L6: the endocrine pancreas

Question 1

What are normal glucose levels?

Answer 1

4.5-5.5 mmoles/L in the blood

Question 2

Sources of glucose

Answer 2

Diet

Can be created by gluconeogenesis in particularly the liver (and sometimes the kidneys)

Question 3

What do the cells use as energy?

Answer 3

Glucose is a major nutrient used as an energy source by all cells. Most cells can also utilise fatty acids and may do so in preference. But the brain can only use glucose and contains little store.

Question 4

What is the brain susceptible to?

Answer 4

Brain is susceptible to hypoglycaemia resulting in brain damage, due to neurones not firing.

Question 5

Structure of the pancreas

Answer 5

Min 5

• exocrine pancreas - ducts that lead to acini
• endocrine pancreas - islet of langerhans - beta cells produce insulin and alpha cells produce glucagon

Question 6

What does insulin do in the body?

Answer 6

Flow chart at min 6

• in response to insulin, glucose will enter muscle cells, some will be used for energy and the rest will be stored as glycogen. Also allows fatty acids to be converted into energy in skeletal muscle cells.
• in response to insulin, glucose will move into the liver and be stored as glycogen. Will also be used as energy.
• in the presence of insulin, glucose will also be taken up into fat cells to be converted into fatty acids which can be used for energy, or the fatty acids can be converted to fat and stored for later energy use.

Question 7

What happens if there is no insulin present but energy is needed?

Answer 7

The fats will be converted back into fatty acids, which will go back into the blood, travel to the liver and the muscle, where they will be used for energy. The liver will also convert the fatty acids to ketones (acidic). So overtime in the absence of insulin, fat and muscle will be broken down.
Without insulin the body will also try and synthesis glucose and release it into the body to compensate for lack of feeding. Can be an issue if there is no glucose for a long period of time.

Question 8

Fate of glucose in the feeding/absorptive state

Answer 8

• 5% stored as glycogen (glycogenesis - liver and muscle)
• 30-40% converted into fat (adipose tissue and liver)
• 50% metabolised (energy)

Question 9

Fate of glucose in the fasting/post-absorptive state.

Answer 9

• glycogen broken down (glycogenolysis)
• glucose produced from amino acids and glycerol (gluconeogenesis)
• glucose spared by fat breakdown and fatty acid release as energy source in non-neural tissues.

Question 10

Properties of insulin

Answer 10

Water soluble:

• carried dissolved in plasma - no special transport proteins
• interacts with cell surface receptors on target cells

Question 11

How is insulin release controlled?

Answer 11

• basal secretion and short pulses
• size of pulse is proportional to rate of rise of plasma glucose
• stimulated by vagal stimulation
• inhibited by sympathetic stimulation

Question 12

Trace of glucose levels

Answer 12

15:55
To keep the blood glucose in a narrow range throughout the day, there is a low steady secretion of insulin overnight, fasting and between meals with spikes of insulin at mealtimes.

Question 13

Mechanism of glucose-stimulated insulin secretion

Answer 13

In a pancreatic beta cell: 16:45

1. Glucose enters pancreatic beta cell through the GLUT2 transporter by diffusion
2. Inside the cell glucose is converted to glucose-6-phosphate and broken down to yield ATP
3. ATP causing ATP-sensitive K+ channels to close causing depolarisation that causes voltage sensitive Ca2+ channels to open
4. Increased cellular Ca2+ activated calcium - calmodulin dependent kinases, stimulating exocytosis of insulin-containing granules
5. Insulin is release to the blood

Question 14

Actions of insulin (anabolic)

Answer 14

Acts on muscle, adipose tissue and liver and stimulates glucose uptake and subsequent utilisation:

• increases glycogen synthesis (liver and muscle)
• increases fat synthesis (liver and fat)
• increases amino acid transport into cells and protein synthesis

Question 15

Insulin-mediated glucose uptake

Answer 15

On muscle and liver cells there are insulin receptors. Once stimulated by the insulin, it tells the cells to insert more GLUT4 channels into the cell membrane. Glucose will then be uptake by those tissues, and used to store glycogen, or used as energy. Stimulates other enzymes to convert glucose into glycogen.

Question 16

When is glucagon released?

Answer 16

Release is stimulated by low plasma glucose levels (starvation) and sympathetic activity by adrenaline.

Question 17

When is glucagon inhibited?

Answer 17

Glucagon release is inhibited by high plasma glucose and fatty acids.

Question 18

Actions of glucagon in the liver (catabolic)

Answer 18

• increases glycogenolysis
• decreases glycogenesis
• increases gluconeogenesis
• increases fat breakdown (fatty acids as energy and release glycerol which can be converted to glucose by the liver)

Question 19

Actions of glucagon in adipose tissue (catabolic)

Answer 19

• increases fat breakdown (fatty acids as energy and release glycerol which can be converted to glucose by the liver)
• increases fatty acid release

Question 20

Effect of decreased insulin on the muscles

Answer 20

Muscles will break down the actin and myosin in muscles releasing amino acids, which can be used to synthesis glucose from the liver.

Question 21

Apart from glucagon and insulin, what other hormones are involved in glucose metabolism?

Answer 21

In response to hypoglycaemia - to raise plasma glucose levels:
- Adrenaline in response to stress
- Glucocorticoids (cortisol)
- Growth hormone
Cortisol and GH block the GLUT4 receptor. So the glucose will remain in the blood and not enter muscle cells.

Question 22

What is diabetes mellitus?

Answer 22

a metabolic disease characterised by chronic hyperglycaemia

Question 23

Differences between type I and type II diabetes

Answer 23

Type I: 10-20% of diabetics. Onset usually in childhood. Not linked to obesity. Linked to ketosis. Controlled by insulin injections, diet and exercise.
Type II: 80-90% of diabetics. Onset usually in adulthood. Linked to obesity. Not linked to ketosis. Controlled by diet, weight loss, exercise, injections.

Question 24

What is type I diabetes?

Answer 24

No or very little insulin being secreted by the beta cells of the pancreas. Insulin dysfunction. Pancreatic beta islet destruction leading to absolute insulin deficiency. Most commonly autoimmune and rarely idiopathic.

Question 25

What is type II diabetes?

Answer 25

Normal insulin levels but the body’s cells cannot respond to it - they are insulin resistant. Over time the sensitivity of the insulin receptors is lost. Varying degrees of insulin resistance and insulin deficiency.

Question 26

What endocrinopathies can lead to diabetes mellitus?

Answer 26

Acromegaly (a growth hormone), Cushing’s syndrome, pheochromocytoma

Question 27

What happens in type 1 diabetics?

Answer 27

No insulin signal is received so glucose stays in the blood. If there is no insulin signal for a long period of time, the liver will respond to the lack of insulin by breaking down glycogen stores (because it thinks the body is not eating), so forms more glucose. Once it has wasted its glycogen stores, from fats the liver will create energy. These will break down into fatty acids and over time these will break down into ketone bodies, which will go into the blood, making it acidic. This leads to coma and death.

Question 28

How can you tell if someone has ketone bodies in the blood?

Answer 28

They have a distinctive sweet/alcohol smell.

Question 29

What happens in type II diabetics?

Answer 29

• genetic causes are unknown
• patients eat too much or do not exercise enough etc.
• they become overweight and need extra insulin as the body becomes ‘resistant’
• islet cells will wear out early so they eventually cannot make enough insulin, or the receptors stop responding to it
• fatty deposits in the pancreas can cause even more damage
• so the body results in either needing more insulin but being unable to produce it or being unable to respond to it.

Question 30

What does insulin deficiency and/or insulin resistance lead to in the muscle?

Answer 30

In the muscle:

• uptake of glucose decreases
• glycogenesis decreases
• uptake of amino acids and protein synthesis decreases (proteolysis increases) so will lose muscle mass

Question 31

What does insulin deficiency and/or insulin resistance lead to in the adipose tissue?

Answer 31

In the adipose tissue:

• uptake of glucose decreases
• lipogenesis and esterification decreases
• increased lipolysis

Question 32

What does insulin deficiency and/or insulin resistance lead to in the liver?

Answer 32

In the liver:

• glycogenesis and glycolysis will decrease
• gluconeogenesis will increase
• gluconeogenesis from muscle amino acids will increase
• ketogenesis from adipose tissue fatty acids will increase

Question 33

Consequences of diabetes on the body

Answer 33

Muscle wasting and weight loss, hyperglycaemia, ketosis, osmotic diuresis in the kidney pulling water across into the urine so dehydration occurs, urine with glucose

Question 34

What happens to glucagon in diabetes?

Answer 34

Excess glucagon will be produced due to the lack of insulin.

Question 35

Classic symptoms of diabetes - acute metabolic

Answer 35

Polyphagia - frequently hungry
Polyuria - frequently urinating
Polydipsia - frequently thirsty

Question 36

Other symptoms of diabetes mellitus

Answer 36

Blurred vision (glucose uptake in the eyeball), fatigue, weight loss, poor wound healing (catabolic signals not anabolic), dry mouth, dry or itchy skin, impotence (male); recurrent infections such as vaginal yeast infections, groin rash or external ear infections

Question 37

Long term microvascular complications of untreated diabetes

Answer 37

• diabetic retinopathy
• diabetic nephropathy
• diabetic neuropathy (PNS) (ulceration, gangrene - amputation)

Question 38

Long term macrovascular complications of untreated diabetes

Answer 38

• coronary heart disease
• peripheral vascular disease
• cerebral vascular disease

Question 39

How does diabetes manifest in the mouth?

Answer 39

Uncontrolled diabetes leads to:

• higher risk of bacterial infections (due to high saliva glucose levels which favour bacterial infection)
• dry mouth (over urinating)
• severe periodontal disease
• slow healing after treatment
• oral fungal infections

Question 40

How is diabetes diagnosed?

Answer 40

Oral glucose tolerance test (GTT)
- fasting overnight followed by an oral dose of 75g of glucose. Fasting levels should be 3.5-5.5mmol, post dose should be 7-9mmol. Should return to fasting level by 2hours. Diabetics will struggle to lower this level.

HbA1c levels (Hb in RBCs)
- in known diabetics. Indicates long-term diabetes control. Measure of glycohemoglobin. Elevated glycohemoglobin levels means long-term glucose control has not been very good. Target <48mmol/L.

Question 41

Treatments for diabetes

Answer 41

• limit uptake of carbohydrates in the stomach
• drugs like metformin that impact the liver by lowering its glucose formation
• drugs to lower fatty acid breakdown
• sulfonylureas impair insulin secretion by trying to increase it
• metformin will try to increase skeletal muscle uptake of glucose by putting in more GLUT transporters

Question 42

What happens if insulin excess is given to diabetes?

Answer 42

• hypoglycaemia - low blood glucose <3.0mM
• nervous system is rapidly affected
• results in confusion, weakness, dizziness and convulsions
• triggers sympathetic activity
• sympathetic signs lost in autonomic neuropathy with no warning
• finally coma and death