Lecture 3: The Endocrine Pancreas Flashcards
energy (food) intake is determined by the balance of activity in which two hypothalamic centres?
- feeding centre > promotes feelings of hunger and drive to eat
- satiety centre > promotes feelings of fullness by suppressing the feeding centre (insulin sensitive)
describe the glucostatic theory
food intake is determined by blood glucose: as [blood glucose] increases, the drive to eat decreases (- feeding centre, + satiety centre)
describe the 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 which depresses feeding activity.
what are the three categories of energy output? describe each
- cellular work > transporting molecules across membranes; growth and repair; storage of energy (e.g. fat, glycogen, ATP synthesis).
- mechanical work > movement, either on a large scale using muscle or intracellularly.
- heat loss > associated with cellular and mechanical work, accounts for half of our energy output.
define metabolism
the integration of all biochemical reactions in the body
what are the three elements of metabolism?
- extracting energy from nutrients in food
- storing that energy
- utlising that energy for work
describe anabolic pathways
- build up
- net effect is synthesis of large molecules from smaller ones, usually for storage purposes
describe catabolic pathways
- break down
- net effect is degradation of large molecules into smaller ones, releasing energy for work.
After eating we enter an absorptive state. Is this an anabolic or catabolic phase?
anabolic phase
Between meals and overnight the pool of nutrients in plasma decreases and we enter a post-absorptive state (aka fasted state) where we rely on body stores to produce energy. Is this an anabolic or catabolic phase?
catabolic
how is [blood glucose] maintained during a fasted state?
- maintained by synthesising glucose from glycogen (glycogenolysis) or amino acids (gluconeogenesis).
what is the normal range of [BG]?
4.2-6.3mM (80-120mg/dl)
what [BG] is considered hypoglycaemia?
[BG] < 3mM
what % of the pancreas had endocrine function?
1%
what are the four types of islet cells and what do they produce?
4 types of islet cells: alpha, beta, delta & F.
- 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.)
does insulin dominate in the fed state or the fasted state?
fed state
does glucagon dominate in the fed or fasted state?
fasted state
what processes does insulin stimulate?
- glucose oxidation
- glycogen synthesis
- fat synthesis
- protein synthesis
what processes does glucagon stimulate?
- glycogenolysis
- gluconeogenesis
- ketogenesis
describe the synthesis and storage of insulin
- synthesised as a large preprohormone, preproinsulin, which is then converted to proinsulin in the endoplasmic reticulum.
- 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.
what stimulates insulin release?
major stimulus is an increase in blood glucose concentration
- amino acids also stimulate
what is excess glucose stored as?
- glycogen in liver and muscle
- triacylglycerols (TAG) in liver and adipose tissue
how does glucose activate beta islet cells?
- when glucose is abundant it enters cells through GLUT proteins and metabolism increases.
- this increases the [ATP] within the cell causing the [ATP] sensitive K+ ion channel on the surface of the beta cell to close.
- intracellular [K+] rises, depolarising the cell.
- voltage-dependent Ca2+ channels open and trigger insulin sensitive vesicle exocytosis into the circulation.
how does insulin stimulate glucose uptake?
- insulin binds to tyroskine kinase recptors on the cell membrane of insulin-dependent tissues.
- in muscle and adipose tissue, insulin stimulates the mobilisation of GLUT-4 which then migrates from the cytoplasm to the cell membrane and is then able to transport glucose into the cell.
which tissues are insulin dependent (require insulin to take up glucose)?
muscle and fat
which GLUT transporter uptakes glucose in the beta-cells of the pancreas and liver?
GLUT-2 (the liver is not an insulin dependent tissue)
which GLUT transporters allow glucose uptake in many tissues e.g. brain, kidney and red blood cells?
GLUT-1 and GLUT-3
how does insulin indirectly alter glucose transport in hepatocytes?
- in fed state, liver takes up glucose because insulin activates hexokinase which lowers [intracellular glucose] creating a gradient favouring glucose movement into cells.
what is the half-life of insulin?
5 minutes
how and where is insulin degraded?
- degraded principally in the liver and kidneys.
- once insulin action is complete, insulin bound receptors are internalised by endocytosis and destroyed by insulin protease, some recycled.
list the stimuli which increase insulin release
- increased [BG]
- increased [plasma amino acids]
- glucagon (insulin required to take up glucose created via gluconeogenesis stimulated by glucagon).
- other (incretin) hormones controlling GI secretion and motility e.g. gastrin, secretin, CCK, GLP-1, GIP.
- vagal nerve activity
list the stimuli which inhibit insulin release
- low [BG]
- somatostatin (GHIH)
- sympathetic alpha-2 effects
- stress e.g. hypoxia
glucagon function
- primary purpose is to raise blood glucose
- actas as a glucose-mobilising hormone, acting mainly on the liver
glucagon half-life
plasma half-life > 5-10mins
degraded mainly by liver
describe glucagon receptors
G-protein coupled receptors linked to the adenylate cyclase/cAMP system which when activated phosphorylate specific liver enzymes causing downstream effects.
activated glucagon receptors stimulate which processes?
- increase glycogenolysis
- increased gluconeogenesis (substrates: aa’s and glycerol (lipolysis))
- formation of ketones from fatty acids (lipolysis)
all of these processes occur in the liver
amino acids in the plasma stimulate the release of both…..
insulin and glucagon
list the stimuli that promote glucagon release
- low [BG] < 5mM
- high [amino acids] > prevents hypoglycaemia following insulin release in response to aa/
- sympathetic innervation and epinephrine, beta-2 effect.
- cortisol
- stress e.g. exercise, infection
list the stimuli that inhibit glucagon release
- glucose
- free fatty acids (FFA) and ketones
- insulin (fails in diabetes so glucagon levels rise despite high [BG]).
- somatostatin
where is somatostatin secreted?
- D-cells of pancreas
- hypothalamus aka GHIH
what is the main pancreatic action of somatostatin?
- to inhibit the activity in the GI tract.
- function appears to be to slow down absorption of nutrients to prevent exaggerated peaks in plasma concentrations.
effect of exercise on blood glucose
- the entry of glucose into skeletal muscle is increased in exercise, even in the absence of insulin.
- exercise also increases the insulin sensitivity of muscle.
how does our body adapt during starvation?
- 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.
what is the last store to be depleted in starvation?
protein stores
is ketone body uptake insulin dependent or independent?
insulin dependent
- in diabetes, life-threatening ketoacidosis may result
pathology of type 1 diabetes
- autoimmune destruction of the pancreatic beta-cells destroys ability to produce insulin and seriously compromises patients ability to absorb glucose from the plasma.
what percentage of diabetic patients are insulin-dependent?
10%
what percentage of diabetic patients are insulin-resistant?
90%
describe a glucose tolerance test
- patients ingest glucose load after fasting [BG] measured.
- [BG] will normally return to fasting levels withing an hour, elevation after 2 hours is indicative of diabetes.
- does not distinguish type 1 from type 2.
del
del
long-term hyperglycaemia can cause which diabetic complications?
- retinopathy
- neuropathy
- nephropathy
- CVD
