Metabolic Changes in Health and Disease

Question 1

Where does glucose travel to after it is absorbed after a meal?

Answer 1

About 95+% of glucose absorbed after a meal travels to the liver in the hepatic portal system

• Approx 35% metabolized in the liver
• Approx 65% continues on, to be distributed to other tissues

Question 2

What are the two states of the metabolism?

Answer 2

1. Fed (absorptive) state
   - Shortly after meal when new nutrients are available
2. Fasted (postabsorptive) state
   - Body needs to draw upon its fuel stores

Question 3

Describe the fed (absorptive) state

Answer 3

In fed state metabolism is anabolic

• Nutrient molecules are used to provide energy stores or to provide needs of growth and maintenance of cells and tissues
• But these needs mean that some molecules are used immediately to provide energy

Question 4

Describe the fed (postabsorptive) state

Answer 4

In fasted state metabolism is catabolic

-The body calls on the energy stores, so they become depleted

Question 5

How does the metabolic state change?

Answer 5

To a large extent, the different metabolic pathways are self- regulating

-Concentrations of substrates and products (direct or down- stream) of reactions determine their rate as does the activity of the relevant enzymes

A number of enzymes are affected by hormones

Question 6

What are the key hormones involved in regulating metabolism?

Answer 6

Insulin
Glucagon
Adrenaline (epinephrine) and noradrenaline (norepinephrine)

Question 7

By what processes do hormones regulate the metabolism?

Answer 7

Actions mediated by activation of intracellular protein kinases and
phosphorylation of key regulatory proteins on tyrosine, serine or threonine residues – covalent modifications alter enzyme activities

Question 8

What is the main purpose of the pancreas?

Answer 8

Most of pancreas has an exocrine function (digestive enzymes) -Endocrine cells only make up about 2% of its mass

Question 9

What is the role of insulin in the hormonal regulation of metabolism?

Answer 9

b-cells stimulated to secrete insulin by elevated blood [glucose] and the parasympathetic nervous system
Drives the fed state
- Stimulates storage of fuels and anabolism

Question 10

What are the 5 ways that insulin stimulates the storage of fuels and anabolism?

Answer 10

1. Stimulates glycogen synthesis in liver and muscle
2. Stimulates uptake of glucose into muscle and adipose tissue
3. Stimulates glycolysis and hence fatty acid synthesis in liver
4. Stimulates formation of triglycerides in fat tissue
5. Stimulates protein synthesis in muscle

Question 11

What is the role of glucagon in hormonal regulation of the metabolism?

Answer 11

a-cells of the pancreas stimulated to secrete glucagon when blood [glucose] falls during the fasting state

Main target is the liver where it:

1. Stimulates release of glucose from glycogen
2. Stimulates gluconeogenesis but inhibits glucose incorporation into glycogen

Stimulates breakdown of triglycerides in fat tissue (?)

Question 12

Where does glucagon take effect?

Answer 12

?? Perhaps slightly in liver but not in adipose tissue

lack of insulin results in increased lipolysis in adipose tissue

Question 13

What determines whether the metabolism is in the fed or the fasted state?

Answer 13

the balance between circulating levels of insulin and glucagon that determine whether metabolism is in the fed or fasting state

Question 14

Where and why is adrenaline and noradrenaline (Amines) released in the body?

Answer 14

Secreted by the adrenal medulla and neurones of the sympathetic nervous system when blood [glucose] falls

Question 15

What role does adrenaline and noradrenaline (Amines) have in hormonal regulation of the metabolism?

Answer 15

Like glucagon they drive breakdown of glycogen and triglycerides

Unlike glucagon, their glycogenolytic action is mainly on muscle (producing glucose-6-P) rather than on liver

The amines lower glucose uptake by muscle, so that fatty acids released by adipose tissue are used as fuel

The amines also increase glucagon secretion and inhibit insulin secretion

Question 16

What is the normal range of blood glucose concentration ([glucose])

Answer 16

Blood [glucose] normally ranges between 80 mg/100 ml before meal to about 120 mg/100 ml after a meal

N.B. Normal blood [glucose] 4-8 mmol/litre (= 80-160 mg/100 ml)

Question 17

How is blood glucose concentration controlled?

Answer 17

Liver is key to regulation of blood [glucose] within such narrow limits
-It can buffer changes because it can take up and release large amounts of glucose
Because secretion of insulin and glucagon are themselves controlled by blood [glucose] and because they have opposite actions on the enzymes that promote glycogen synthesis and breakdown, their relative concentrations are key to keeping blood [glucose] within narrow limits

Question 18

What blood [glucose] defines hypoglycaemia?

Answer 18

Lowered blood [glucose] (<3 mmol/litre)

Question 19

What blood [glucose] defines hyerglycaemia?

Answer 19

Elevated blood [glucose] (>11 mmol/litre)

Question 20

What are the total energy stores available to a fasting human?

Answer 20

approx 162000 kcal

Question 21

How many calories does a man weighing 70kg require a day?

Answer 21

requires about 1600

kcal/day at rest and as much as 6000 kcal/day when active

Question 22

How long would fuel stores last during starvation?

Answer 22

Fuels stores are sufficient for about 1-3 months of starvation, depending on level of physical activity

Question 23

What occur in the first stages of starvation?

Answer 23

Carbohydrate stores will only last a day or less (depending on level of activity) , so blood [glucose] will tend to fall

Because the brain is completely dependent on glucose, metabolism must adjust itself to maintain [glucose] at an adequate level

Unfortunately triglycerides have a limited ability to be converted to glucose

Proteins potentially can yield glucose (gluconeogenesis), but these need to be preserved as much as possible

Muscle shifts from its use of glucose as a fuel to using fatty acids released from adipose tissue (so sparing glucose for the brain)

The liver uses fats mobilized from adipose tissue and pyruvate, lactate and alanine (from breakdown of protein) from muscle to make as much glucose as possible for export into the blood (for the brain)

Question 24

What occurs in the later stages of starvation?

Answer 24

After about 3 days large amounts of ketone bodies begin to be formed by the liver (as a consequence of breaking down fatty acids and limitations in the activity of the TCA cycle)

Over the first few days of fasting the brain becomes more tolerant of lowered blood [glucose] and gains the ability to use ketone bodies to meet some of its fuel requirements

This ability of the brain to use ketone bodies gradually increases over weeks of starvation, so the need for glucose is lowered

Because the body uses less glucose, the need for amino acids to fuel gluconeogenesis is also reduced so there is a reduction in the rate at which muscle is broken down

-This is really important for survival

Question 25

What are the main symptoms diabetes mellitus?

Answer 25

The name diabetes refers to the fact that untreated sufferers urinate profusely As a consequence such sufferers experience great thirst The untreated condition is also accompanied by body wasting because of loss of muscle and fat tissue -The individual is also hungry The term 􏰀mellitus􏰁 means 􏰀sweet like honey􏰁 It refers to the presence of sugar in the urine

Question 26

What is the history of diabetes mellitus?

Answer 26

Commonest serious metabolic disease affecting hundreds of millions of people worldwide in Medieval times it was referred to as 􏰀the pissing evil􏰁 The condition has been known for thousands of years

Question 27

What are the two main forms of diabetes mellitus?

Answer 27

Type 1 (insulin-dependent = juvenile onset) ``` Type 2 (non-insulin-dependent = insulin-resistant = adult onset) ```

Question 28

What is type 1 diabetes?

Answer 28

Usually an autoimmune condition in which b-cells of pancreas are destroyed Therefore little insulin can be secreted in response to rise in blood [glucose] Accounts for about 10% of cases of diabetes mellitus Treated by injecting insulin when required

Question 29

What is type 2 diabetes?

Answer 29

Accounts for about 90% of all cases of diabetes mellitus Typically this type of diabetes has a late age of onset (middle age) although recently there have been more cases among the young Normally less severe than type 1 diabetes and in many cases can be managed by exercise and losing weight Cause(s) not clear, but seems to be associated lifestyle (little exercise, ready access to food and obesity), and there can be a genetic component -Tissues are insensitive to the effects of insulin.

Question 30

What are blood glucose levels like in people with diabetes mellitus?

Answer 30

In untreated people with diabetes blood [glucose] is always elevated When they ingest glucose, the rise in blood level is higher and longer than in a non-diabetic individual

Question 31

Why are blood [glucose] higher in people with untreated diabetes mellitus?

Answer 31

The deficiency in insulin or insensitivity of tissues to insulin, means that glucose cannot be taken up by cells and so remains in the blood

Question 32

What non insulin hormonal issue arises due to diabetes mellitus?

Answer 32

blood glucagon levels are higher than normal

Question 33

How does diabetes mellitus effect metabolism?

Answer 33

Because tissues are not influenced by insulin, metabolism is largely similar to that seen during prolonged fasting -Despite high levels of blood glucose (which cannot be used -famine amid plenty)

Question 34

What four steps lead to the unique blood makeup of those with diabetes mellitus?

Answer 34

1. Glycolysis is slowed 2. Gluconeogenesis (new glucose) is stimulated (using amino acids produced by protein breakdown) 3. Fatty acids (from adipose tissue) are broken down and used to form ketone bodies 4. Newly formed glucose and ketone bodies pass into the blood

Question 35

Why is untreated diabetes is associated with excessive urination?

Answer 35

1. In the glomeruli of the kidney glucose leaves the blood and passes into the urine along with ions and other relatively small molecules 2. Normally transporters in the proximal convoluted tubule reabsorb all the glucose and return it to the blood 3. In diabetes if the blood [glucose] rises beyond a certain level, the amount that passes into the kidney tubules is so great that the transporters cannot remove it all 4. This glucose adds to the osmotic strength of the urine 5. This makes it harder for the kidney to reabsorb water from the urine 6. The result is that the urine volume is greatly increased -It also explains why the urine of a diabetic contains glucose 7. In severe cases, acidic ketone bodies also appear in the urine (ketoacidosis) adding slightly to the osmotic strength. -It also explains why the urine of a diabetic contains ketones

Question 36

What are the deleterious effects of diabetes mellitus?

Answer 36

In long-term high blood [glucose] can damage tissues: Blood vessels (polyneuropathy) Eyes (Retinal blood vessels) Kidneys (urine infection; scarring and swelling in glomeruli leading to appearance of protein in the urine) Cardiovascular disease (largely a result of narrowing of blood vessels) Ketone bodies cause acidosis, which cannot be fully counteracted As a result, an individual with uncontrolled diabetes can go into a coma as a result of low blood pH coupled with dehydration

Question 37

What results in increased lipolysis in adipose tissue?

Answer 37

The absence of insulin