The endocrine pancreas 1 and 2

Question 1

What are the two centres that determine food intake and where are they ?

Answer 1

The hypothalamus

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

Question 2

How is the activity in the hypothalamic centres controlled?

Answer 2

• Activity in each is controlled by a complex balance of neural and chemical signals as well as the presence of nutrients in plasma.
• Glucostatic theory: food intake is determined by blood glucose: as [BG] increases, the drive to eat decreases (- Feeding Centre; + Satiety centre)
• Lipostatic theory: food intake is determined by fat stores: as fat stores increase, the drive to eat decreases (- feeding centre; + Satiety Centre). Leptin is a peptide hormone released by fat stores (adipose tissue) which depresses feeding activity.

Question 3

What are the categories of energy output?

Answer 3

• 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 4

What are the three elements of metabolism?

Answer 4

1. Extracting energy from nutrients in food
2. Storing that energy
3. Utilising that energy for work

Question 5

What are the metabolic pathways?

Answer 5

• Anabolic pathways = Build Up. Net effect is synthesis of large molecules from smaller ones, usually for storage purposes.
• Catabolic pathways = Break Down. Net effect is degradation of large molecules into smaller ones, releasing energy for work.

Question 6

How is blood glucose maintained?

Answer 6

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

Question 7

What is the normal range of blood glucose?

Answer 7

4.2-6.3mM

Question 8

What types of islet cells are there in the pancreas

Answer 8

• Alpha cells produce GLUCAGON
• Beta cells produce INSULIN
• Sigmoid cells produce SOMATOSTATIN
• F cells produce pancreatic polypeptide (function not really known, may help control of nutrient absorption from GIT.)

Question 9

What happens (in terms of hormones and results) when we are in a fed state?

Answer 9

• Insulin dominates
• Glucose taken up by cells from plasma ([BG] decreases)
• Increased glucose oxidation
• Increased glycogen synthesis
• Increased fat synthesis
• Increased protein synthesis

Question 10

What happens (in terms of hormones and results) when we are in a fasted state?

Answer 10

• Glucagon dominates
• Glucose released into plasma from stores ([BG] increases)
• Increased glycogenolysis
• Increased gluconeogenesis
• Increased ketogenesis

Question 11

Describe the production of insulin

Answer 11

• Peptide hormone produced by pancreatic beta cells
• Stimulates glucose uptake by cells
• Synthesized as a large preprohormone, preproinsulin, which is then 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 beta cell is activated and secretion occurs

Question 12

What happens to insulin in the absorptive state?

Answer 12

• Glucose, amino acids (aa) and fatty acids enter blood from GI Tract
• Both glucose and aa’s stimulate insulin secretion but the major stimulus is blood glucose concentration
• Insulin dominates the absorptive state (only hormone which lowers [BG])
• Most cells use glucose as their energy source during the absorptive state
• Any excess is stored as glycogen in liver and muscle, and as triacylglycerols (TAG) in liver and adipose tissue
• Amino acids are used mainly to make new proteins with excess being converted to fat
• Also form an energy source
• Fatty acids are stored in the form of triglycerides in adipose tissue and liver

Question 13

Describe the mechanism f control of insulin secretion by [BG]

Answer 13

• Beta-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 KATP channel to close
• Intracellular [K+ ] rises, depolarising the cell
• Voltage-dependent Ca2+ channels open and trigger insulin vesicle exocytosis into the circulation
• When [BG] is low, [ATP] is low so KATP channels are open so K+ ions flow out removing +ve charge from the cell and hyperpolarizing it, so that voltage-gated Ca2+ channels remain closed and insulin is not secreted

Question 14

What is the primary action of insulin (in detail)?

Answer 14

• Binds to tyrosine kinase receptors on the cell membrane of insulin-sensitive tissues (muscle and adipose tissue) to increase glucose uptake by these tissues
• Insulin is the ONLY hormone that lowers [BG]
• Insulin stimulates the mobilization of specific glucose transporters, GLUT-4, which reside in the cytoplasm of unstimulated muscle and adipose cells
• When stimulated by insulin GLUT4 migrates to the membrane and is then able to transport glucose into the cell
• When insulin stimulation stops, the GLUT-4 transporters return to the cytoplasmic pool
• The glucose taken up by cells is primarily used for energy
• Most types of tissue do NOT require insulin to take up glucose, ONLY muscle and fat are insulin sensitive

Question 15

What are the types of GLUT-transporters and where do they work?

Answer 15

• GLUT4: muscle and fat
• GLUT1: Basal glucose uptake in many tissues e.g. brain, kidney and red blood cells
• GLUT3: similar
• GLUT2: Beta-cells of pancreas and liver

Question 16

What are the additional actions of insulin?

Answer 16

a) Increases glycogen synthesis in muscle and liver
- Stimulates glycogen synthase and inhibits glycogen phosphorylase
b) Increases amino acid uptake into muscle, promoting protein synthesis
c) Increases protein synthesis and inhibits proteolysis
d) Increases triacylglycerol synthesis in adipocytes and liver i.e. stimulates lipogenesis and inhibits lipolysis
e) Inhibits the enzymes of gluconeogenesis in the liver
f) Has a permissive effect on Growth Hormone
g) Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase (Very important clinically)

Question 17

What are the stimuli which increase insulin release?

Answer 17

1. Increased [BG]
2. Increased [amino acids] plasma
3. Glucagon (insulin required to take up glucose created via gluconeogenesis stimulated by glucagon)
4. Other (incretin) hormones controlling GI secretion and motility eg gastrin, secretin, CCK, GLP-1, GIP
   - Released by ileum and jejunum in response to nutrients
   - Early insulin release prevents glucose surge when absorption occurs.
5. Vagal nerve activity

Question 18

What are the stimuli which inhibit insulin release?

Answer 18

1. Low [BG]
2. Somatostatin (GHIH)
3. Sympathetic alpha 2 effects
4. Stress e.g. hypoxia

Question 19

What is glucagon?

Answer 19

• Peptide hormone produced by alpha-cells of the pancreatic islet cells in same fashion as all peptide hormones
• Primary purpose is to raise blood glucose
• It is a glucose-mobilizing hormone, acting mainly on the liver
• Plasma half-life 5-10mins, degraded mainly by liver

Question 20

What is the purpose of glucagon?

Answer 20

Primarily opposes the action of insulin, forming part of the glucose counter-regulatory control system which includes the hormones epinephrine, cortisol and GH. It is most active in the post-absorptive state

Question 21

Describe glucagon receptors

Answer 21

Glucagon receptors are G-protein coupled receptors linked to the adenylate cyclase/cAMP system which when activated phosphorylate specific liver enzymes

Question 22

What are the actions of glucagon?

Answer 22

• increased glycogenolysis
• increased gluconeogenesis (substrates: aa’s and glycerol (lipolysis))
• formation of ketones from fatty acids (lipolysis)

Question 23

Amino acids are a potent stimulus for glucagon. What would happen if they were not?

Answer 23

• Amino acids in the plasma stimulate release of both insulin and glucagon
• This is an adaptation to adjust for the composition of a meal very high in protein (typical of carnivores!)
• If it were not for the effect of aas on glucagon then the insulin-stimulating effects of aas would result in very low [BG]
• This is counteracted by the glucose mobilizing effects of glucagon and so [BG] is maintained.

Question 24

What are the stimuli which promote glucagon release?

Answer 24

1. Low [BG]
2. High [amino acids]
   - Prevents hypoglycemia following insulin release in response to aa
3. sympathetic innervation and epinephrine, beta 2 effect
4. cortisol
5. stress e.g. exercise, infection

Question 25

What are the stimuli which inhibit glucagon release

Answer 25

1. glucose
2. free fatty acids (FFA) and ketones
3. insulin (fails in diabetes so glucagon levels rise despite high [BG] )
4. somatostatin

Question 26

Describe the ANS innervation of islet cells

Answer 26

• Increased parasympathetic activity (vagus) results in an insulin and to a lesser extent glucagon, in association with the anticipatory phase of digestion.
• Increased sympathetic activation promotes glucose mobilization which results in an increase in glucagon, epinephrine and inhibition of insulin, all appropriate for fight or flight response

Question 27

give a summary of the glucose counter-regulatory controls

Answer 27

• Muscle glycogenolysis: epinephrine
• Liver glycogenolysis: glucagon and epinephrine
• Gluconeogenesis: Glucagon, epinephrine, cortisol and GH
• Inhibition of glucose uptake: GH and cortisol
  Lipolysis: Glucagon, epinephrine, cortisol and GH
  Protein catabolism: Cortisol

Question 28

What is the effect of exercise on blood glucose?

Answer 28

• The entry of glucose into skeletal muscle is increased during exercise, even in the absence of insulin
• Exercise also increases the insulin sensitivity of muscle, and causes an insulin-independent increase in the number of GLUT-4 transporters incorporated into the muscle membrane
• This effect persists for several hours after exercise and regular exercise can produce prolonged increases in insulin sensitivity.

Question 29

What happens during starvation?

Answer 29

• When nutrients are scarce, body relies on stores for energy (when adipose tissue is broken down fatty acids are released)
• FFA’s can be readily used by most tissues to produce energy and liver will convert excess to ketone bodies which provides an additional source for muscle and brain!
• Important: After a period of starvation, the brain adapts to be able to use ketones.

Question 30

What is type 1 diabetes mellitus?

Answer 30

• Autoimmune destruction of the pancreatic beta-cells destroys ability to produce insulin and seriously compromises patients ability to absorb glucose from the plasma
• Untreated type 1 diabetes leads to many complex changes in the body which ultimately cause starvation and death
• Current day: patients need daily insulin injections, (peptide hormones cannot be given orally).
• Type I patients have an absolute need for insulin, without it they become excessively wasted, develop ketoacidosis, coma and die.
• “Starvation in the midst of plenty”

Question 31

What is ketoacidosis?

Answer 31

• In poorly controlled insulin-dependent diabetes a lack of insulin depresses ketone body uptake
• They build up rapidly in the plasma and because they are acidic create life threatening acidosis (ketoacidosis or ketosis) with plasma pH < 7.1
• Death will occur within hours if untreated
• Ketones detectable in urine and produce distinctive acetone smell to breath

Question 32

What is type 2 diabetes mellitus?

Answer 32

• Peripheral tissues become insensitive to insulin = insulin resistance
• Muscle and fat no longer respond to normal levels of insulin
• This is either due to an abnormal response of insulin receptors in these tissues or a reduction in their number
• Btea-cells remain intact and appear normal, there may even be hyperinsulinemia

Question 33

What os the treatment of type 2 diabetes mellitus?

Answer 33

• Initial treatment is aimed at trying to restore insulin sensitivity of tissues with exercise and dietary change (If caught at pre-diabetic stage can prevent progression to full blown diabetes)
• If this fails, oral hypoglycaemic drugs will be used, Metformin is the first line treatment (inhibits hepatic gluconeogenesis and antagonises action of glucagon)
• Sulphonylureas are a class of drug which act to close the KATP in beta cells and therefore stimulate Ca2+ entry and insulin secretion.
• Obviously requires functioning beta cells, so cannot be used to treat type I
• Eventually many type II patients end up taking insulin (very pharmacological doses) in order to prevent hyperglycemia

Question 34

What is the glucose tolerance test?

Answer 34

• Hyperglycemia (elevated [BG]) is the diagnostic criterion for diabetes
• Detected by performing a “Glucose Tolerance Test”
  Patient ingests glucose load after fasting [BG] measured
• [BG] will normally return to fasting levels within an hour, elevation after 2 hours is indicative of diabetes
• Does not distinguish Type I from II.

Question 35

What reasons are there for concern about hyperglycaemia in both type 1 and type 2 diabetes mellitus patients?

Answer 35

• Glucose is a highly reactive molecule which can eventually produce long-term problems that may be very serious = diabetic complications:
• Retinopathy
• Neuropathy
• Nephropathy
• Cardiovascular Disease

Question 36

What are the physiological changes that happen with a change in [BG]?

Answer 36

4. 6mM [BG]= inhibition of insulin secretion 3.8mM [BG]= glucagon, epinephrine and GH secretion
5. 2mM [BG]= cortisol secreted 2.8mm [BG]= cognitive dysfunction 2.2mM [BG]= lethargy 1.7mM [BG]= coma 1.1mM [BG]= convulsions 0.6mM [BG]= permanent brain damage and death