The Endocrine Pancreas 1 and 2 Flashcards
what equation can be used to calculate body energy?
Body energy = energy intake – energy output
Energy (food) intake is the determined by the balance of activity in two hypothalamic centres, what are they?
Feeding Centre
Satiety Centre
what does the Feeding Centre do?
promotes feelings of hunger and drive to eat
what does the Satiety Centre do?
promotes feelings of fullness by suppressing the Feeding Centre
Activity in each the fedding centre and satiety centrw is controlled by a complex balance of ______ and ________ signals as well as the presence of nutrients in plasma.
neural
chemical
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). Leptin is a peptide hormone released by fat stores which depresses feeding activity
what is leptin?
Leptin is a peptide hormone released by fat stores which depresses feeding activity
Obesity results from disruption of what pathways
energy intake and energy output
what is energy output?
Energy output describes all the processes we perform simply in order to stay alive, and those that we perform voluntarily, as well as the heat loss associated with these
what are the 3 categories of energy output?
Cellular work
Mechanical work
Heat loss
what cellular work contributes to energy output?
transporting molecules across membranes; growth and repair; storage of energy (eg. fat, glycogen, ATP synthesis)
what mechanical work contributes to energy output?
movement, either on large scale using muscle or intracellularly
what heat loss contributes to energy output?
associated with cellular and mechanical work accounts for half our energy output
what is the only part of energy output that is voluntary?
Only part of energy output we can regulate voluntarily is mechanical work done by skeletal muscle
Most common health advice provided by healthcare professional is what?
Eat less, exercise more!
Metabolism =
integration of all biochemical reactions in the body
whata re the 3 elements of metabolism?
- Extracting energy from nutrients in food
- Storing that energy
- Utilising that energy for work
what are anabolic pathways?
Build Up. Net effect is synthesis of large molecules from smaller ones, usually for storage purposes
build up and contribute to storage
what are catabolic pathways?
Break Down. Net effect is degradation of large molecules into smaller ones, releasing energy for work
break down large molecules releasing energy power
what is the anabolic phase?
After eating we enter an Absorptive State where ingested nutrients supply the energy needs of the body and excess is stored. This is an anabolic phase
what is the catabolic phase?
Between meals and overnight the pool of nutrients in the plasma decreases and we enter a Post-absorptive State (aka Fasted State) where we rely on body stores to provide energy. This is a catabolic phase
The Brain is an “obligatory ________ utiliser”!
glucose
Why si it important to maintain BG in relation to the brain?
Most cells can use fats, carbohydrates or protein for energy but the brain can only use glucose (except in extreme starvation – see ketone production later), so in the post-absorptive state, even though no new carbohydrate is gained by the body we MUST maintain blood glucose concentration [BG] sufficient to meet the brain’s requirements
Failure to maintain BG results in what and what may it lead to?
hypoglycaemia (low blood glucose) which can lead to coma and death
how is BG maintained?
BG is maintained by synthesising glucose from glycogen (glycogenolysis) or amino acids (gluconeogensis)
what is glycogenolysis?
glycogen, the primary carbohydrate stored in the liver and muscle cells of animals, is broken down into glucose to provide immediate energy and to maintain blood glucose levels during fasting
Glycogenolysis occurs primarily in the liver and is stimulated by the hormones glucagon and epinephrine (adrenaline)
what is gluconeogensis?
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates
what is the normal range of BG?
Normal range of [BG] = 4.2-6.3mM (80-120mg/dl)
****5 mmoles useful to remember****
Hypoglycaemia = [BG] < _mM
Hypoglycaemia = [BG] < 3mM
So, whatever you are eating or doing, [BG] is maintained over a fairly tight range. This is possible due to the actions of what two key endocrine hormones produced in the pancreas?
Insulin and Glucagon
How much of the pancreas if endocrine and how much is exocrine?
99% of the pancreas operates as an exocrine gland releasing enzymes and NaHCO3 via ducts into the alimentary canal to support digestion
Only 1% of the pancreas has endocrine function. It’s hormones are produced in the Islets of Langerhans
The Islets of Langerhans are scattered throughout the pancreas, 1-2 million islets, each with a copious blood supply
What are the 4 types of islet cells
a, b, d & F
a cells of the Islets of Langerhans produce what?
GLUCAGON
b cells of the Islets of Langerhans produce what?
INSULIN
delta cells of the Islets of Langerhans produce what?
SOMATOSTATIN
F cells of the Islets of Langerhans produce what?
F cells produce pancreatic polypeptide (function not really known, may help control of nutrient absorption from GIT.
controls of blood glucose depend son the balance between what?
Depends on balance between insulin and glucagon
(not their actual concentration but the balance between the 2)
what does more insulin that glucagon reuslt in?
Glucose taken up by cells from plasma ([BG] decreases)
what does more glucagon that insulin reuslt in?
Glucose released into plasma from stores ([BG] increases)
what is insulin?
Peptide hormone produced by pancreatic b cells
Stimulates glucose uptake by cells
how is insulin made?
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 b cell is activated and secretion occurs.
During the _________ State glucose, amino acids (aa) and fatty acids enter blood from GI Tract. Both ________ and ___ stimulate _______ secretion but the major stimulus is ______ _____ ___________
During the Absorptive State 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 during what state
the absorptive state
what is the only hormone that lowers [BG]
insulin
Most cells use ______ as their energy source during the _________ state. Any excess is stored as ________ in liver and muscle, and as __________ ____ in liver and adipose tissue
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
what are amino acids used for?
Amino acids are used mainly to make new proteins with excess being converted to fat
Also form an energy source
what are fatty acids stored as and where?
Fatty acids are stored in the form of triglycerides in adipose tissue and liver
What is the mechanism of control of insulin secretion by [BG]?
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 KATP channel to close. Intracellular [K+] rises, depolarising the cell. Voltage-dependent Ca2+ channels open and trigger insulin vesicle exocytosis into the circulation
why is insulin not released when BG is low?
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
what is the primary action of insulin?
Binds to tyrosine kinase receptors on the cell membrane of insulin-sensitive tissues to increase glucose uptake by these tissues
Insulin is the ONLY hormone that ______ ___
Insulin is the ONLY hormone that lowers [BG]
what glucose transporters are there in muscle and adipose tissue and how do they work?
In muscle and adipose tissue, insulin stimulates the mobilization of specific glucose transporters, GLUT-4, which reside in the cytoplasm of these 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
Tyrosine kinase receptor so phosphorylate other proteins to switch things on and off and creates a cascade within the cell and one of the actions is causes exocytosis of vesicle and glut 4 to the membrane
what are insulin dependant tissues?
adipose tissue
muscle
Do tissues require insulin to take up glucose?
Most types of tissue do NOT require insulin to take up glucose, ONLY muscle and fat are insulin dependent
______ and ___ make up a large proportion of the body
______ is » 40% BW and ____ 20-25% (in normality)
So a very large proportion of the body is ________ ___ ________ for its glucose uptake
muscle and fat make up a large proportion of the body
Muscle is » 40% BW and fat » 20-25% (in normality)
So a very large proportion of the body is dependent on insulin for its glucose uptake
In other tissues glucose uptake is via other GLUT-transporters, which are NOT insulin-dependent
what are they? and where are they found?
GLUT-1 Basal glucose uptake in many tissues eg brain, kidney and red blood cells
GLUT-3 Similar
GLUT-2 b-cells of pancreas and liver
is the liver insulin dependant?
The liver is not an insulin-dependent tissue. Liver takes up glucose by GLUT 2 transporters, which are insulin independent
Glucose enters down concentration gradient
Is glucose transport in hepatocytes affected by insulin?
although insulin has no direct effect on the liver, glucose transport into hepatocytes is affected by insulin status
How does insulin alter glucose transport in hepatocytes
picture 1 - In fed state, liver takes up glucose because insulin activates hexokinase which lowers [glucose]ic creating a gradient favouring glucose movement into the cells
picture 2 - In fasted state, liver synthesises glucose via glycogenolysis and gluconeogenesis, increasing [glucose]ic creating a gradient favouring glucose movement out of the cells into the blood
additional actions of insulin:
how does insulin affect glycogen?
Increases glycogen synthesis in muscle and liver
Stimulates glycogen synthase and inhibits glycogen phosphorylase
additional actions of insulin:
how does insulin affect amino acid uptake?
Increases amino acid uptake into muscle, promoting protein synthesis
additional actions of insulin:
how does insulin affect protein synthesis?
Increases protein synthesis and inhibits proteolysis
additional actions of insulin:
how does insulin affect triacylglycerol synthesis?
Increases triacylglycerol synthesis in adipocytes and liver i.e. stimulates lipogenesis and inhibits lipolysis.
additional actions of insulin:
what eznymes does insulin inhibit in the liver?
Inhibits the enzymes of gluconeogenesis in the liver
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
all of the above are additional actions on insulin. what kind of processes are they?
All of the above are anabolic processes – laying down energy stores – or inhibit catabolism
additional actions of insulin:
how does insulin interact with growth hormone?
Has a permissive effect of growth hormone (see GH lecture)
Insulin promotes action of growth hormone and growth hormone inhibits insulin
additional actions of insulin:
how does insulin affect K+ ions?
Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase. Very important clinically.***
All these additional roles of insulin are possible because of what?
activation of multiple signal transduction pathways associated with the Insulin Receptor
what is the process of insulin altering metabolism of a cell?
how is insulin degraded?
Insulin has a half-life of around 5 minutes and is 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
image showing summary of all the effects of insulin
what are all the stimuli which increase insulin release?
- Increased [BG]*****
- Increased [amino acids]plasma
- Glucagon (insulin required to take up glucose created via gluconeogenesis stimulated by glucagon)
- Other (incretin) hormones controlling GI secretion and motility eg gastrin, secretin, CCK, GLP-1, GIP. Released by ileum and jejunem in response to nutrients. Early insulin release prevents glucose surge when absorption occurs. Incretin hormones is the general terms for GI hormones – help stimulate the release of insulin prior to the glucose hitting the blood
- Vagal nerve activity (see next slide) - same as GI hormones and anticipates you eating something and taking in glucose
what stimuli inhibit insulin release?
- Low [BG]
- Somatostatin (GHIH)
- Sympathetic a2 effects
- Stress e.g. hypoxia - Stress results in reduced insulin recreation as you want the glucose in the blood readily available particularly to the brain
Does vagal activity cause insulin release?
Vagal activity stimulates release of major GI hormones, and also stimulates insulin release
How does insulin release differ when getting IV glucose comapred to oral glucose of the same amount?
Vagal activity stimulates release of major GI hormones, and also stimulates insulin release, therefore meaning that the insulin response to an intravenous glucose load is less than the equivalent amount of glucose administered orally, ie:
i.v. glucose leads to increased insulin by direct effect of glucose on b cells.
Oral loading of same amount of glucose leads to increased insulin by both direct effect on b cells and vagal stimulation of b cells, plus incretin effects!
what is incretin?
a group of metabolic hormones that stimulate a decrease in blood glucose levels
what type of hormone is glucagon and where is it produced?
Peptide hormone produced by a-cells of the pancreatic islet cells in same fashion as all peptide hormones
what is the purpose of glucagon?
Primary purpose is to raise blood glucose
It is a glucose-mobilizing hormone, acting mainly on the liver
how is glucagon degraded?
Plasma half-life 5-10mins, degraded mainly by liver
Glucagon primarily opposes the action of ________, forming part of the glucose _________________ ________ ________ which includes the hormones epinephrine, cortisol and GH. It is most active in the _____________ state
Glucagon 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
what are glucagons receptors?
G protein coupled receptors
Glucagon receptors are G-protein coupled receptors linked to the adenylate cyclase/cAMP system which when activated phosphorylate specific liver enzymes resulting in what?
- increased glycogenolysis (glycogen broken dowin into glucose)
- increased gluconeogenesis (substrates: aa’s and glycerol (lipolysis)) - formation of glucose
- formation of ketones from fatty acids (lipolysis)
All these processes occur in the liver
**** Net result is elevated [BG]****
Summary picture:
Fasted-state metabolism must maintain plasma glucose for the brain
Amino acids are also a potent stimulus for glucagon secretion. What would happen if it wasn’t?
hypoglycaemia
amino acids stimulate insulin release which in the abscene og glucagon would stimulate glucose uptake into cells, dramatically lowerin [BG]
potentially catastrophic for the brain
increased glucose = increased insulin and decreased glucagon
decreased glucose = increased glucagon and decreased insulin
how do amino acids affect the release of insulin and glucagon?
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!)
How would a high protein meal with very little carbohydrate affect BG?
aas = increased insulin = decreased [BG]
aas = increased glucagon = increased [BG]
aas = amino acids
If it were not for the effect of aas on ________ then the insulin-stimulating effects of aas would result in very ____ [BG]. This is counteracted by the glucose mobilizing effects of glucagon and so [BG] is ___________
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
So, whatever you are eating or doing, the endocrine system is working to ensure that there is enough glucose circulating to supply the needs of the what?
brain = “obligatory glucose user”.
What can other tissues use to produce energy apart form glucose?
Most other tissues can readily use FFAs and ketones to produce energy
What happens in the post-absorptive state when there are lower insulin levels
In the post-absorptive state, lower 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
what are 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, b2 effect
- cortisol
- stress e.g. exercise, infection - Makes sure brain has adequate glucose to get you out of the stressful situation
what are 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 - turns down insulin and glucagon
how does increased parasympathetic activity affect insulin and glucagon?
increased parasympathetic activity (vagus) = increased insulin and to a lesser extent increased glucagon, in association with the anticipatory phase of digestion
how does increased sympathetic activity affect insulin and glucagon?
increased sympathetic activation promotes glucose mobilization = increased glucagon, increased epinephrine and inhibition of insulin, all appropriate for fight or flight response.
what 4 hormones make up the glucose counter-regulatory control?
glucagon
epinephrine
cortisol
GH
what makes up the glucose counter-regulatory control and how is it done?
All act to raise BG
All do it by different ways
What type of hormone is somatostatin (SS), what makes it and where
Peptide hormone, secreted by D-cells of the pancreas (and hypothalamus aka GHIH)
what is the function of SS?
Main pancreatic action is to inhibit activity in the GI Tract
Function appears to be to slow down absorption of nutrients to prevent exaggerated peaks in plasma concentrations
Aka GHIH it inhibits secretion of GH from the anterior pituitary
How is SS used clinically?
Synthetic SS may be used clinically to help patients with life-threatening diarrhoea associated with gut or pancreatic tumours
Is SS an counter-regulatory hormone?
SS is NOT a counter-regulatory hormone
How does SS affect insulin and glucagon?
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
What happen when a patient has a pancreatic SS-secreting tumour?
Patients with pancreatic SS-secreting tumours develop the symptoms of diabetes which disappear when the tumour is removed
A
Green – stimulatory process
Red – inhibitory processes
Low blood glucose
B
Elevated plasma [aa]
C
Elevated blood glucose
how does exercise affect BG?
The entry of glucose into skeletal muscle is increased during exercise, even in the absence of insulin
There is an insulin-independent increase in the number of GLUT 4 transporters incorpotated into the muscle membrane
How does exercise affect insulin sensitivity?
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
How long do the effects of exercise on BG last?
This effect persists for several hours after exercise and regular exercise can produce prolonged increases in insulin sensitivity
In non-active muscle, ______ binds to its receptor, which then leads to glucose transporters, GLUT_, migrating to the cell membrane, allowing _______ to enter
In non-active muscle, insulin binds to its receptor, which then leads to glucose transporters, GLUT4, migrating to the cell membrane, allowing glucose to enter
In active muscle, GLUT4 transporters can migrate to the membrane without ______ being present, so exercise causes glucose uptake __________ of _______
It also increases the _________ of the muscle to insulin
In active muscle, GLUT4 transporters can migrate to the membrane without insulin being present, so exercise causes glucose uptake independently of insulin
It also increases the sensitivity of the muscle to insulin
How does the body get energy during starvation?
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!
after a period of starvation, what the does the brain use for energy?
After a period of starvation, the brain adapts to be able to use ketones
Why is adipose tissue broken down first in starvation and what is the last store in starvation to be deplted?
This serves to “spare protein” which would otherwise be broken down excessively to provide gluconeogenic substrates. (Loss of protein -very weakening, vulnerable to infection). Last store to be depleted in starvation.
Works well as long as there is a functioning pancreas secreting insulin as ketone body uptake is insulin dependent
In diabetes, lif threatening ketoacidosis may result (see later)
what does ketone bodies need for uptake?
ketone body uptake is insulin dependent
is starvation in a diabetic person more life threatening?
In diabetes, life threatening ketoacidosis may result (see later) as ketone bodies uptake is insulin dependant
what is diabetes mellitus?
Loss of control of blood glucose levels
diabetes = flow, mellitus = sweet
patients produce large volumes of sweet tasting urine
Occurs in two forms: Type I and Type II
what is the cause of 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
10% of diabetic patients are insulin-dependent
What does untreated type 1 diabetes cause?
Untreated type 1 diabetes leads to many complex changes in the body which ultimately cause starvation and death.
Before the discovery of insulin, survival, post-diagnosis, was between 2 weeks and 18 months
What is the management of type 1 diabetes and what happens if this doesnt happen?
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”
Summary diagram:
homeostatic control of blood glucose and then in diabetes
Body thinks it doesn’t have any glucose so starts making more and again still cant be taken up and you are then in a viscous cycle
How has sirvival time changed before and after the discovery of insulin?
Pre-insulin’s discovery, survival post-diagnosis was between 2 weeks and 18 months. After insulin, >75 years, >300 million lives saved by insulin
JJR Macleod, Aberdeen medical graduate and later Physiology Professor won Nobel Prize in 1923 for discovery of insulin with Canadian colleagues
what happens when nutrients are scare?
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!
What happens to ketone boddies in insulin dependant diabetes?
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
how are ketones detected?
Ketones detectable in urine and produce distinctive acetone smell to breath
what is type 2 diabetes?
Type II Diabetes – Non-Insulin Dependent Diabetes Mellitus (NIDDM)
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 insulin-resistant (NIDDM)
insulin not causing a response so make some more
What features of a person are typically associated with type 2 diabetes?
Typically associated with obesity
Usually appears >40yrs but age decreasing
High sugar and animal fat diet together with little exercise are major contributors
[BG] elevated in both Type I and Type II Diabetes for different reasons:
Type I = inadequate insulin release = increased [BG]
Type II = inadequate tissue response = increased [BG]
Hyperglycaemia (elevated [BG]) is the diagnostic criterion for diabetes.
How is it detected?
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.
What is a concern that can result form poorly controlled diabetes?
Hyperglycaemia
The reason for concern about hyperglycaemia in both type I and type II patients is that glucose is a highly reactive molecule which can eventually produce long-term problems that may be very serious = diabetic complications: what are they?
Retinopathy
Neuropathy
Nephropathy
Cardiovascular Disease
