Endocrine Pancreas Flashcards
(129 cards)
1
Q
What is energy intake determined by?
A
Balance of activity in 2 hypothalamic centres
2
Q
What does the feeding centre promote?
A
Promotes feelings of hunger and drive to eat
3
Q
What does the satiety centre promote?
A
Promotes feelings of fullness by suppressing the feeding centre
4
Q
How is activity in the feeding and satiety centres controlled?
A
A complex balance of neural and chemical signals as well as the presence of nutrients in plasma
5
Q
Glucostatic theory
A
Food intake is determined by blood glucose: as [BG] increases, the drive to eat decreases
(- Feeding Centre;+ Satiety centre)
6
Q
Lipostatic theory
A
Food intake is determined by fat stores: as fat stores increase, the drive to east decreases (- feeding centre; + satiety centre).
7
Q
What are the 3 categories of energy output?
A
- 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 intracellular
- Heat loss: associated with cellular and mechanical work accounts for half our energy output
8
Q
What is the only part of our energy output we can regulate voluntarily?
A
Mechanical work done by skeletal muscle
9
Q
Metabolism
A
Integration of all biochemical reactions in the body
10
Q
What are the 3 elements of metabolism?
A
- Extracting energy from nutrients in food
- Storing that energy
- Utilising that energy for work
11
Q
Anabolic pathways
A
Build Up. Net effect is synthesis of large molecules from smaller ones, usually for storage purposes.
12
Q
Catabolic pathways
A
Break Down. Net effect is degradation of large molecules into smaller ones, releasing energy for work.
13
Q
What state do we enter after eating?
A
Absorptive State where ingested nutrients supply the energy needs of the body and excess is stored. This is an anabolic phase
14
Q
What state do we enter between meals and overnight?
A
Post-absorptive State (aka Fasted State) where we rely on body stores to provide energy. This is a catabolic phase.
15
Q
What is meant by the brain being an obligatory glucose utiliser?
A
Most cells can use fats, carbohydrates or protein for energy but the brain can only use glucose
16
Q
What affect does the brain have on the post-absorptive state?
A
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.
17
Q
Why does hypoglycaemia occur?
A
Failure to maintain [BG] sufficient to meet the brain’s requirements results in hypoglycaemia which can lead to coma and death
18
Q
How is BG maintained?
A
Synthesising glucose from glycogen (glycogenolysis) or amino acids (gluconeogenesis)
19
Q
Why does BG rise in diabetes?
A
In diabetes, glucose cannot be taken up by cells so BG rises and glucose is detected in the urine
20
Q
What is the only structure to have access to BG when it falls below normal range?
A
Brain
21
Q
What is the normal range of [BG]?
A
4.2-6.3 mM
22
Q
When does hypoglycaemia occur?
A
[BG] <3mM
23
Q
What 2 key endocrine hormones maintain [BG]?
A
- Insulin
- Glucagon
24
Q
What does 99% of the pancreas produce?
A
Operates as an exocrine gland releasing NaHCO3 via ducts into the alimentary canal to support digestion
25
What produces the endocrine hormones of the pancreas?
Islets of Langerhans
26
What are the 4 types of Islets of Langerhans?
- Alpha cells
- Beta cells
- Delta cells
- F cells
27
What do the a cells produce?
Glucagon
28
What do the B cells produce?
Insulin
29
What do the delta cells produce?
Somatostatin
30
What do the F cells produce?
Pancreatic polypeptide ( function not really known, may help control of nutrient absorption)
31
How many islets are there scattered throughout the pancreas?
1-2 million each with a copious blood supply
32
What does control of BG depend on?
Balance between insulin and glucagon
33
What state does insulin dominate?
Fed state
34
What state does glucagon dominate?
Fasted state
35
What does an increase in insulin result in?
- Increased glucose oxidation
- Increased glycogen synthesis
- Increased fat synthesis
- Increased protein synthesis
36
What does an increase in glucagon result in?
- Increased glycogenolysis
- Increased gluconeogenesis
- Increased ketogenesis
37
What is insulin?
Peptide hormone produced by pancreatic B cells
38
What does insulin stimulate?
Glucose uptake by cells
39
How is insulin synthesised?
Synthesized as a large preprohormone, preproinsulin, which is then converted to proinsulin in the ER.
40
How does proinsulin become insulin?
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 cell is activated and secretion occurs.
41
What enters the blood from the GIT during the absorptive state?
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
42
What is the only hormone which lowers BG?
Insulin
43
What happens to excess glucose during the absorptive state?
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
44
What are amino acids used to do?
Amino acids are used mainly to make new proteins with excess being converted to fat. Also form an energy source.
45
How are fatty acids stored?
Fatty acids are stored in the form of triglycerides in adipose tissue and liver
46
What special channel do B cells possess?
B cells have a specific type of K+ ion channel that is sensitive to the [ATP] within the cell = KATP channel
47
How does glucose enter cells when it is abundant?
When glucose is abundant it enters cells through glucose transport proteins (GLUT) and metabolism increases.
48
Once glucose enters the cell and increases metabolism what happens?
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.
49
How does low [BG] prevent insulin being secreted?
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.
50
What is the primary action of insulin?
Binds to tyrosine kinase receptors on the cell membrane of insulin-sensitive tissues (muscle and adipose tissue) to increase glucose uptake by these tissues.
51
What does insulin stimulate with regards to GLUT4?
Insulin stimulates the mobilization of specific glucose transporters, GLUT-4, which reside in the cytoplasm of unstimulated muscle and adipose cells.
52
What happens to GLUT4 after being stimulated by insulin?
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.
53
What is the glucose taken up by cells primarily used for?
The glucose taken up by cells is primarily used for energy.
54
What are the only insulin sensitive tissues?
Muscle and fat
55
What percentage of the body do muscle and fat make up?
- Muscle ~40%
| - Fat ~20-25%
56
How is glucose take up in tissues other than muscle and fat?
In other tissues glucose uptake is via other GLUT-transporters, which are NOT insulin-dependent.
(GLUT-1, GLUT-2, GLUT-3)
57
What do GLUT 1,3 and 2 facilitate the movement of?
- GLUT-1: Basal glucose uptake in many tissues eg brain, kidney and red blood cells.
- GLUT-3: Similar to GLUT-1
- GLUT-2: Cells of pancreas and liver
58
How does the liver take up glucose?
The liver is not an insulin-sensitive tissue. Liver takes up glucose by GLUT 2 transporters, which are insulin independent.
59
How does glucose enter the liver?
Down a concentration gradient
60
In terms of glucose transport, what affect does insulin have on the liver?
Although insulin has no direct effect on the liver, glucose transport into hepatocytes is affected by insulin status.
61
Why does the liver take up glucose in the fed state?
In fed state, liver takes up glucose because insulin activates hexokinase which lowers [glucose]ic creating a gradient favouring glucose movement into the cells.
62
What does liver do in the fasted state?
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.
63
What anabolic actions does insulin have?
- 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
64
Other than its effect on glucose and its anabolic actions, what other 2 actions does insulin have on the body?
- Has a permissive effect on Growth Hormone
| - Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase. Very important clinically.***
65
Why are the additional actions of glucose possible?
All of the additional roles are possible because of activation of multiple signal transduction pathways associated with the Insulin Receptor:
66
What is the half-life of insulin?
Insulin has a half-life of ~5 minutes and is degraded principally in the liver and kidneys.
67
What happens once insulin action is complete?
Once insulin action is complete insulin-bound receptors are internalised by endocytosis and destroyed by insulin protease, some recycled.
68
Give examples of 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
- Vagal nerve activity
69
Give examples of stimuli which inhibit insulin release?
- Low [BG]
- Somatostatin (GHIH)
- Sympathetic a2 effects
- Stress e.g. hypoxia
70
Why is the response to and IV glucose load less than that of an equivalent oral load?
- 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
- IV glucose increases insulin by direct effect of increased glucose on B cells
- Oral load increases insulin by direct effect on B cells and vagal stimulation on B cells (plus incretin effects)
71
What is glucagon?
Peptide hormone produced by a-cells of the pancreatic islet cells in same fashion as all peptide hormones
72
What is the primary purpose of glucagon?
Primary purpose is to raise blood glucose. It is a glucose-mobilizing hormone, acting mainly on the liver
73
What is the half-life of glucagon?
Plasma half-life 5-10mins, degraded mainly by liver
74
When is glucagon most active?
Post-absorptive state
75
What hormones make up the glucose counter-regulatory control system?
- Epinephrine
- Cortisol
- GH
- Glucagon
76
What are the glucagon receptors?
Glucagon receptors are G-protein coupled receptors linked to the adenylate cyclase/cAMP system
77
What do the glucagon receptors do when activated?
When activated phosphorylate specific liver enzymes
78
What does phosphorylation of specific liver enzymes by glucagon receptors result in?
- Increase glycogenolysis
- Increase gluconeogenesis (substrates: aa’s and glycerol (lipolysis))
- Formation of ketones from fatty acids (lipolysis)
79
What is the net result of activation of glucagon receptors?
Elevated [BG]
80
Describe the rate of secretion of glucagon?
Glucagon release is relatively constant although secretion increases dramatically when [BG] < 5.6mM
(normal [BG] 4.2-6.3mM). Nevertheless the ratio to insulin is more significant than actual concentration.
81
What do amino acids in the plasma stimulate the release of?
Amino acids in the plasma stimulate release of both insulin and glucagon.
82
Why is important for amino acids to stimulate both insulin and glucagon?
If it were not for the effect of amino acids on glucagon then the insulin-stimulating effects of amino acids would result in very low [BG]. This is counteracted by the glucose mobilizing effects of glucagon and so [BG] is maintained.
83
What can other tissues use as energy sources instead of glucose?
FFAs and ketones to produce energy
84
Why is there glucose sparing for obligatory glucose users in the post-absorptive state?
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.
85
Give examples of stimuli that promote glucagon release?
- Low [BG]
- High [amino acids] . Prevents hypoglycaemia following insulin release in response to aa.
- Sympathetic innervation and epinephrine, B2 effect
- Cortisol
- Stress e.g. exercise, infection
86
Give examples of stimuli that inhibit glucagon release?
- Glucose
- Free fatty acids (FFA) and ketones
- Insulin (fails in diabetes so glucagon levels rise despite high [BG)
- Somatostatin
87
What effects does the parasympathetic system have on insulin and glucagon release?
Increased parasympathetic activity (vagus) leads to increase in insulin and to a lesser extent increase in glucagon, in association with the anticipatory phase of digestion.
88
What effect does the sympathetic system have on insulin and glucagon?
Increase in sympathetic activation promotes glucose mobilization which leads to increased glucagon, increased epinephrine and inhibition of insulin, all appropriate for fight or flight response.
89
What is somatostatin?
Peptide hormone, secreted by D-cells of the pancreas (and hypothalamus aka GHIH).
90
What is the main pancreatic action of somatostatin?
Inhibit activity in the GIT
91
What is the function of SS in inhibiting the GIT?
Function appears to be to slow down absorption of nutrients to prevent exaggerated peaks in plasma concentrations.
92
Why may synthetic somatostatin be used clinically?
Synthetic SS may be used clinically to help patients with life-threatening diarrhoea associated with gut or pancreatic tumours
93
What do patients with SS secreting tumours often develop?
Patients with pancreatic SS-secreting tumours develop the symptoms of diabetes which disappear when the tumour is removed.
94
Although SS is not a counter regulatory hormone, what effect does it have on both insulin and glucagon?
It strongly suppresses the release of both insulin and glucagon in a paracrine fashion
95
What does GHIH inhibit release of from the anterior pituitary?
GH
96
What is increased during exercise even in the absence of insulin?
Entry of glucose into skeletal muscle is increased
97
What effect does exercise have on [BG]?
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.
98
What can regular exercise produce?
The effect of exercise persists for several hours and regular exercise can produce prolonged increases in insulin sensitivity
99
How does glucose enter the cell in non-active muscle?
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.
100
How does glucose enter the cell in active muscle?
- 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.
101
What does the body rely on when nutrients are scarce?
Stores for energy
102
What happens to the brain after a period of starvation?
Brain adapts to be able to use ketones
103
How are stores used during starvation?
Adipose tissue is broken down and fatty acids are released
104
Why are spare FFAs converted to ketones and used by the brain in starvation?
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!
105
Diabetes mellitus
Loss of control of blood glucose levels
106
How does T1DM occur?
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.
107
What is another name for T1DM?
Insulin dependent diabetes mellitus (IDDM)
108
What can untreated T1DM lead to?
Untreated type 1 diabetes leads to many complex changes in the body which ultimately cause starvation and death.
109
What do T1DM have an absolute need for?
Insulin
110
How does ketoacidosis occur in T1DM?
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.
111
How are ketones detectable?
In urine and produce distinctive acetone smell to breath
112
What is another name for T2DM?
Non-insulin dependent diabetes mellitus (NIDDM)
113
How does T2DM occur?
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.
114
What may B cells be in T2DM?
Hyperinsulinaemia
115
What is T2DM typically associated with?
Obesity
116
When does T2DM usually occur?
>40 years
117
What is initial treatment of T2DM aimed at?
Initial treatment is aimed at trying to restore insulin sensitivity of tissues with exercise and dietary change
118
What treatment options are there for T2DM?
- Lifestyle changes
- Metformin
- Sulfonylureas
- Other oral hypoglycaemic drugs
- Insulin
119
What does metformin do?
Inhibits hepatic gluconeogenesis and antagonises action of glucagon
120
What do sulfonylureas do?
Sulphonylureas are a class of drug which act to close the KATP in B cells and therefore stimulate Ca2+ entry and insulin secretion.
121
Why is [BG] elevated in T1DM?
Inadequate insulin release increase [BG]
122
Why is [BG] elevated in T2DM?
Inadequate tissue response increase[BG]
123
What is the diagnostic criteria for diabetes?
Hyperglycaemia
124
What test is performed to diagnose diabete1s?
Oral glucose tolerance test
125
How is the OGTT carried out?
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
126
What diabetic complications can occur?
- Retinopathy
- Neuropathy
- Nephropathy
- Cardiovascular disease
127
Who is hypoglycaemic a particular problem in?
Type 1 patients
128
What are the stages of hypoglycaemia?
- 4.6mM [BG]: Inhibition of insulin secretion -3.8mM [BG]: Glucagon, epinephrine and GH secretion
- 3.2mM [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
129
What is leptin?
Leptin is a peptide hormone released by fat stores which depresses feeding activity
