Endocrine pancreas 1+2 Flashcards
The balance of activity in which 2 hypothalamic centres determines energy (food) intake? and how is it controlled?
Feeding centre - promotes feelings of hunger and drive to eat
Satiety centre - promotes feelings of fullness by suppressing the Feeding centre
In both - activity is controlled by a complex balance of neural and chemical signals as well as the presence of nutrients in plasma
What is the glucostatic theory
food intake is determined by blood glucose: as [BG] increases, the drive to eat decreases (- Feeding Centre; + Satiety centre)
What is the lipostatic theory?
food intake is determined by fat stores: as fat stores increase, the drive to eat decreases (- feeding centre; + Satiety Centre).
What is leptin?
A peptide hormone released by fat stores which depresses feeding activity
How does obesity result?
imbalance in energy balance - too much input not enough output
rare for it to come about due to metabolic problem
What are the 3 categories of energy output?
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 (voluntary – posture etc and involuntary – cellular level etc)
Heat loss - associated with cellular and mechanical work accounts for half our energy output
What is the only part of energy output that can be regulated?
The mechanical work doen by skeletal muscle
What are the 3 elements of metabolism
Extracting energy from nutrients in food
Storing that energy
Utilising that energy for work
Why is it important to maintain blood glucose concentration?
We need sufficient levels of glucose in the blood to meet the brain’s requirements
The brain gets first dibs on any glucose in the blood (it will take it to the detriment of any other tissues in the body) – needs it to function properly
hypoglycaemia can lead to coma and death
What is glycogenolysis?
synthesising glucose from glycogen (stored in muscle)
What is gluconeogenesis?
Synthesising glucose from amino acids
Normal blood glucose range
4.2-6.3 mM (80-120mg/dl)
remember 5 mmoles as this is pretty much normal
What normally happens if blood glucose levels become too low?
Brain only has access to [BG]
Overflow due to problem with glucose metabolism can cause what?
overflow of glucose into urine
What is lipogenesis?
excess glucose moves into fat stores
What is lipogenesis? what is stimulated by
excess glucose moves into fat stores
stimulated by insulin binding to receptor on fat cell
What is glucagon responsible for?
Increasing blood glucose levels - peptide hormone produced by alpha cells of the pancreatic islet cells
What is insulin responsible for?
Decreasing blood glucose levels
What does the pancreas release through ducts to support digestion?
enzymes
NaHCO3
Only 1% of the pancreas has endocrine function. Where are it’s hormones produced?
In the Islets of Langerhans
What are the 4 types of Islet cells?
alpha cells produce GLUCAGON
beta cells produce INSULIN
delta cells produce SOMATOSTATIN
F cells produce pancreatic polypeptide (function not really known, may help control of nutrient absorption from GIT.)
In what ways does insulin reduce [BG]? (4)
Increases glucose oxidation
Increases Glycogen synthesis
Increases fat synthesis
Increases protein synthesis
In what ways does glucagon increase [BG]? (3)
Increases Glycogenolysis
Increases Gluconeogenesis
Increases Ketogenesis
What happens during the absorptive state?
Glucose, amino acids and fatty acids enter the blood from the GI tract
Both stimulate insulin secretion but the major stimulus is [BG]
What is the only hormone that lowers [BG]?
Insulin
What is glucose stored as in liver and adipose tissue
Triacylglycerols
What is glucose stored as in liver and muscle
glycogen
What is the mechanism by which [BG] controls insulin secretion
High [BG]
Metabolism increases
ATP increases
K-ATP channels (specific to pancreatic B cells) close
cell depolarises and calcium channels open
Ca2+ entry acts as an intracellular signal
Ca2+ signal triggers exocytosis and insulin is secreted
What happens to close Ca2+ voltage gated channels and stop insulin secretion?
When [BG] is low, [ATP] is low so KATP channels are open
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
Primary action of insulin
Binds to tyrosine kinase receptors on the cell membrane of insulin-sensitive tissues to increase glucose uptake by these tissues.
In muscle and adipose tissue, insulin stimulates the recruitment of GLUT4 transporter to the membrane
Glucose can then be transported into the cell
when insulin stimulation stops then GLUT 4 transporters return to cytoplasm pool
the glucose taken up by cells is primarily used for energy
Which are the only types of tissue that are insulin dependent?
Muscle and fat (takes up large proportion of body mass - so actually a lot of the body is dependent on insulin)
not all tissues require insulin to take up glucose - instead its via GLUT transporters
Functions of GLUT1, GLUT2 and GLUT3
GLUT1 + GLUT2 - Basal glucose uptake in many tissues eg brain, kidney and red blood cells.
GLUT 3 - B cells of pancreas and liver
Liver and glucose uptake
liver is not insulin dependent
takes up glucose via GLUT 2 transporters (insulin independent)
Glucose enters down conc gradient
although insulin has no direct effect on the liver, glucose transport into hepatocytes is affected by insulin status
How does insulin status indirectly affect glucose transport into hepatocytes?
after eating, insulin promotes intracellular glucose metabolism so lowering the [glucose]IC
this creates a concentration gradient favouring glucose movement into the cells
How does the liver release glucose in fasted state (post-absorptive)?
The liver synthesises glucose via glycogenolysis and gluconeogenesis (stimulated by glucagon)
this increases [glucose]ic creating a gradient favouring glucose movement out of the cells into the blood.
Additional actions of insulin - activation of multiple signal transduction pathways associated with the insulin receptor
Increases glycogen synthesis in muscle and liver. Stimulates glycogen synthase and inhibits glycogen phosphorylase.
Increases amino acid uptake into muscle, promoting protein synthesis.
Increases protein synthesis and inhibits proteolysis
Increases triacylglycerol synthesis in adipocytes and liver i.e. stimulates lipogenesis and inhibits lipolysis.
Inhibits the enzymes of gluconeogenesis in the liver
Has a permissive effect on Growth hormone
Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase. Very important clinically.*** Diabetes – lose K+ entry? - hyperkalaemia
Half life of insulin
5 minutes
Where is insulin degraded principally
In the liver and the kidneys
What happens once insulin action is complete?
Insulin-bound receptors are internalised by endocytosis and destroyed by insulin protease, some recycled.
Stimuli that increase insulin release (5)
Increased [BG]
Increased [amino acids]plasma
Glucagon - insulin takes up glucose which is created by gluconeogenesis which is stimulated by glucagon
vagal nerve activity
Other hormones controlling GI secretion and motility
Stimuli which inhibit insulin release
low [BG]
Somatostatin GHIH
Sympathetic alpha 2 effects
stress - hypoxia
Vagal activity
Vagal activity stimulates release of major GI hormones, and also stimulates insulin release
therefore meaning that the insulin response to an IV glucose load is less than the equivalent amount of glucose administered orally (goes through gut)
Half life of glucagon
5-10 mins in plasma
degraded mainly by liver
What is involved in the glucose counter-regulatory control system
Glucagon
Epinephrine
Cortisol
Growth hormone
When is glucagon most active?
Post-absorptive state (between meals/at night)
What are glucagon receptors like?
G protein coupled receptors linked to the adenylate cyclase/cAMP system - when activated phosphorylate specific liver enzymes
What happens when specific liver enzymes are phosphorylated after glucagon binds
increased glycogenolysis
increased
gluconeogenesis (substrates: aa’s and glycerol (lipolysis))
formation of ketones from fatty acids (lipolysis)
Stimuli that promote glucagon release
Low [BG] (<5mM)
high [amino acids] - prevent hypoglycaemia
Sympathetic innervation and epinephrine, B2 effect
Cortisol
Stress - exercise, infection
Stimuli that inhibit glucagon release
BG
free fatty acids and ketones
Insulin
somatostatin
Autonomic nervous system innervation of islet cells
generally…
increased parasympathetic activity (vagus) increases insulin and to a lesser extent increases glucagon, in association with the anticipatory phase of digestion.
increased sympathetic activation promotes glucose mobilisation which increases glucagon which increases epinephrine and inhibition of insulin - all appropriate for fight or flight response.
Somatostatin (also known as growth hormone inhibiting hormone)
Somatostatin is a peptide hormone secreted by Delta cells of the pancreas
Main pancreatic action is to inhibit activity in the GI Tract.
It seems to slow down absorption of nutrients to prevent exaggerated peaks in plasma concentrations.
SS is NOT a counter-regulatory hormone in the control of blood glucose but it does strongly suppresses the release of both insulin and glucagon in a paracrine fashion.
Effect of exercise on [BG]
The entry of glucose into skeletal muscle is increased during exercise, even in the absence of insulin.
Exercise also increases the sensitivity of muscle to insulin, and causes an insulin-independent increase in the number of GLUT-4 (on skeletal muscle) transporters incorporated into the muscle membrane.
regular exercise can produce prolonged increases in insulin sensitivity
critical in improving type 2 diabetes - – exercise lowers BG without requiring insulin
Starvation
When nutrients are scarce, body relies on stores for energy – when adipose tissue is broken down fatty acids are released.
Free FA’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 (in extreme cases)!
this serves to ‘spare protein’ as otherwise too much protein would be lost - very weakening, vulnerable to infection
After a period of starvation what does the brain do
adapts to be able to use ketones as an energy source
How does life- threatening acidocis come about in diabetes type 1
in poorly controlled insulin-dependent diabetes a lack of insulin depresses ketone body uptake (because insulin supports this 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. (normal = 7.4)
Death will occur within hours if untreated.
Type 2 diabetes - non-insulin dependent diabetes mellitus
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.
B-cells remain intact and appear normal, there may even be hyperinsulinaemia.
90% of diabetic patients are of this type
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.
[BG] elevated in both Type I and Type II Diabetes for different reasons:
Type 1 - inadequate insulin release
Type 2 - inadequate tissue response
Hyperglycaemia (elevated [BG]) is the diagnostic criterion for diabetes - detected by GTT
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.
[BG] elevated in both Type I and Type II Diabetes for different reasons:
Type 1 - inadequate insulin release
Type 2 - inadequate tissue response
Hyperglycaemia (elevated [BG]) is the diagnostic criterion for diabetes - detected by GTT
Diabetic complications (4)
Retinopathy
Neuropathy
Nephropathy
Cardiovascular Disease
