The endocrine pancreas 1

Question 1

What centres determine our intake of food (energy)?

Answer 1

Food intake is controlled by two hypothalamic centres:

• Feeding centre - promotes hunger and drive to eat
• Satiety centre - promotes feelings of fullness by suppressing the Feeding Centre

Question 2

What controls the activity of the feeding and satiety centres?

Answer 2

Controlled through a complex balance of neural and chemical signals as well as nutrients in the plasma.

There are 2 theories saying that either blood Glucose levels (glucostatic theory) or Lipid levels (lipostatic theory) drive our feelings of hunger

Question 3

What is Leptin?

Answer 3

Hormone released by fat stores in the body to depress feelings of hunger

(very much involved in lipostatic theory)

Question 4

What are the 3 big ways (categories) in which we use energy?

Answer 4

Cellular work:

• transporting molecules across membranes
• growth and repair
• storage of energy (eg. fat, glycogen, ATP synthesis).

Mechanical work:

• movement, either on large scale using muscle or intracellularly

Heat loss:

• associated with cellular and mechanical work
• accounts for half our energy output.

Question 5

When talking about metabolism, there are anabolic and catabolic pathways. What are these?

Answer 5

Anabolic pathways (build-up):

• Synthesis of large molecules from small ones
• Usually for storage (think glycogen or something)

Catabolic pathways (break-down):

• Degradation of large molecules into smaller ones, releasing energy for work.

Question 6

What is meant by anabolic and catabolic phases?

Answer 6

Anabolic phase:

• Absorptive state - entered after we eat
• Ingested nutrients supply the energy needs of the body and excess is stored

Catabolic phase:

• Post-absorptive (fasted) State - between meals and overnight
• Energy is derived from energy stores - thus larger molecules broken down into smaller ones to release energy

Question 7

What is meant by an ‘obligatory glucose user?’

Answer 7

Cells/tissues that can only use glucose to provide their energy - such as the brain

Most cells can use fats, carbohydrates or protein for energy but the brain can only use glucose (unless in extreme starvation)

Question 8

How do obligatory glucose users maintain a sufficient supply of blood glucose?

Answer 8

BG is maintained by synthesising glucose from glycogen (glycogenolysis) or amino acids (gluconeogensis)

If systemic BG levels drop below a certain level - only the brain receives the BG

Question 9

What is the normal range for blood glucose?

Answer 9

Normal range of [BG] = 4.2 - 6.3mM (80-120mg/dl)

5 mmoles useful to remember

Question 10

What Blood glucose level is considered to be Hypoglycaemia?

Answer 10

Hypoglycaemia = [BG] < 3mM

Question 11

What hormones are used to regulate the levels of blood glucose?

Where are these secreted from?

Answer 11

Insulin

Glucagon

PANCREAS

Question 12

How much of the pancreas is exocrine and how much is endocrine?

Answer 12

99% exocrine

1% endocrine

Question 13

What structure and cells in the pancreas release insulin and glucagon?

Answer 13

Endocrine stuff done in Islets of Langerhans

Glucagon = Alpha cells

Insulin = Beta cells

Other:

• Somatostatin = Delta cells
• Pancreatic polypeptide = F cells

Question 14

What is the function of Insulin and Glucagon?

Answer 14

Insulin causes glucose uptake into cells, from the plasma. It decreases blood glucose levels.

Glucagon causes glucose release into the plasma - increasing blood glucose levels

Question 15

Describe the ratios of insulin:glucagon in different metabolic states

Answer 15

Absorptive (anabolic) state - Insulin dominates

Fasted (catabolic) state - Glucagon dominates

Question 16

Describe how insulin is synthesised & secreted

Answer 16

Insulin is a peptide hormone - so is synthesised in Beta cells as a preprohormone (preproinsulin) which is converted to proinsulin in the ER

Proinsulin is then packaged as granules in secretory vesicles.

Within the granules, the proinsulin is cleaved again to give insulin and C-peptide. Insulin is stored in this form until the b cell is activated and secretion occurs.

Question 17

What controls the secretion of insulin?

Answer 17

The Major stimulus is [glucose]_plasma

However, Amino acids & glucose in the GI tract stimulate insulin release from the pancreas as well

Question 18

Describe the mechanism through which [BG] can cause insulin secretion

Answer 18

B-cells have a specific type of K+ ion channel that is sensitive to the [ATP] within the cell = KATP channel.

When glucose is abundant it enters cells through glucose transport proteins (GLUT) and metabolism increases.

This increases [ATP] within the cell causing the K⁺ATP channel to close.

Intracellular [K+] rises, depolarising the cell.

Voltage-dependent Ca2+ channels open and trigger insulin vesicle exocytosis into the circulation.

Question 19

Explain why low blood glucose levels (seen in fasted state) do not cause secretion of insulin?

Answer 19

Low [BG] means low metabolic activity in the B cell - so [ATP] in B cells is also low

Low [ATP] means K_ATP channels remain open - so K⁺ ions flow out

This hyperpolarises the cell - meaning that voltage-gated Ca²⁺ channels remain closed and insulin is not secreted

Question 20

What receptor does insulin bind to on target cells?

Answer 20

Binds to tyrosine kinase receptors on the cell membrane of insulin-sensitive tissues to increase glucose uptake by these tissues

Question 21

What happens when insulin binds to a Tyrosine kinase receptor?

Answer 21

Insulin binding stimulates the mobilization of specific glucose transporters - GLUT4 - which reside in the cytoplasm of muscle and adipose cells

GLUT4 travels to the cells membrane - where it can transport glucose into the cell

When insulin stimulation stops - it fucks off back to the cytoplasm

Question 22

What is meant by the term ‘insulin dependence’?

Answer 22

Most types of tissue do NOT require insulin to take up glucose, ONLY muscle and fat are insulin-dependent.

However, these tissues make up a lot of you

Question 23

In tissues that are NOT insulin-dependent, what Glucose transporters are used for glucose uptake into cells?

Answer 23

GLUT1 - Basal glucose uptake in many tissues eg brain, kidney and red blood cells.

GLUT3 - Similar to GLUT1

GLUT2 - b-cells of pancreas and liver

Question 24

How does Glucose uptake work in the liver?

Answer 24

Liver is NOT insulin-dependent and uses GLUT2 transporters

Glucose uptake just follows a concentration gradient

However, insulin status affects glucose transport into hepatocytes - by altering the intracellular concentrations of Glucose

Question 25

How does Insulin affect the transport of Glucose into hepatocytes?

Answer 25

In fed state, liver takes up glucose because insulin activates hexokinase which lowers [glucose]_ic

This creates a gradient favouring glucose movement into the cells.

When fasted, liver synthesises glucose via glycogenolysis and gluconeogenesis, increasing [glucose]ic

This creates a gradient favouring glucose movement out of the cells into the blood.

Question 26

What are the additional actions of Insulin, outsides of increasing glucose uptake?

Answer 26

1) Stimulates Glycogen synthesis in liver & muscle
2) Stimulates Protein synthesis
3) Stimulates lipogenesis
4) Inhibits gluconeogenesis
5) Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase

Question 27

How is insulin degraded?

Answer 27

It is principally degraded in the liver and kidneys

Once insulins action is complete, it is internalised by endocytosis and destroyed (although some is recycled)

Question 28

What are the stimuli that increase insulin secretion?

Answer 28

Increased [blood glucose]

Increased [Amino acids]_plasma

Glucagon (insulin required to take up glucose created via gluconeogenesis stimulated by glucagon)

Other (incretin) hormones - mainly GI ones (gastrin, secretin etc)

Vagal nerve activity

Question 29

What are the main stimuli that inhibit the secretion of insulin?

Answer 29

Low [blood glucose]

Somatostatin (GHIH)

Sympathetic a2 effects

Stress - eg Hypoxia

Question 30

What is the effect of vagal activity on insulin release?

What does this mean when comparing the insulin response to IV glucose or oral glucose?

Answer 30

Vagal activity (when we eat) stimulates the release of major GI hormones and also stimulates insulin release

This means the insulin response to intravenous glucose is actually smaller than that of oral glucose

IV glucose only stimulates B cells in pancreas whereas oral glucose has vagal action, direct B cell stimulation and the effects of incretin