Insulin, Glucagon and Diabetes Mellitus

Question 1

What two hormones does the pancreas secrete?

Answer 1

Insulin and glucagon

Question 2

What are the two major types of cell composing the pancreas?

Answer 2

Acini and the Islet of Langerhans

Question 3

What do the Acini cells do?

Answer 3

They secrete digestive juices into the small intestine (duodenum)

Question 4

What do the Islet of Langerhans do?

Answer 4

They secrete insulin and glucagon into the blood.

Question 5

What are the three major types of cells the Islet contain?

Answer 5

Alpha, beta and delta cells

Question 6

What is the percentage of alpha cells and what do they secrete?

Answer 6

25%, secretes glucagon

Question 7

What is the percentage of beta cells and what do they secrete?

Answer 7

60%, secrete insulin

Question 8

What is the percentage of delta cells and what do they secrete?

Answer 8

10%, secrete somatostatin (secretes within the islets and not into the blood)

Question 9

What is somatostatin?

Answer 9

Also known as growth hormone-inhibiting hormone. It is the same hormone that controls the somatotopes in the anterior pituitary, however, where it is made in the islets, its job is to regulate the alpha and beta cells

Question 10

True or False. The three hormones (insulin, glucagon and somatostatin) cannot antagonize each other.

Answer 10

False.
The three hormones can antagonize each other:
* insulin inhibits glucagon secretion.
* glucagon inhibits insulin secretion.
* somatostatin inhibits insulin and glucagon secretion

Question 11

what is the composition of insulin?

Answer 11

It’s a protein composed of two amino acids chains connected with two disulphide bonds. insulin loses its functional activity if the sulphide bonds are broken.

Question 12

What are the steps leading to the synthesis of insulin?

Answer 12

Insulin RNA attaches to the endoplasmic reticulum (ER) to form a precursor, insulin preprohormone ==> preprohormone cleaved in the ER to form proinsulin ==> further cleaved in Golgi apparatus to form insulin, ==> Insulin is packed into secretory granules ==> secreted into blood when glucose levels are elevated.

Question 13

What is the plasma half-life of insulin?

Answer 13

5-6 minutes.

Question 14

What happens to insulin when glucose levels go back to normal?

Answer 14

Thanks to it’s short half-life, insulin can be quickly turned off

Question 15

Assuming that insulin is not being synthesized or secreted, what is the total clearance of insulin and where does it happen?

Answer 15

10-15 minutes, cleared mainly by the liver

Question 16

What happens if insulin is continually secreted?

Answer 16

It can overcome the clearance rate and stay elevated for a long time.

Question 17

The insulin receptor is a protein with how many subunits?

Answer 17

4

Question 18

What are subunits?

Answer 18

A subunit is a piece of protein that needs to form with other subunits to become functional

Question 19

What are the 4 subunits composing the insulin receptor?

Answer 19

two alpha subunits that lie outside the cell membrane and two beta subunits that cross the cell membrane into the cytoplasm.

Question 20

What happens to insulin minutes after consuming a meal/nutrients?

Answer 20

Insulin rises which promotes glucose uptake in tissues especially muscles and allows storage of glucose in the liver

Question 21

What is the most important effect of insulin?

Answer 21

The most important effects of insulin is to cause glucose to be absorbed by liver. Insulin enhances glucose phosphorylation by an enzyme called glucokinase. Phosphorylation of glucose is a charged phosphate on the glucose unit. Then glucose-P can not escape the liver. It will be transformed into glycogen.

Question 22

What are the actions of insulin that increase the glycogen in the liver?

Answer 22

Insulin stimulates the enzyme glucokinase in liver ==> enhances glucose phosphorylation ==>enhances uptake of glucose from blood by the liver cell.

Insulin activates enzyme glycogen synthase (synthetase) ==> promotes glycogen synthesis (polymerization of glucose).

Insulin inactivates glucose phosphatase (enzyme that removes phosphate) ==> reduces the splitting of phosphate from the phosphorylated glucose ==> reduces the release of the free glucose back into blood.

Insulin inactivates the liver phosphorylase (enzyme that causes the glycogen in the liver to split into glucose) ==> prevents the breakdown of glycogen into glucose in the liver.

Question 23

What is the consequence of insulin’s action on blood glucose from liver in between meals?

Answer 23

About 2 hours after meal is over, the blood glucose concentration begin to fall to baseline levels, and then drops below baseline. This is due to effects of insulin, the blood glucose is lower.

That drop in blood glucose cause decrease of insulin secretion from islet,
As insulin dissapears, the following effects occur:
In liver, glycogen phosphorylase is activated ==> causes glycogen splitting into glucose-phosphate ==> stops synthesis of glycogen ==> prevents glucose uptake from blood.

Enzyme glucose phosphatase is activated ==> causes phosphate to split away from glucose ==> allows free glucose to diffuse back into blood.

Question 24

What is the role of glucose metabolism in muscle? when a muscle is at rest

Answer 24

When muscle is at rest glucose required by muscles is minimal.
o Muscle membrane is only slightly permeable to glucose.
o Insulin is not absolutely required.
o Energy mainly depends on fatty acids.

Question 25

What is the role of glucose metabolism in muscle, when the muscle is at rest shortly after a meal?

Answer 25

When muscle is at rest, soon after a meal is eaten:
* Glucose concentration in the blood is higher
* Insulin release is stimulated in islets
* Glucose uptake into muscle cells is enhanced by up to 15 fold
* Muscle can use glucose for energy
* Or, the extra glucose is stored as glycogen in the muscles.

Question 26

How are the glucose needs of the muscles met when the muscles are being used?

Answer 26

o insulin promotes glucose uptake, assuming the person has eaten a meal recently
o the increased blood flow promotes glucose uptake, regardless of insulin
o metabolic activity of the working muscle promotes glucose uptake, regardless of insulin

Question 27

True or False. When glucose enters a muscle it can not escape back into the blood. Thus, glucose does not need to be phosphorylated to trap it in a muscle.

Answer 27

True

Question 28

A resting muscle might require insulin to get glucose. An active muscle does not need insulin to obtain glucose. So what happens when an active muscle also experiences insulin?

Answer 28

It will take up even more glucose

Question 29

What is the effect of insulin on the nervous system?

Answer 29

Insulin is not required for glucose uptake in the brain, spinal cord and peripheral nerves.

These tissues always get the glucose they need, since they are essential for life.

The body is even willing to sacrifice other parts, like muscles, to keep the blood glucose steady.

It is essential that blood glucose levels are maintained at 80 - 120 mg/dl ( 5 - 6 mmol/l ). If the blood glucose decreases less than 45 mg/dl ( < 2.5 mmol/l ), severe hypoglycemia occurs leading to coma. The coma is due to significant decline in brain activity due to relative lack of glucose.

Question 30

Insulin reduces fat utilization for energy and promotes the synthesis of new fatty acids in the liver. How are they then transported to the adipose tissues?

Answer 30

Fatty acids are synthesized in the liver ==> become triglycerides in liver ==> triglycerides are released from liver cells to blood in the lipoproteins ==> insulin activates lipoprotein lipase (enzyme) in the capillary walls of the adipose tissue ==> lipase splits the triglycerides again into fatty acids to be absorbed into adipose cells ==> fatty acids in the cell are converted back to triglycerides for storage.

Question 31

How does insulin promote the storage of fat in adipose tissue?

Answer 31

o Insulin promotes glucose uptake into the adipose cell ==> glucose forms large amount of α-glycerol phosphate which combines with fatty acids to form triglycerides to be stored in adipose cell.
o Insulin inhibits the action of hormone-sensitive lipase (enzyme) ==> this inhibits the hydrolysis of triglycerides stored in adipose cell ==> this inhibits the release of fatty acids from adipose cell into blood.

Question 32

What is the impact of low insulin on fat metabolism?

Answer 32

In the absence of insulin, the enzyme hormone-sensitive lipase in the adipose cell becomes strongly activated ==> hydrolysis of the stored triglycerides (TG) ==> large amount of fatty acids and glycerol are released into blood ==> increase of free fatty acids (FFA) in blood for energy utilization.
Excess free fatty acids (FFA) in the plasma promote the conversion of fatty acids into phospholipids and cholesterol (two major products of fat metabolism) in the liver.
Phospholipids, cholesterol and excess triglycerides are released into the blood in the lipoproteins,
cause the concentration increase of these three substances to 300% during brief period of insulin lack,
If its chronic, it will lead to rapid development of atherosclerosis. Atherosclerosis is a complex inflammation and damage to blood vessels.

Question 33

What are the consequences of fat being constantly used for energy?

Answer 33

Increased fatty acids are transported into mitochondria in liver cell ==> oxidation of fatty acids occurs in mitochondria ==> causes release of extreme amounts of acetyl-CoA ==> Acetyl-CoA is condensed to form acetoacetic acid to be released into blood ==> acetoacetic acid is transported to peripheral cells.
Lack of insulin decreases the use of acetoacetic acids in the peripheral cell for energy ==> if there is excess concentration of acetoacetic acids in blood, the pH of blood drops ==> a severe acidosis may occur

Acetoacetic acids are also converted into β-hydroxybutyric acid and acetone. The presence of large amounts of β-hydroxybutyric acid and acetone along with the acetoacetic acid in the body fluid is “ketosis” ==> cause severe acidosis and ketosis ==> coma ==> death.

Question 34

What is the role of insulin in switching between carbohydrate and fat metabolisms?

Answer 34

• In a healthy person, the use of fat for energy is important, however, it should never reach the point of causing acidosis or ketosis because insulin will turn on again after the next meal.
• Insulin promotes the use of carbohydrates for energy and depresses the use of fats.
• Lack of insulin causes the reversed utilization for energy.
• The blood glucose concentration controls the switching mechanism:
  o Low glucose concentration ==> suppression of insulin ==> increase use of fat for energy ( except in the brain ) and suppress the use of glucose.
• When glucose concentration is high ==> stimulates insulin secretion ==> increase of glucose utilization for energy.

Question 35

What kind of effect does insulin have to promote proteins?

Answer 35

an anabolic effect

Question 36

How does the anabolic effect of insulin to promote proteins work?

Answer 36

it promotes amino acids uptake in the muscle cells ==>insulin stimulates the DNA transcription ( in cell nucleus ) and ribosomes (in cytoplasm) to form new proteins ==> Insulin inhibits proteolysis (catabolism of protein) ==> insulin decrease the release rate of amino acid from cells (especially from muscle cells).

Insulin suppresses gluconeogenesis (formation of glucose from amino acids) by inactivating the enzyme for gluconeogenesis ==>more amino acids are available for protein synthesis.

The combined influence of growth hormone (GH) and insulin together leads to an accelerated rate of growth in babies.

Question 37

What is the effect of lack of insulin on protein metabolism?

Answer 37

When insulin is absent, protein catabolism increases and protein synthesis stops. The amino acids increase dramatically in blood. Gluconeogenesis can now occur in liver to create new glucose. If insulin is chronically absent or dysfunctional, this is classic diabetic condition of accelerated protein loss with resulting decrease in lean body mass.

Question 38

Who has won a Nobel prize for insulin, when and why?

Answer 38

Frederick Banting and J.J.R Macleod. 1923, Nobel prize in physiology or medicine for discovering insulin

Frederick Sanger. 1958, Nobel prize in chemistry for determining structure of insulin

Dorothy Crowfoot Hodgkin. 1964, Nobel prize in chemistry for developing crystallography (insulin structure)

Rosalyn Sussman Yalow. 1977, Nobel prize in medicine for the development of radioimmunoassay of insulin

Question 39

What are the events leading up to the discovery of insulin?

Answer 39

In 1869, a medical student in berlin, Paul Langerhans identified some tissue clumps scattered throughout the pancreas.
In 1889, the polish-german physician Oscar Minkowski, with Joseph von Mering removed the pancreas of a dog, the dog’s urine became sweet.
In 1921, canadian scientist Frederick Banting, Charles Best, J.J.R. Macleod and James Collip discovered insulin by purifying it from a dog’s pancreas

1922, Eli Lilly made large quantities and began selling it for medical use. Major advancement in diabetes treatment.

Question 40

What two things control insulin secretion?

Answer 40

Blood glucose and amino acids

Question 41

How does blood glucose control insulin secretion?

Answer 41

Rapid increase in blood glucose leads to a biphasic insulin response.
Resting blood glucose ( 80-90 mg/dl ) stimulates approximately 25 ng/min/kg of insulin.
If the blood glucose concentration is increased to 2 to 3 times above normal level, insulin secretion increases in two stages:
Within first 3 to 5 minutes insulin concentration increases almost 10-folds; then it decreases halfway back, because the increased transport of glucose into liver, muscle and other cells.
At about 15 minutes insulin secretion rises a second time and reaches to a new plateau which is approximately 20 times normal level in 2 to 3 hours.

Question 42

How do some amino acids control insulin secretions?

Answer 42

Recall that insulin causes amino acids to be transported into muscles, liver, and adipose tissue. The body can use this feature to clear out excess amino acids.

• Arginine and lysine have the similar effects on promoting insulin secretion.
• Amino acids cause a small increase in insulin secretion when it is administered. This can occur without the rise of blood glucose.
• If amino acids and glucose both rise in blood, the secretion of insulin is strongly promoted, it even doubles. Thus amino acids and glucose are synergistic, they do more than just the simple sum of their individual effects.

Question 43

What is glucagon?

Answer 43

small hormone secreted by alpha cell of the islets in pancreas when blood glucose falls.
* It is a polypeptide with just 29 amino acids.
* It has a powerful hyperglycemic effect. Just 1 μg/kg of glucagon can elevate blood glucose concentration 25% in 20 minutes!

Question 44

How does glucagon have a strong effect on glucose?

Answer 44

• Glucagon increases the breakdown of liver glycogen into glucose (glycogenolysis).
• Glucagon increases gluconeogenesis in the liver.

Question 45

How does glucagon increase the breakdown of liver glycogen?

Answer 45

o Glucagon activates liver cell membrane and promotes degradation of glycogen into glucose-1-phosphate ==> glucose-1-phosphate is dephosphorylated ==> glucose is released from the liver cells into blood.

Question 46

How does glucagon increases gluconeogenesis in the liver?

Answer 46

o Glucagon activates enzymes for promoting amino acids uptake by liver cells, and activates enzymes for conversion of amino acids to glucose by gluconeogenesis.

Question 47

What are the effects of glucagon on lipid metabolism?

Answer 47

• Glucagon increase lipase activity in adipose cells ==> increase fatty acids available to energy system.
• Glucagon inhibits triglyceride storage in the liver.
• Thus, glucagon opposes the effects of insulin on carbohydrate and fat metabolism.

Question 48

What is the most potent factor that regulates glucagon secretion?

Answer 48

Low blood glucose concentration

Question 49

What is the effect of blood glucose on glucagon secretion?

Answer 49

Exactly opposite to that of insulin secretion

Low blood glucose = More glucagon secretion
High blood glucose = Less glucagon secretion

Question 50

Could an increase in amino acids, notably alanine and arginine, stimulate glucagon secretion?

Answer 50

Yes, it promotes the breakdown of amino acids into glucose

Question 51

True or False. An increase in amino acids might cause an increase in both insulin and glucagon levels.

Answer 51

True

Question 52

What does somatostatin do in terms of glucagon and insulin secretions?

Answer 52

• Somatostatin depresses both insulin and glucagon secretion ==> decreases the use of the absorbed nutrients by tissues ==> prevent rapid exhaustion of food ==> making food available over a longer period of time.

Question 53

How do insulin and glucagon work together to regulate blood glucose?

Answer 53

Both insulin and glucagon act as important feedback control system for maintaining a normal blood glucose concentration.

Question 54

How does the liver act as a blood glucose buffer system?

Answer 54

When blood glucose concentration rise too high after a meal ==> increase of insulin secretion ==> increase of glucose storage in the liver as glycogen ==> blood glucose decreases toward normal.

When blood glucose concentration falls (between meals) ==> stimulates secretion of glucagon ==> glucose releases from liver back into blood.

Question 55

The insulin feedback mechanism is much more important than the glucagon feedback mechanism but when does the glucagon mechanism become invaluable?

Answer 55

o Starvation,
o Excessive utilization of glucose during exercise,
o Other stressful situation.

Question 56

What happens in severe hypoglycemia?

Answer 56

In severe hypoglycemia, low blood glucose on hypothalamus stimulates the sympathetic nervous system ==> causes secretion of epinephrine from adrenal medulla ==> release of glucose from liver to protect against severe hypoglycemia.

In severe and prolonged (chronic) hypoglycemia, both growth hormone and cortisol are secreted ==> decrease glucose utilization by most cells of the body ==> help for returning blood glucose concentration toward normal.

Question 57

What is the importance of good blood glucose regulation?

Answer 57

Glucose is the best nutrient for energy for brain, retina, and germinal epithelium of the gonads. Therefore it is important to maintain blood glucose concentration at a sufficiently high level to provide energy.

It is also important that the blood glucose concentration not rise too high, because glucose exerts large amount of osmotic pressure in the extracellular fluid. If blood glucose concentration is too high it causes considerable cellular dehydration.

Too high blood glucose causes loss of glucose in urine ==> causes osmotic diuresis by kidneys, which can deplete the body of its fluids and electrolytes.

Question 58

What is type 1 diabetes?

Answer 58

Insulin-dependent Diabetes Mellitus
* The secretion of insulin from beta islet cells is significantly diminished.
* Usually due to autoimmune disease destroying islet tissues.
* It requires insulin injections to regulate blood glucose and to maintain blood glucose to near-normal levels.

Question 59

What is type 2 diabetes?

Answer 59

Non-Insulin Dependent Diabetes Mellitus
o Normal or high insulin levels associated with high blood glucose levels.
o Insulin receptor may be deficient or absent on target cell, (obesity decreases insulin receptors).
o Receptors may not bind insulin properly.

Question 60

What is gestational diabetes?

Answer 60

o Elevated blood glucose levels during pregnancy only,
o Has high incidence of type II diabetes for the mother in later life.

Question 61

What is the general pathology of diabetes?

Answer 61

Most of the pathological features of diabetes mellitus can be attributed to the following major effects of insulin lack.

• Decreased utilization of glucose by body cell.
• Increased mobilization of fats from fat storage ==> deposition of cholesterol in arterial walls ( atherosclerosis ).
• Decrease protein storage in tissues of the body.

Question 62

How does the pathology of diabetes affect glucose?

Answer 62

• Normal blood glucose range: 70 - 110 mg/dl or 3.9 - 6.1 mmol/l,
• “Controlled “ blood glucose range: 160 - 249 mg/dl or 8.9 - 13.9 mmol/l,
• Poorly controlled blood glucose levels: greater than 250 mg/dl or 14 mmol/l.

Question 63

What are the signs and symptoms of diabetes?

Answer 63

• glucose “spill-over” into the urine (glucosuria) when blood glucose concentration rise above the threshold of 180 mg/dl.
• Increase of urine production (polyuria) results in whole body dehydration (osmotic diuresis). This condition brings on a strong thirst to drink water (polydipsia).
• Energy use depends almost entirely on fat ==>causes increased acidosis and ketosis.

Question 64

What are treatments of diabetes?

Answer 64

Lifestyle changes such as diet and moderate exercise are recommended. Strenuous exercise required a doctors clearance to make sure it is safe.

Moderate exercise like walking is extremely effective because the moving muscles absorb glucose, which lowers blood glucose and has a lasting effect.

Type 1 diabetes is normally treated with insulin injections. Type 2 or gestational diabetes will be treated with a variety of other drugs to promote good glycemic control. If it is not well controlled, type 2 diabetes may require insulin injections.