The Endocrine Pancreas Flashcards
1
Q
Energy intake is determined by the balance of activity in which two hypothalamic centres?
A
Feeding centre (promotes feelings of hunger + drive to eat) Satiety centre (supresses feeding centre + promotes feeling of fullness)
2
Q
What is the glucostatic theory?
A
Food intake is determined by blood glucose
As BG increases, drive to eat decreases
3
Q
What is the lipostatic theory?
A
Food intake is determined by fat stores, as fat stores increase, drive to eat decreases
4
Q
What hormone is implicated in the lipostatic theory?
A
Leptin (a peptide hormone released by fat stores which depresses feeding activity)
5
Q
Body energy =?
A
Energy intake - energy output
6
Q
What are the 3 categories of energy output?
A
Cellular work
Mechanical work
Heat loss
7
Q
What is cellular work?
A
Transporting molecules across membranes, growth and repair, storage of energy etc.
8
Q
What is mechanical work?
A
Movement (on large scale or intracellularly)
9
Q
What % of energy output does heat loss contribute?
A
50%
10
Q
Define metabolism
A
Integration of all biochemical reactions in the body
11
Q
What 3 things does the metabolism involve?
A
Extracting energy from nutrients
Storing that energy
Utilising that energy for work
12
Q
What are anabolic pathways?
A
BUILD UP
Net effect is to synthesise large molecules from smaller ones, usually for storage
13
Q
What are catabolic pathways?
A
BREAKDOWN
Net effect is degradation of large molecules into smaller ones, releasing energy for work
14
Q
What state do we enter after we eat and what does this involve?
A
We enter an absorptive state, whereby ingested nutrients supply the energy needs of the body + excess is stored, this is an anabolic phase
15
Q
What state do we enter between meals + overnight and what does this involve?
A
Nutrients in the plasma decreases and we enter a post-absorptive state, where we rely on body stores to provide energy
This is a catabolic phase
16
Q
What can cells use for energy?
A
Carbs, fat, protein (expect brain which can only use glucose or ketones)
17
Q
How do we maintain BG during times of not eating?
A
Breaking down glycogen into glucose (glycogenolysis) or making glucose from amino acids (gluconeogenesis)
18
Q
Which two hormones keep blood glucose in a tight range?
A
Insulin
Glucagon
19
Q
Where are the endocrine hormones produced in the pancreas?
A
Islets of Langerhans
20
Q
How many Islets of Langerhan are in the pancreas?
A
1-2mil
21
Q
What are the two types of cells present in Islets?
A
Alpha - produce glucagon
Beta - produce insulin
Delta - produce somatostatin
F cells - produce pancreatic polypeptide
22
Q
What happens when insulin predominates over glucagon?
A
Blood glucose decreases as glucose taken up by cells
Increased glycogen production, fat synthesis and protein synthesis
23
Q
What happens when glucagon predominates over insulin?
A
Glucose released into plasma from stores (BG increases)
Increased glycogenolysis, gluconeogenesis, ketogenesis
24
Q
What kind of hormone is insulin?
A
Peptide
25
What is the role of insulin?
Stimulates glucose uptake by cells
26
How is insulin made?
Synthesised as large preprohormone, preproinsulin, which is converted into proinsulin in the ER
This is packaged into granules, within these proinsulin is cleaved to give insulin and C peptide
Insulin is stored until B cell is activated and secretion occurs
27
What occurs during the absorptive state?
Glucose, amino acids, fatty acids enter the blood via GIT
Glucose (mainly) + AA stimulate insulin secretion
28
Which hormone dominates the absorptive state?
Insulin
29
What is excess glucose stored as?
Glycogen in liver + muscle or TAGs in liver + adipose tissue
30
What are amino acids used to make? What are excess converted into?
Proteins
| Excess converted into fat
31
What are fatty acids stored as?
Triglycerides in adipose tissue and liver
32
Describe the mechanism of control of insulin secretion by blood glucose concentration
B-cells have a specific K+ channel that is sensitive to [ATP] inside the cell (KATP channel)
If glucose is abundant it enters the cell via GLUT transporters and metabolism increases, so intracellular [ATP] increases causing KAPT to close, so intracellular [K+] increases --> depolarisation of the cell
Voltage caged Ca2+ channels open + trigger insulin vesicle exocytosis into the circulation
33
Explain why when [BG] is low, insulin is not released by B cells
When [BG] is low, [ATP] is low, so KATP channels are ions flow out removing the +ve charge from the cell + hyperpolarising it, so voltage gated Ca2+ channels remain closed + insulin is not secreted
34
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
35
How does insulin stimulate increased glucose uptake by binding to insulin sensitive tissues?
Stimulates the mobilisation of specific glucose transporters, GLUT4, which reside in the cytoplasm of unstimulated muscle + adipose cells
When stimulated GLUT4 migrates to cell membrane + is able to transport glucose into the cell
36
What happens to GLUT4 receptors when insulin levels drop?
GLUT4 transporters return to the cytoplasmic pool
37
Which tissues are insulin sensitive? What does this mean
Adipose and muscle tissue are insulin sensitive (i.e. they require insulin to take glucose into their cells)
Most types of tissue do not require insulin to take up glucose
38
How do other tissues take up glucose?
They have other GLUT transporters which are not insulin dependent (GLUT1 to GLUT3)
39
Why is insulin so significant despite the fact it is only required for the uptake of glucose into two types of tissue?
These tissues constitute 60-65% of body weight, so a large proportion of the body is dependent on insulin for glucose uptake
40
What are the actions of GLUT1 and 3?
Basal glucose uptake in many tissues, e.g. brain, kidney, red blood cells
41
Where are GLUT2 receptors found?
B cells of pancreas and liver
42
How does the liver take up glucose?
Via GLUT2 transporters (NON-insulin dependent)
Glucose enters down its concentration gradient
NB: glucose transport into hepatocytes is affected by insulin status
43
How does the liver alter the concentration gradient to allow more glucose to move into hepatocytes when [BG] is high?
Insulin activates hexokinase (which converts glucose into glucose-6-phosphate to keep [glucose]ic low and ensures a gradient favouring glucose movement into cells)
44
How does the liver create a concentration gradient to allow more glucose to leave the cell when [BG] is low?
Liver synthesises glucose via glycogenolysis + gluconeogenesis, increasing [glucose]ic, creating a gradient favouring glucose movement out of cells into the blood
45
What additional effects does insulin have in the muscle and liver?
Increases glycogen synthesis
| Stimulates glycogen synthase + inhibits glycogen phosphorylase
46
What specific action does insulin have in the muscle?
Increases AA uptake, promoting protein synthesis
| Also inhibits proteolysis
47
What additional effect does insulin have in adipocytes + the liver?
Stimulates lipogenesis + inhibits lipolysis
48
How does insulin affect gluconeogenesis in the liver?
Inhibits all the enzymes of gluconeogenesis
49
How does insulin affect growth hormone?
Permissive effect on growth hormone
50
How does insulin affect blood potassium?
Lowers blood potassium, as it promotes K ion entry into cells by stimulating Na/K ATPase
51
Where is insulin degraded?
Liver and kidneys
52
What happens to the insulin receptor after insulin has bound to it and had its effect?
Insulin bound receptors are internalised by endocytosis + destroyed by insulin protease
53
Which stimuli increase insulin release?
1. Increased [BG]
2. Increased [blood AA]
3. Glucagon
4. Incretin hormones controlling GI secretion + motility
5. Vagal nerve activity
54
Why does glucagon cause insulin release?
Insulin req. to take up glucose created via gluconeogenesis stimulated by glucagon
55
What are examples of incretin hormones which stimulate insulin release?
Gastrin, secretin, CCK, GLP-1, GIP
56
What are incretin hormones?
Hormones released by the ileum + jejunum in response to nutrients to prevent glucose surge when absorption occurs
57
What stimuli inhibit insulin release?
1. Low [BG]
2. Somatostatin
3. Sympathetic a2 effects
4. Stress, e.g. hypoxia
58
Why is less insulin released from an IV load compared to an oral load of the same amount of glucose?
Oral loading leads to insulin production by direct effect of increased [BG] on beta cells, and vagal stimulation and incretin effects
59
What is the primary purpose of glucagon?
Raised [BG]
60
Where does glucagon mostly act?
The liver
61
Where is glucagon degraded?
Liver
62
When is glucagon most active?
In the post absorptive state
63
What hormones are in the glucose counter-regulatory control system?
Glucagon
Epinephrine
Cortisol
GH
64
What kind of receptors are glucagon receptors?
G-protein coupled receptors linked to the adenylate cyclase/cAMP system (when activated phosphorylates specific liver enzymes)
65
What does stimulation of glucagon receptors lead to?
Increased glycogenolysis
Increased gluconeogenesis
Formation of ketones from fatty acids (lipolysis)
==> Increased [BG]
66
Give examples of substrates for gluconeogenesis
AA, glycerol
67
What are the only two substrates the brain can use for energy?
Ketones, glucose
But remember it is an obligatory glucose user
68
What is more significant that measuring glucagon concentration?
Determining its ratio to insulin
69
High levels of amino acid in the plasma have what effect on glucagon levels?
Cause increased glucagon levels (same as insulin), this is an adaption to adjust for composition of a meal very high in protein
70
What would happen if you ate a really high protein/low carb meal and glucagon didn't rise?
AAs --> inc. insulin --> reduced [BG], this would lead to a very low [BG], if glucagon wasn't stimulated to increase [BG]
71
What stimuli promote glucagon release?
1. Low [BG]
2. High [blood AA]
3. Sympathetic innervation and epinephrine, b2 effect
4. Cortisol
5. Stress, e.g. exercise, infection
72
What stimuli inhibit glucagon release?
1. Glucose
2. FFA + ketones
3. Insulin
4. Somatostatin
73
How does parasympathetic activity (vagus) affect insulin secretion in the islet cells?
Leads to increased insulin production + to a lesser extent increased glucagon in anticipatory phase of digestion
74
How does sympathetic activity affect insulin secretion in the islet cells?
Promotes glucose mobilisation --> increased glucagon, epinephrine + inhibition of insulin for flight or fight response
75
What is the main pancreatic action of somatostatin?
Inhibit activity in GIT - slows down absorption of nutrients to prevent exaggerated peaks in plasma conc.
76
How does somatostatin affect insulin and glucagon release?
Strongly supresses the release of both in a paracrine fashion
77
What stimulates the secretion of somatostatin?
Elevated plasma [AA] and elevated [BG]
78
How does exercise affect [BG]?
Increases entry of glucose into skeletal muscle even in absence of insulin
Also increases insulin sensitivity of muscle, leads to insulin-independent increase in GLUT4 receptors in muscle membrane
79
How long does the effect of exercise on insulin receptors persist?
Several hours
| Regular exercise can produce prolonged increases in insulin sensitivity
80
What occurs in the body during starvation?
Adipose tissue broken down into FFA which can be used by most tissues for energy
Liver converts excess to ketone bodies which can be used by the brain
81
What happens to the brain after a period of starvation?
It adapts to be able to use ketones
82
Why is it important to try and use FFA and ketones to fuel the body?
To spare protein which would be broken down in gluconeogenesis - this is very weakening, and makes you vulnerable to infection
83
What is the pathophysiology of type 1 diabetes mellitus?
Autoimmune destruction of pancreatic B cells
84
How does having poorly controlled type 1 diabetes affect the way you take up ketones?
Lack of insulin depresses ketone body uptake --> ketoacidosis (life-threatening acidosis)
85
What is the pathophysiology of type 2 diabetes mellitus?
Peripheral tissue become insensitive to insulin (insulin resistance)
i.e. there is abnormal response of insulin receptors in muscle/fat or reduction in their number
86
How are beta-cells affected in type 2 DM?
Remain normal, there may actually be hyperinsulinaemia
87
Which kinds of patients typically have type 2 diabetes?
>40 years
Obese
High sugar, animal fat diet, with little exercise
88
What is involved in the initial treatment of type 2 diabetes?
Trying to restore insulin sensitivity with lifestyle changes (diet, exercise)
89
What is the first line drug in T2DM?
Metformin
90
How does metformin work?
Inhibits hepatic gluconeogenesis + antagonises action of glucagon
91
How do sulphonylureas work?
Close the KATP in B cells + stimulate Ca entry and insulin secretion
92
Why is [BG] raised in type 1 diabetes?
There is inadequate insulin release
93
Why is [BG] raised in type 2 diabetes?
Where is inadequate tissue response to the insulin made
94
What are the main diabetic complications?
Retinopathy
Neuropathy
Nephropathy
CV disease
