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Lecture Notes (Chapt 79) Insulin, Glucagon, and Diabetes Mellitus.

"Hometown Heroes"

Objective 79.1 Recognize the endocrine and exocrine functions of the pancreas. Identify
insulin and its action on glucose transport through cellular membranes

 Pancreas secretes two important hormones:

 Insulin
 Glucagon

Physiological Anatomy of Pancreas

 Composed of two major types of cells

 Acini
- Secretes digestive juices into the small intestine ( duodenum ).
 Islets of Langerhans
 Secrete insulin and glucagon into blood.
 1 - 2 millions islets in pancreas.
 0.3 mm in diameter.
 Around the small capillaries.
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 Contains three major types of cells.

Alpha (α) cell - 25%, secrete glucagon
Beta (β) cell - 60%, secrete insulin
Delta (δ) cell - 10%, secrete somatostatin
 Interrelations between the hormones
 Insulin inhibits glucagon secretion.
 Somatostatin inhibits insulin and glucagon secretion.

 Islets of Langerhans were discovered in the year 1869 by a German pathological anatomist
Paul Langerhans at the age of 22.

Insulin
Chemistry of Insulin

 Small protein with molecular weight (MW) of 5808,

 Composed of two amino acid (aa) chains connected
with two disulphide bonds,
 Bonds are important because when the sulphur bonds
are broken insulin loses its functional activity
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 Synthesized in beta cells in the following steps:

 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,
 Insulins are packed into secretory granules,
 Secreted into blood.
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Pharmacokinetics of Insulin

 Plasma half life time is 5 - 6 minutes ( i.e. half of the peak levels are gone in 6 minutes ),
 Insulin function can be rapidly turned on and turned off,
 Total clearance: 10 - 15 minutes, mainly in the liver

Target Cell Receptors for Insulin

 Receptor protein (MW 300,000) has four (4) subunits:

 Two alpha (α) subunits
- Lie outside the cell membrane.
 Two beta (β) subunits
- Penetrate through membrane,
- Protruding into cell cytoplasm.
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Objective 79.2 Identify the hepatic and extrahepatic effects of insulin on carbohydrate metabolism.
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Effects of Insulin on Carbohydrates

Metabolism: after eating...

 Promoting glucose uptake, storage and use in liver

 After a meal one of the most important effects of insulin is to cause glucose to be
absorbed and stored in the liver as glycogen.

 Insulin stimulates the enzyme glucokinase  enhance glucose

phosphorylation ( a charged phosphate on the glucose unit )  enhance
uptake of glucose from blood by the liver cell.

 Insulin activates enzyme glycogen synthase ( synthetase )  promote

glycogen synthesis ( polymerization of glucose ).

 Insulin inactivates glucose phosphatase ( enzyme )  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.

 All the above actions increase the glycogen in the liver.

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Release of glucose from liver between meals:

After meal is over, the blood glucose concentration begin to fall to a low level,
 cause decrease of insulin secretion from islet,
 lead to opposite effects:
 activates enzyme phosphorylase  causes glycogen splitting into
glucose-phosphate  stops synthesis of glycogen  prevents
glucose uptake from blood.

 activates enzyme glucose phosphatase  causes phosphate to split

away from glucose  allows free glucose to diffuse back into blood.

 Promoting glucose metabolism in muscles.

 When muscle is at rest glucose required by muscles is minimal.

 Muscle membrane is only slightly permeable to glucose.
 Insulin is not absolutely required.
 Energy mainly depends on fatty acids.
 After a meal at muscle rest
 Glucose concentration in the blood is high,
 Insulin release is stimulated,
 Glucose uptake into muscle cells is enhanced,
 Glucose use for energy is increased,
 Extra glucose is stored as glycogen in the muscles.
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 Note: Insulin can increase the transport rate of glucose into muscle cell
by at least 15-folds.

 During exercise ( moderate or heavy ) glucose delivery and uptake are met by
 insulin,
 the increased blood flow,
 metabolic activity of the working muscle.

Note: Once glucose is inside either the liver or muscle cell, the "phosphorylated"
glucose remains in the cell. However, the de-phosphorylated glucose can leave
the liver cell but not the skeletal muscles. This is an important difference between
the muscle and liver cell.

Note:
 Different from most other tissues insulin is not required for glucose uptake in the
brain, spinal cord and peripheral nerves.

 Glucose uptake occurs by "mass action effect", i.e. the greater the glucose levels,
the greater the uptake, and the lower the plasma glucose, the lower the uptake.

 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 ( significant decline in CNS activity
due to relative lack of glucose ).

Effect of Insulin on Fat ( Lipid ) Metabolism

 Insulin reduces fat utilization for energy by promoting glucose use.

 Insulin promotes fatty acid synthesis

 Fatty acids are synthesized in the liver to triglycerides (usual form of storage fat)
 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.

 Insulin promotes the storage of fat in adipose cell.

 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.

 Insulin inhibits the action of hormone-sensitive lipase ( enzyme )  inhibits

the hydrolysis of triglycerides stored in adipose cell  inhibits the release of
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fatty acids from adipose cell into blood.

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Objective 79.3 Identify the effects of states of insulin lack or excess on lipid metabolism.

 Effects of insulin lack on lipid metabolism

 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,
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 cause the concentration increase of these three substances to 300% during

brief period of insulin lack,
 leads to rapid development of atherosclerosis.

 Increased fatty acids transported into mitochondria in liver cell  Oxidation of

fatty acids in mitochondria causes release of extreme amounts of acetyl-CoA 
Acetyl-CoA is condensed to form acetoacetic acid to be released into blood
 transported to peripheral cells.
 Lack of insulin decreases the use of acetoacetic acids in the peripheral cell 
excess concentration of acetoacetic acids in blood ( a severe acidosis ).

 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.

Role of Insulin in "Switching" Between Carbohydrate and Fat ( Lipid ) Metabolism

 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:
 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.

Objective 79.4 Identify the effects of insulin on protein metabolism and growth.

Effect of Insulin on Protein Metabolism

 Insulin promotes amino acids uptake in the cell.

 Insulin stimulates the DNA transcription ( in cell nucleus ) and ribosomes (in cytoplasm)
to form new proteins.

 Insulin inhibits proteolysis ( catabolism of protein )  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.
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Note: The combined influence of growth hormone (GH) and insulin together leads to an
accelerated rate of growth ( see Fig 79.5 ).

 Insulin lack on protein metabolism:

 Protein catabolism increases.
 Protein synthesis stops.
 Amino acids increase dramatically in blood.
- This is classic diabetic condition of accelerated protein loss with resulting
decrease in lean body mass.

Objective 79.5 Identify and characterize the primary regulatory mechanism for insulin secretion
and its functional significance. Identify other factors that enhance insulin secretion.

Control of Insulin Secretion

 Secretion of insulin controlled by blood glucose

 Rapid increase in blood glucose leads to a biphasic insulin response ( Fig 79.6 ).
 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 ( see Fig 79.7).

 Secretion of insulin controlled by some of amino acids

 Arginine and lysine have the similar effects on insulin secretion.
 Amino acids cause a small increase in insulin secretion when it is administered
without the rise of blood glucose.
 With the rise of blood glucose, amino acids enhance the secretion of insulin
strongly ( doubling ).
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Objective 79.6 Identify glucagon, its target actions, factors that influence its secretion, and its
means of regulation.

Glucagon and Its Functions

 Glucagon
 A hormone secreted by alpha cells of islet in pancreas when blood glucose
concentration falls.
 A polypeptide ( MW 3485 ) with 29 amino acids.
 Has a powerful hyperglycemic effect ( 1μg/kg of glucagon can elevate blood
glucose concentration 25% in 20 minutes ).

Effects of glucagon on glucose metabolism

 Glucagon increases the breakdown of liver glycogen into glucose ( glycogenolysis ).

 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.

 Glucagon increases gluconeogenesis in the liver.

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

Note: Both of the above actions serve to maintain or elevate blood glucose levels.

Effects of glucagon on lipid metabolism

 Glucagon increase lipase activity in adipose cells  increase fatty acids available to
energy system.
 Glucagon inhibits triglyceride storage in the liver.

Objective 79.7 Identify the principal and supporting regulatory mechanisms for blood glucose
levels, and their significance.

Regulation of Glucagon

 Blood glucose concentration is the most potent factor that controls glucagon secretion.
 The effect of blood glucose on glucagon secretion is exactly opposite to that of insulin
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secretion.
 Low levels of blood glucose stimulates glucagon release.
 High levels of blood glucose inhibits glucagon release.

 Increase in amino acids ( alanine and arginine ) stimulates glucagon secretion, 

promotes conversion of amino acids to glucose.

 Somatostatin

 Secreted from delta cells of islet.

 It depresses 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.

Blood Glucose Regulation

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

 Liver acts as a blood glucose buffer system:

 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.

 Insulin feedback mechanism is much more important than the glucagon mechanism. But
the glucagon mechanism becomes very valuable in the following conditions:
 Starvation,
 Excessive utilization of glucose during exercise,
 Other stressful situation.

 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 prolonged 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.
Importance of Blood Glucose Regulation
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 Glucose is the only nutrient for energy that normally can be used by 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.
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Objective 79.8 Identify diabetes mellitus, its potential causes, and major pathophysiological
consequences.

Diabetes Mellitus

Types of Diabetes

 Type I ( Insulin-dependent; IDDM )

 Caused by secretion of insulin from beta cells of islet diminished.

 It requires insulin injections to regulate blood glucose and to maintain blood
glucose to near-normal levels.

 Type II ( Non-insulin dependent; NIDDM )

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

 Gestational diabetes

 Elevated blood glucose levels during pregnancy only,

 Has high incidence of type II diabetes for the mother in later life.

Pathology of Diabetes
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 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.

Note: 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.

Markers of Diabetes

 Glucose "spill-over" into the urine ( glucosuria ) ( when blood glucose concentration
rise above "threshold" - 180 mg/dl ).

 Increase of urine production ( polyuria ) results in whole body dehydration ( osmotic

diuresis ). This condition brings on polydipsia ( strong desire to drink water ).

 Energy use depends entirely on fat  causes increased ketone production, i.e.
acetone, acetoacetic acid, etc. ( acidosis ).