3 - endocrine pancreas

what is food intake determined by?

2 hypothalamic centres

- feeding centre

- satiety centre

what is the glucostatic theory

food intake is determined by blood glucose - as blood glucose increases, the drive to eat decreases

what is the lipostatic theory

food intake is determined by fat stores - as fat stores increase the drive to eat decreses

what peptide hormone is released by fat stores to decrease feeding activity

leptin

what is energy output

all the processes performed to stay alive and those performed voluntary as well as heat loss associated with these

what are the 3 categories of energy output

- cellular work

- mechanical work

- heat loss

what is cellular work

transportation of mlecules across membranes

growth and repair

storage of energy

what is mechanical work

movement on a large scale using muscle or intracellularly

what is heat loss associated with

associated with cellular and mechanical work - accounts for 50% of energy output

what is metabolism

integration of all biocehmical reactions in the body

what are the 3 elements of metabolism

extracting energy from nutrients

storing energy

utilising energy for work

net effect of anabolic pathways

synthesis of large molecules from smaller ones usually for storage purposes

net effect of catabolic pathways

degradation of large molecules into smaller ones releasing energy

what happens after eating - what state does the body enter?

enter absorptive phase

- ingested nutrients supply energy needs of body and excess if stored

- a type of anabolic pathway

what happens to the body after meals and overnight? - what state does the body enter?

- pool of nutrients in plasma decreases

- enter POST ABSORPTIVE state or fasted state

- rely on body stores for energy

- this is a catabolic phase

what does the brain use for energy?

glucose only except in extreme starvation where ketones are used

how is blood glucose maintained

synthesising glucose from glycogen (glycogenolysis) or amino acids (gluconeogenesis)

normal blood glucose range

4.2 - 6.3 mM (80-120mg/dl)

5mM key value

when is someone hypoglycaemic

BG <3mM

what happens to excess glucose

broken down and converted into free fatty acids then converted to farry acids via glyocgenesis

what happens to proteins in terms of energy storage

proteins get broken down into amino acids in amino acid pool and used to build proein and fats to contribute to fat stores through lipogenesis

what happens when blood glucose fails

blood glucose is maintained by breaking down glycogen stores thorugh glycogenolysis

creation of new glucose from amino acids through gluconeogenesis

what are glycogenolysis and gluconeogenesis stimulated by

glucagon

- when all the glucose is gone all you need is glucagon

what is glucagon

a catabolic hormone secreted by pancreas to break down gluycogen to release glucose to maintin blood glucose

what is insulin

an anabolic hormone that stimulates glycogenolysis to release glycogen from glucose

- lowers BG

what are the endocrine cells of the pancreas

islets of langerhans

cell types in islets of langerhans

alpha cells

beta cells

delta cells

gamma cells

epsilon cells

where are pancreatic hormones produced

islets of langerhans

what is inuslin produced by and what is its function

beta cells

- decrease BG levels

what is amylin produced by and its function

beta cells

- slows gastric emptying to prevent spikes in BG

what is glucagon produced by and its function

alpha cells

- increases BG

what is somatostatin produced by and its function

delta cells

- regulates islet cell secretion of other hormones

what is pancreatic polypeptide produced from and its function

gamma cells or F cells

- function not entirely known - GI function

what is grehlin produced by and its funciton

epsilon cells

- increase appetite

what does the pancreas release into alimentary canal to help with digestion

enzymes and sodium bicarbonate via ducts

what does control of BG depend on

balance between insulin and glucagon

what happens when glucose is taken up by cells from plasma

BG decreases

enter fed state so insulin increases

- increased glucose oxidation

- increased glycogen synthesis

- increased fat synthesis

- increased protein synthesis

what happens when glucose is released into plasma from stores

BG increases

enter fasted state so glucagon increases

- increased glycogenolysis

- increased gluconeogenesis

- increased ketogenesis

what type of hormone is insulin

peptide hormone

What cells produce insulin?

Beta cells

What is the function of insulin?

Stimulates glucose uptake by cells

lowers blood glucose

Describe the synthesis of insulin.

Synthesized as proprohormone (preproinsulin) which is converted to proinsulin in the endoplasmic reticulum

What happens to proinsulin in secretory vesicles?

Proinsulin is cleaved to give insulin and C-peptide

How is insulin stored before secretion?

Insulin is stored in granules until beta cells are activated and secretion occurs

what happens in the absorptive state

amino acids and fatty acids enter blood from GIT

both glucose and amino acids stimulate insulin secretion but major stimulus is BG concentration

what hormone dominates the absorptive state

insulin

what do most cells use for energy during absorptive state

glucose

what is excess glucose stored as and where

stored as glycogen in liver and muscle and triclyglycerols (TAG) in liver and adipose tissue

mechanism of secretion of insulin by BG

beta cells have specific K+ ion channels sensitive to ATP

when glucose is abdundant it enters cells through GLUT4 and metabolism increases

increased ATP causing K ATP channel to close

intracellular K+ increases and depolarises cell

voltage gated Ca2+ channels open and trigger insulin vesicle exoctyosis

when BG is low, what is also low and what happens?

ATP is also low

- so K ATP channels are open so K+ ions flow out

what happens when blood glucose is low

ATP is low so K ATP channels are open

K + ions flow out removes positive charge from cell

hyperpolarises cell

voltage gated Ca2+ channels remain closed and insulin is NOT SECRETED

what receptors does insulijn bind to?

tyrosine kinase receptors on cell membranes of insulin dependent tissues

what does insulin stimulate in adipose tissue and muscle

mobilisation of GLUT4

- GLUT4 migrates to membrane to transport glucose into cell

when insulin stimulation stops, the GLUT 4 transporters return to the cytoplasmic pool

what are the only insulin dependent tissues

muscle and fat (adipose tissue)

what are GLUT 1 and 3 used for

basal glucose uptake in brain, kidneys and RBCs

what is GLUT2 used for

beta cells of pancreas and liver

the liver is not insulin dependent so how is glucose transported in liver?

liver takes up glucose by GLUT2 which is insulin dependent

- glucose enters DOWN concentration gradient

- glucose is transported into hepatocytes and affected by insulin status

in the fed state, why would the liver take up glucose

insulin activates hexokinase which lowers glucose creating a concentration gradient favouring glucose movement into cells

in the fasted state, what happens with glucose and the liver

the liver synthesises glucose via glycogenolysis and gluconeogenesis

- this increases glucose and creates a gradient favouring movement out of the cells into blood

what are the additional actions of insulin

increases glycogen synthesis in muscle and liver - stimulates glycogen synthase and inhibits glycogen phosphorylase

increases amino acid uptake into muscle promoting protein synthesis and inhibits proteolysis

increases TAG and synthesis in adipocytes and liver i.e. stimulates lipogenesis and inhibits lipolysis

inhibits enzymes of gluconeogenesis in liver

permissive effects on GH

promotes K+ entry into cells by stimulating Na+/K+ ATPase

where is insulin degraded

liver and kidneys

how is insulin degraded

once action is complete, insulin bound receptors are internalised by endocytosis and destroyed by insulin protease - some is recycled

stimuli that INCREASE insulin release

increased BG

increased amino acids in plasma

glucagon

other incretin hormones controlling GI secretion and motility

vagal nerve activity

stimuli which DECREASE insulin activity/promote glucagon release

low blood glucose <5mM

high amino acids

somatostatin GHIH

sympathetic innervation and epinephrine, beta 2 effects

cortisol

stress e.g. infection

what is insulin half life

5 minutes

what is an obligatory glucose utiliser

must use glucose as primary energy source under normal conditions

e.g. brain

what is a non obligatory glucose utiliser

can switch between free fatty acids, carbohydrates and proteins for energy

e.g. muscle and fat

failure to maintain blood glucose causes…

hypoglycaemia which can lead to death

in the post absorptive state what does low insulin levels mean?

a large mass of tissue

i.e. muscle and fat, cannot readily access glucose and so there is glucose sparing for obligatory glucose users

insulin site of action

• Muscle: The primary site for glucose disposal. 

• Adipose Tissue (Fat): For energy storage. 

• Liver: To regulate the production and release of glucose. 

what does insulin stimulate the liver and muscles to do?

convert excess glucose into glycogen, a storage form of carbohydrate

what does insulin suppress?

glycogenolysis and gluconeogenesis ensuring the liver does not add more glucose to an already high supply in the blood

acts as a brake on the liver

insulin effect on adipose tissue

promotes lipogenesis and inhibits lipolysis

increases amino acid uptake and protein synthesis while inhibiting protein degradation

primary site of action for glucagon

the liver

what does exercise cause

glucose uptake independently of insulin

exercise also increases insulin sensitivity of muscle

type 1 diabetes

Autoimmune destruction of the pancreatic b-cells destroys ability to produce insulin and seriously compromises patients ability to absorb glucose from the plasma. 

type 2 diabetes

Type 2: non-insulin dependant diabetes  b-cells remain intact and appear normal, there may even be hyperinsulinaemia. 

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. 

-typically obese, >40yo

blood glucose elevation type 1 vs type 2

type 1 - inadequate insulin release increases BG

type 2 - inadequate tissue response increases BG

what is the diagnostic criteria for diabetes

hyperglycaemia - elevated blood glucose

how is hyperglycaemia detected?

glucose tolerant 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. 

diabetic ketoacidosis

excessively high blood glucose due to lack of insulin due to dysfunctional pancreas,high plasma glucagon, becomes acidic, life threatening, pH < 7.1

diabetic complications

Retinopathy 

Neuropathy 

Nephropathy 

Cardiovascular Disease 

Acute concern in T1DM is ketoacidosis! 

staging of physiological changes in blood glucose:

4.6mM [BG] →                       

 3.8mM [BG] →

3.2mM [BG] →                                                 

2.8mm [BG] →                                          

2.2mM [BG] →                                                        

1.7mM [BG] →                                                                

 1.1mM [BG] →                                                      

0.6mM [BG] →

inhibition of insulin secretion       

glucagon, epinephrine and GH secretion

cortisol secreted  

cognitive dysfunction    

lethargy   

coma

convulsions

permanent brain damage and death

what do you use to treat ketoacidosis

insulin

what do you use to treat hypoglycaemia

glucose

synthetic somatostatin may be used clinically to help patients with what?

life threatening diarrhoea associated with gut or pancreatic tumours

what does somatostatin suppress?

the release of both insulin and glucagon in a paracrine fashion

stimuli that inhibit glucagon release

1. glucose  

2. free fatty acids (FFA) and ketones  

3. insulin  (fails in diabetes so glucagon levels rise despite high [BG] ) 

 4.somatostatin  

in ANS innervation of islet cells: increase in parasympathetic activity (vagus)

increases insulin and decreases glucagon (to a lesser extent), in association with the anticipatory phase of digestion

in ANS innervation of islet cells: increase in sympathetic activation

promotes glucose mobilisation → increases glucagon, increases epinephrine and inhibition of insulin, all appropriate for fight or flight response