 more glucose enters the beta cell through its transporter protein and is phosphorylated and respired
- B1 the concentration of ATP in the cytoplasm therefore rises, in proportion to how much glucose the cell is respiring
- B1 ATP binds to the potassium channels in the cell surface membrane and closes them, so potassium ions can no longer diffuse out
- B1 positive charge builds up inside and the membrane depolarises, which opens voltage-gated calcium channels and calcium ions diffuse in
- A1 the calcium causes vesicles of insulin to fuse with the cell surface membrane and release their contents by exocytosis
Question 24 marks
Explain how insulin lowers the concentration of glucose in the blood, making clear why it is wrong to say that insulin converts glucose into glycogen.
Mark scheme
- B1 insulin binds to receptors on liver, muscle and adipose cells; it is a signal and never touches a glucose molecule, and the conversions are done by enzymes inside those cells
- B1 vesicles carrying glucose transporter proteins fuse with the cell surface membrane, so more glucose enters by facilitated diffusion
- B1 insulin activates the enzymes of glycogenesis, so glucose entering liver and muscle cells is stored as glycogen, and it also raises the rate of respiration of glucose and promotes its conversion into fat
- A1 it inhibits the alpha cells at the same time, so the opposing glucagon signal is switched off and less glucose is released from the liver
Question 34 marks
Compare type 1 diabetes with type 2 diabetes, referring to the cause of each, the insulin present in the blood and how each is usually managed.
Mark scheme
- B1 in type 1 the beta cells have been destroyed by the person's own immune system, whereas in type 2 the target cells respond poorly to insulin and secretion may fall later
- B1 in type 1 little or no insulin is produced, whereas in type 2 insulin is produced, sometimes in excess, but the receptors respond weakly to it
- B1 type 1 must be managed with insulin injections matched to meals and exercise, whereas type 2 is usually managed first by diet, weight loss and exercise, with drugs and sometimes insulin later
- B1 the two are separated by cause and not by age: type 2 is regularly diagnosed in teenagers and type 1 can begin at fifty
Question 44 marks
In a glucose tolerance test a person's blood glucose concentration is 5.6 mmol per dm3 when fasting, rises to 9.8 mmol per dm3 at 30 minutes, and has returned to 5.6 mmol per dm3 at 120 minutes. Calculate the percentage increase in concentration between fasting and 30 minutes, and calculate the mean rate of fall between 30 and 120 minutes.
Mark scheme
- M1 the increase is 9.8 − 5.6 = 4.2 mmol per dm3
- M1 percentage increase is the increase divided by the starting value and multiplied by 100, so 4.2 ÷ 5.6 × 100
- A1 75 per cent
- A1 the fall of 4.2 mmol per dm3 takes 90 minutes, so the mean rate is 4.2 ÷ 90 = 0.047 mmol per dm3 per minute
Question 54 marks
Insulin has to be injected rather than swallowed. Suggest why, and suggest why a person with type 2 diabetes can often control their blood glucose by diet and exercise alone while a person with type 1 cannot.
Mark scheme
- B1 insulin is a protein, and a protein that is swallowed is hydrolysed by proteases in the stomach and small intestine
- B1 it would be broken down into amino acids, which are absorbed but have none of the effects of the hormone, so it must enter the blood without passing through the gut
- B1 in type 2 diabetes the beta cells still secrete insulin, so reducing the glucose load of meals and losing weight can improve how well the target cells respond and let the person's own insulin cope
- A1 in type 1 the beta cells have been destroyed, so there is no insulin to improve the response to, and the hormone itself has to be replaced
Question 63 marks
Name the cells that secrete insulin and the cells that secrete glucagon, and name the patches of tissue in the pancreas that contain both kinds of cell.
Mark scheme
- B1 beta cells secrete insulin
- B1 alpha cells secrete glucagon
- B1 both are found in the islets of Langerhans, the endocrine tissue scattered through the pancreas
Worth remembering
- About 5 mmol per dm3, held there by insulin from beta cells and glucagon from alpha cells.
- Insulin is a signal, not an enzyme: receptors, transporters, and the enzymes of glycogenesis.
- Glucagon and adrenaline act on the liver through cyclic AMP; the liver is the organ that puts glucose back.
- In a beta cell: glucose in, ATP up, potassium channel shut, depolarised, calcium in, vesicles fuse.
- Type 1 is destroyed beta cells; type 2 is cells that no longer respond. Cause, not age.