PBL 1: T1DM Flashcards
1
Q
What is the normal range of plasma glucose concentratons in the fasted state
A
4-5mM
2
Q
What is the normal range of plasma glucose concentratons in the fed state
A
Can be raised normally to 8-12mM after a meal
3
Q
What are the prinicipal regulators of glucose homeostasis?
A
Hormones insulin and glucagon
4
Q
Insulin is produced from which cells?
A
Secreted by beta cells in the Islets of Langerhans
5
Q
Describe the process of insulin production in the beta cells
A
- Insulin production begins with the translation of the insulin RNA by ribosomes in the ER. This forms preproinsulin.
- This preproinsulin is cleaved, removal of the signal sequence, in the ER to form proinsulin
- Proinsulin is composed of 3 amino acid chains: A, B and C chain
- Proinsulin is further cleaved in the Golgi apparatus, removal of the C chain, to form insulin.
- Insulin is a small protein composed of two amino acid chains: A and B.
- The insulin and C chain are packaged into vesicles.
- Approx. 5-10% is still in the proinsulin form.
6
Q
Describe how high blood glucose levels causes insulin release from beta cells
A
- At times where there is a high blood glucose level, GLUT2 transports glucose into the beta cells.
- GLUT 2 is a low affinity, high capacity glucose transporter. The glucose goes down its concentration gradient.
- Glucose that enter the cell gets phosphorylated to glucose-6-phosphate by glucokinase, starting glycolysis.
- Glucokinase has a low affinity for glucose and so its activity under normal physiological conditions varies markedly, according to the concentration of glucose.
- From glycolysis, TCA cycle and electron transport chan ATP is formed.
- When ATP levels reach above a certain threshold, it acts to inhibit the ATP-sensitive potassium channel, reducing the entry of potassium.
- The cell becomes more negative as less potassium enter, which causes the voltage gated calcium channels to open. This results in the influx of calcium into the beta cell.
- Calcium causes the exocytosis of the insulin containing vesicles.
- Insulin is released into the portal system.
7
Q
- The insulin circulates in the vascular almost in the ____ form.
A
Unbound
8
Q
Insulin binds to which receptors
A
The insulin receptor
9
Q
Where are the insulin receptors located
A
Found in hepatocytes, stratified muscle and adipocytes
10
Q
The insulin receptor is which type of receptor
A
A tyrosine kinase receptor i.e. causes its actions via phosphorylation
11
Q
Describe the structure of the insulin receptor
A
The insulin receptor is a combination of four subunits held together by disulphide linkages
- Two alpha subunits that lie entirely outside the cell membrane
- Two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm.
12
Q
The insulin binds with the ____ subunits on the insulin receptor
A
Alpha
13
Q
When the insulin binds what happens to the insulin receptor and the cell
A
- The insulin binds with the alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, the portions of the beta subunits protruding into the cell become auto-phosphorylated.
- Autophosphorylation of the beta subunits of the receptor activates a local tyrosine kinase, which in turn causes activation of insulin-receptor substrates (IRS), which through downstream phosphorylation activates Akt.
- The phosphorylation cascade results in an increase in GLUT4 expression.
14
Q
The phosphorylation cascade, a result of insulin binding to insulin receptor, increases the expression of which GLUT receptor
A
GLUT 4
15
Q
The overall effect of insulin
Insulin _____ the glucose transport in muscles and adipose tissue
A
Increases
16
Q
The overall effect of insulin
Insulin _____ the glucose phosphorylation
A
Increase
17
Q
The overall effect of insulin
Insulin _____ the glycogen synthesis
A
Increase
18
Q
The overall effect of insulin
Insulin _____ gluconeogenesis
A
Decreases
19
Q
The overall effect of insulin
Insulin _____ glycogenolysis (breakdown of glycogen)
A
Decrease
20
Q
The overall effect of insulin
Insulin _____ glycogen synthesis
A
Increase
21
Q
The overall effect of insulin
Insulin _____ glycolysis
A
Increase
22
Q
The overall effect of insulin
Insulin _____ triglyceride synthesis
A
Increase
23
Q
The overall effect of insulin
Insulin _____ fatty acid synthesis in the liver
A
Increase
24
Q
The overall effect of insulin
Insulin _____ lipolysis
A
Decrease
25
_The overall effect of insulin_
Insulin _____ amino acid transport
Increase
26
_The overall effect of insulin_
Insulin _____ protein degradation
Decrease
27
What is the effect of insulin on the liver
* Increases glycogen synthesis
* Increases fatty acid synthesis
* Inhibits gluconeogenesis (PEPCK & G6Pase)
28
What is the effect of insulin on muscles
* Increases glucose transport (GLUT4)
* Increases glycogen synthesis
29
What is the effect of insulin on adipose tissue
* Increases glucose transport (GLUT4)
* Suppresses lipolysis (lipid breakdown)
* Increases fatty acid synthesis
30
Insulin has a plasma half-life of ___ minutes
6 minutes
31
insulin is completely cleared from the circulation within \_\_\_\_minutes
1-15 minutes
32
Insulin is degraded by which enzyme
Insulinase
33
Insulin degradation occurs where
Mostly in the liver and to a lesser extent in the kidneys and muscles.
By the enzyme insulinase
34
Fill in the blanks
35
Define the term diabetes mellitus
Diabetes mellitus is a family of endocrine disorders that are characterised by a state of **chronic** **hyperglycaemia** (high blood glucose levels in the plasma) due to either **insulin** **resistance** (cells don’t respond to insulin) and/or **insulin** **deficiency** (beta cells don’t make the insulin).
36
Define the term "type 1 diabetes mellitus"
T1DM is defined as an autoimmune disease characterised by the **irreversible** **damage** to **beta** **cells** in the Islets of Langerhans. This reduces the amount of insulin produce and prevents the body from regulating blood glucose levels.
37
Describe the aetiology of Type 1 diabetes mellitus
* The cause of T1DM is still unclear. There may be a genetic component as people with other autoimmune conditions and those with a family history of autoimmune conditions appear to be at higher risk.
* It may be triggered by precipitating events such as exposure to certain viruses e.g. Coxsackie B virus and enterovirus, bacteria (e.g. strain of TB), cow’s milk etc.
38
What are the signs and symptoms of type 1 diabetes mellitus?
* Presents with an acute onset
* Commonly T1DM presents with a classic triad of symptoms
* Polyuria (excessive volume of urine)
* Polydipsia (excessive thirst)
* Unexplained weight loss
* Other symptoms include:
* Fatigue
* Blurred vision (due to retinopathy)
* Smell of acetone from breath (due to ketogenesis)
39
Fill in the blanks for T1DM
40
Describe the pathogenesis of type 1 diabetes mellitus?
* The cause is unclear however is thought it is a result of when genetically susceptible individuals are exposed to one or more precipitating event(s), which triggers their immune system in developing beta cell autoimmunity. This leads to the progressive loss of beta cells.
* The progressive loss can occur over a prolonged period (months to year) in which the patient is asymptotic, but would be positive for relevant autoantibodies. Symptoms of T1DM only occurs when 80-90% of the functional capacity of beta cells has been lost.
41
Describe the autoimmunity mechanism that results in Type 1 diabetes mellitus
* Autoimmunity in T1DM is identified by the presence of autoantibodies- antibodies that mistakenly target and react to beta cells. This triggers the immune response.
* Pre-diabetic pancreas is characterised by an inflammatory lesion within the Islet of Langerhans, with an infiltration by mononuclear cells containing activated macrophages, CD8+ T cells, CD4+ T cells, suppressor T lymphocytes and B lymphocytes. This causes the destruction of the beta cells specifically; alpha and delta cells are unaffected.
42
Name some of the susceptible genes that are thought to predisposition people to type 1 diabetes
No simple pattern of genetic predisposition. Multiple genes have been associated with susceptibility to T1DM. However, multiple people with the mutations do not develop T1DM.
* **HLA** eg DR3/4 – DR2/8
* HLA region within the major histocompatibility complex on the short arm of chromosome 6
* DR3 + 4: Increase susceptibility to T1DM in Caucasians
* Insulin (VNTR)
* PTPN22
* IL2RA
* CTLA-4
* IFIH1
43
Name some of the precipitating events which could trigger type 1 diabetes in genetic predisposed people
* Multifactorial- patients are required the genetic predisposition.
* These events can be the following, though a lot is not well known:
* Virus exposure: (Enteroviruses esp Coxsackie), rotavirus
* Bacteria (eg Mycobacteria Avium paraTB)
* Environmental, in the womb or after birth
* Dietary (Cow’s milk, Wheat proteins, Vitamin D deficiency)
* Insulin resistance (e.g. puberty)
* ? Psychological stress
44
Name some of the autoantibodies associated with T1DM
* **ICA** (islet cell antibody)
* **I-A2** (insulinoma-associated antigen-2)
* **IAA** (insulin auto-antibody)
* **GAD65** (glutamic acid decarboxylase 65)
* **ZnT8** (zinc transporter)
45
Name some of the clinical tests to investigate T1DM
1. HbA1c (gold standard)
2. Fasting blood glucose
3. 75g oral glucose tolerance test
46
Describe the HbA1c test
* Glucose binds directly and irreversibly to haemoglobin to form HbA1c. .
* Involves a blood sample every 3-6 months in the diabetic clinic. In the blood sample, the glycated haemoglobin are counted, which determines how much glucose is attached to haemoglobin. The proportion of HbA1c in the blood gives a measure of glucose control over the previous 3 months (as RBC have a lifespan of around 3-4 months).
* Commonly performed on diabetics to help long-term management plans
47
What are the value cutoffs for HbA1c in T1DM
* \< 42mmol/mol: normal
* 42-47mmol/mol: pre-diabetes
* \> 48mmol/mol: diabetes
48
Describe the fasting blood glucose test
Involves taking a blood sample from a patient who has been fasting for at least 8 hours, to check blood glucose levels.
49
What are the value cutoffs for the fasting blood glucose test in T1DM
**_\<_ 6.0mmol/l**: normal
**6.1-6.9mmol/l:** impaired
**_\>_ 7mmol/l:** diabetes
50
Describe the 75g oral glucose tolerance test for T1DM
* Patient is fasted for at least 8 hours and their blood glucose level is measured (blood sample).
* Patient is given a 75g oral glucose load. The blood glucose level is taken at regular intervals after the glucose load, either at regular intervals e.g. 30 mins, or a single test after 2 hours, most common.
* The blood glucose level after 2 hours can indicate diabetes
51
What are the value cutoffs for the oral glucose tolerance test in T1DM
_\<_ 7.7mmol/l: normal
7.8-11mmol/l: impaired
_\>_ 11.1mmol/l : diabetes
52
* The main method of management of T1DM is 3-fold. These are
1. Attention to diet
2. Exercise
3. Insulin therapy
53
What is the short term goal for T1DM treatment
To prevent short term complications such as hypoglycaemia or hyperglycaemia
54
What is the long term goal for T1DM treatment
the prevention of chronic complications by maintaining blood glucose levels as close to normal as possible.
55
Insulin is injected into which layer of the body
Subcutaneous
56
List the various forms of insulin that is available
* Rapid-acting
* Short-acting
* Intermediate-acting
* Long-acting
* Pre-mixed
57
What is the ordinary insulin injecting regiment for T1DM
* Ordinarily, a patient with severe type 1 diabetes is given a single dose of one of the longer-acting insulins each day to increase overall carbohydrate metabolism throughout the day.
* Additional quantities of short-acting insulin are then given during the day at the times when the blood glucose level tends to rise too high, such as at mealtimes.
58
How can a type 1 diabetic have good glycaemic control
* Requires attention to diet, exercise, and insulin therapy
* Self-monitoring of blood glucose (SMBG) is a core component and management of that reading (too low: consume glucose containing food/drink; too high: administer insulin)
59
Name the 3 types of glucose measuring devices
1. Blood testing meters
2. Flash glucose monitoring or FreeStyle Libre
3. Continous glucose monitoring
60
Describe the use of blood testing meters in measuring glucose levels in T1DM
* Involves using a lancet to pierce the skin so a drop of blood comes to the surface. The test strip is dipped into the drop of blood and then the machine will give you a reading.
* Accurate as it measures plasma (aka blood) glucose levels
61
Describe the use of flash glucose monitoring or Freestyle libre in measuring glucose levels in T1DM
* Sensor on the skin, lasts 14 days
* It measures the interstitial glucose level; therefore, the reading may not be accurate. Consequently, still required to take blood testing meters around with them in case.
* Good for treading glucose levels, allowing the patient to have an element of prediction as the arrow indicates if a decline in glucose level is an oncoming hypoglycaemia or if its normal and retest after 10 minutes.
62
Miao miao device is used with which kind of glucose monitoring device
Flash glucose monitoring or freestyle libre
63
Describe the use of flash glucose monitoring or Freestyle libre with miao miao in T1DM
* flash glucose monitoring or Freestyle libre monitors the interstitial glucose levels.
* Does not involve constant injections
* The miao miao acts as a transmitter that can be attached on top of the Freestyle Libre, which continuously reads the FGM or FreeStyle libre and sends the data to your phone.
* This can alert the diabetic if their levels get too low/high
64
Describe the use of continous glucose monitoring in measuring glucose levels in T1DM
* Small device which measures the interstitial glucose level continuously.
* It transmits data to display device, which can shows treads and can alert if glucose levels are not within range.
* Good for treading glucose levels, allowing the patient to have an element of prediction as the arrow indicates if a decline in glucose level is an oncoming hypoglycaemia or if its normal and retest after 10 minutes.
65
Each patient has an individualized insulin regiment. What are the 3 main types of insulin regiments
1. Multiple daily injection basal-bolus insulin regimens
* 1st line choice
2. Mixed (biphasic) regimen
3. Continuous subcutaneous insulin infusion (insulin pump)
66
Describe the multiple daily injection basal-bolus insulin regimens for T1DM
* 1st line choice
* One or more separate daily injections of intermediate-acting insulin or long-acting insulin analogue as the basal insulin; alongside multiple bolus injections of short-acting insulin before meals.
* This regimen offers flexibility to tailor insulin therapy with the carbohydrate load of each meal.
67
Describe the mixed (biphasic) insulin regimens for T1DM
o One, two, or three insulin injections per day of short-acting insulin mixed with intermediate-acting insulin.
o The insulin preparations may be mixed by the patient at the time of injection, or a premixed product can be used.
68
Describe the continous subcutaneous insulin infusion (insulin pump) insulin regimens for T1DM
o A regular or continuous amount of insulin (usually in the form of a rapid-acting insulin analogue or soluble insulin), delivered by a programmable pump and insulin storage reservoir via a subcutaneous needle or cannula.
69
Describe an insulin pump
* Device that administers insulin
* An insulin pump is a small electronic device that gives your body the regular insulin it needs throughout the day and night.
* The pump is attached to your body by a cannula, which goes just under your skin. The cannula needs changed every two or three days
70
Describe the two types of insulin pump used for T1DM
_Tethered pump_ - attached to your body by another small tube that connects to your cannula
_Patch pump_ - Patch pumps have no extra tubing, which means the pump sits directly on your skin and it works by using a remote
71
Describe artificial pancreas as a possible treatment for T1DM
* Insulin pump controlled by continuous glucose monitor
* An artificial pancreas is a man-made device that is designed to release insulin in response to changing blood glucose levels in a similar way to a human pancreas.
* The glucose measuring device measure glucose levels and the result is fed into a small computer which calculates how much insulin (if any) needs to be delivered by the insulin pump. The dose is then delivered into the body, completing the cycle.
72
What treatments/technologies are available on the NHS?
* Blood testing meters
* Flash glucose monitoring (FGM) or FreeStyle Libre (brand name)
* Insulin pumps (rarely)
* Insulin
* Needles
* Lancets etc
73
At the current moment insulin is the only treatment for T1DM. What is a possible treatment for the future?
* Islet cell transplant
* Current research investigating beta-cell transplants and stem cells
74
Type 1 diabetes accounts for about what percentage of all patients with diabetes
5-10 %
75
What is the geographical epidemiology for T1DM
It is more common in Europeans and less common in Asians
76
What age group is most commonly diagnosed with T1DM
It is the most commonly diagnosed diabetes of youth (under 20 years of age) and causes ≥85% of all diabetes cases in this age group worldwide
77
Define the term hypoglycaemia
Hypoglycaemia is a deficiency of blood glucose defined as a concentration \<2.5 mmol/L. It can result from a variety of reasons
78
What are the possible reasons why a T1 diabetic would have a hypoglycaemia
* Taking oral hypoglycaemics (e.g. sulphonylurea) or too much insulin
* Alcohol (binge or heavy drinking).
* Certain medications, e.g. propranolol
* Inappropriate levels of exercise or food intake. Type 1 diabetics control their blood glucose by balancing insulin dosage, food intake and energy expended through exercise
* Rare cases include liver, kidney, pancreas or thyroid disease.
* Another cause is advanced insulin-secreting tumours elsewhere in the body.
79
What are the early signs/symptoms of hypoglycaemia
* **Confusion**- may appear drunk
* Feeling hungry
* **Trembling** or shakiness
* **Sweating**
* Anxiety or **irritability**
* Going pale
* Tachycardia or palpitations
* Tingling in the extremities or lips.
80
What are possible risk factors for hypoglycaemia in a T1 diabetic
* The dose, timing and type of insulin used in the management.
* Condition in which exogenous insulin is given e.g. temperature etc if using insulin pumps
* The degree of absolute endogenous insulin deficiency
* Hypoglycaemia unawareness
81
What are the possible treatments for hypoglycaemia in a T1 diabetic
* Hypoglycaemia needs to be treated with a combination of **rapid acting glucose** and **slower acting carbohydrates** such as biscuits for when the rapid acting glucose is used up.
* Options for treating severe hypoglycaemia are **IV dextrose** and **intramuscular glucagon**.
82
What are the two types of short term complication for T1DM
1. **Hypoglycaemia**
2. **Hyperglycaemia** (and DKA)
83
How is hyperglycaemia in T1 diabetics treated
* Patients will get to know their own individual response to insulin and be able to administer a dose to correct the hyperglycaemia. For example, they may learn that 1 unit of novorapid reduces their sugar level by around 4 mmol.
* Be conscious that it can take several hours to take effect and repeated doses could lead to hypoglycaemia.
84
Chronic exposure to hyperglycaemia can cause damage to the body. Describe the damage it can cause
* Chronic exposure to **hyperglycaemia** causes damage to the **endothelial cells** of blood vessels. This leads to leaky, malfunctioning vessels that are unable to regenerate.
* High levels of sugar in the blood also causes **suppression of the immune system**, and provides an optimal environment for infectious organisms to thrive.
85
What are the two types of long term complication for T1DM
1. Macrovascular complications (damage to big blood vessels)
2. Microvascular complications (damage to small blood vessels)
86
Describe the macrovascular complications that can arise from T1DM
* Macrovascular damage is damage to big blood vessels
* **Coronary artery disease** is a major cause of death in diabetics
* Peripheral ischaemia causes poor healing and ulcers
* Stroke
* Hypertension
* These complications are dependent on other risk factors
87
Describe the microvascular complications that can arise from T1DM
* Microvascular damage is the damage to small blood vessels
* Neuropathy
* Retinopathy
* Nephropathy
* These complications are dependent on glycaemic control- patients with poorly controlled diabetes are at higher risk of microvascular complications.
88
Macrovascular complications are dependent on?
A) Other risk factors
B) Glycaemic control
A) Other risk factors
89
Microvascular complications are dependent on?
A) Other risk factors
B) Glycaemic control
B) Glycaemic control
90
Which group of people are not treated for T1DM with the HbA1c test? Why?
HbA1c is not used in pregnancy.
This is because it is unreliable in pregnancy as physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised
91
Which cells secrete insulin and to which group of cells in the pancreas do they belong?
Beta cells of the pancreatic Islets of Langerhans
92
Precisely how do the cells that secrete insulin react to increasing concentrations of circulating glucose?
* Glucose enters the beta cells in the pancreatic islets via GLUT-2 receptors.
* The glucose that enters gets metabolised and forms ATP
* The rising ATP levels inhibits the ATP sensitive potassium channels, preventing potassium efflux
* This causes the beta cell to depolarise opening voltage gated calcium channels, causing calcium influx
* The calciumc causes the exocytosis of the insulin containing vesicles
93
What is the general structure of the human insulin molecules in the bloodstream?
Insulin consists of two polypeptide chains (A and B), which are linked by disulphide bonds
94
What protein, secreted with insulin, can be used as a marker for insulin production?
C-peptide
The C-peptide is cleaved when proinsulin is converted to insulin
95
Describe the transduction of the insulin signal in the effector cell
* Insulin binds to the alpha subunits of the insulin receptor
* The insulin receptor has 4 subunits: 2 alpha and 2 beta
* Binding of insulin causes the beta subunits of the insulin receptors to autophosphorylate
* This autophosphorylation causes tyrosine kinase activation- causing the enzyme cascade to become activated.
* Downstream effects caues the GLUT4 receptors to translocate to the cell membrane
* Glucose enters the cell via these GLUT4 receptors
96
Which form of diabetes is usually an HLAassociated autoimmune disease
Type 1
