1
Q
what is diabetes
A
Diabetes is a disease of the pancreas that sits underneath the stomach and the liver.
- When you eat something and it hits your stomach, the pancreas detects these changes in glucose level and will secret insulin to bring the level back down if the concentration is high
- If blood glucose goes down the pancreas secretes glucagon, which increases endogenous blood glucose levels through glycogenolysis.
2
Q
what are the complications associated with diabetes
A
- The leading cause of heart disease- is heart attack from a patient who has uncontrolled diabetes to avoid this need to have tight glycaemic control.
- Leading cause of blindness in ageing people- here you have retinopathy and the hardening of capillaries
- Also, the leading cause of renal failure is- the disruption of amyloid and the destruction of kidney function.
- Ulceration and amputation
3
Q
what are the alpha and beta cells
A
Within the pancreas, there are alpha and beta cells
- There is a single islet of Langerhans and within these cells are a ball of red cells which is the insulin-producing beta cells
- The beta cells are insulin-producing and the alpha cells produce glucagon so when your blood glucose drops, glucagon is released and tells your liver to release glucose
- When your blood glucose increase, insulin is produced in the beta cells
- The alpha and beta cells are sensitive to glucose
- In patients who have type 1 diabetes the beta cells are destroyed
4
Q
what is T1D
A
- The islet of Langerhans is almost undetectable, you don’t see any of the red cells which make insulin.
- The black dots are the cells of that patient’s immune system
- They are moved through the body and moved through all the other cells in the pancreas and they have targeted the insulin-producing cells
- Destroying the insulin-producing cells in an autoimmune manner
- Don’t understand what are the exact triggers of T1D but once triggered then it doesn’t stop and you get a destruction of the insulin-producing cells and it is lifelong.
5
Q
what is T2D
A
- The beta cells are still there but they are usually struggling against insulin resistance, obesity, and high circulating levels of fat that affect the production of insulin from the pancreas.
- The structure of the islets is disrupted
- In patients who have uncontrolled T2D the pancreas will try to make more insulin to try and get it to get into the healthy range
6
Q
what is the difference between t1D and t2D
A
Both types of diabetes are the destruction of beta cells in Type 1 it occurs quickly wheras I type 2 it happens over a period of time
Type 1 need to manage by educating patients how to inject themselves and in type 2 if discovered early enough can try and get the beta cells back by educating with lifestyle intervention or drugs such as metformin
7
Q
what are the characteristics of T1D
A
- Insulin-dependent diabetes mellitus (IDDM)
- Early/juvenile onset, 5-10% of diabetes
- Autoimmune destruction of b-cells.
- Dependent on insulin injections from an early age.
- WHO 422 Million, ~10% with Type 1 Diabetes.
8
Q
how do you test your blood glucose level
A
Done by measuring blood glucose by finger pricking, calculating carbohydrates, injecting insulin, need to see if you need to make any adjustments. If not cautious can get hypo/hyperglycaemia which can produce complications if not controlled.
Can be frustrating because lots of fingerpicking (it hurts) and there is an increased risk of infection.
9
Q
what is the basal-bolus regime
A
- Basal-bolus regime is a combination of insulin injections which will help give the best chance of a normal, healthy blood glucose range.
- Short-acting insulin injections are administered with mealtimes and the long-acting which you inject that last up to 12-24 hrs
- Not easy to master trial and error to try to mimic the blood glucose level of a healthy pancreas
10
Q
what are the criteria of the basal-bolus regime and when is this an exception for young children
A
Basal Bolus Regime
- All children and young people should be offered a basal-bolus regime from the time they are diagnosed
Except:
- If a child needs such a small dose of insulin that it is too difficult to get the dosing right
- If it is felt inappropriate to expect a child <5yrs to have 4 or more injections a day
11
Q
what are the advantages of the basal-bolus regime
A
flexible
freedom
tighter control
12
Q
what are the disadvantages of basal bolus regime
A
more injections
commitment
young children
13
Q
what is carbscount
A
Carbscount is a book which allows patients to understand how much insulin they need depending on what they have eaten
- Done by giving them a book or putting them in a structured education programme
14
Q
what is mysugr
A
digital technologies which are easy to access as it is done through your phone and don’t need to see HCP all the time and you can just record everything on your phone
-aimed at younger people
15
Q
what is glucose buddy
A
Ones that mimic structured programmes
E.g. Glucose Buddy
Available on your phone and it is about peer support, talking with other people about your experience, struggles etc
Informal way to connect with people eg putting up recipes which are low carb
16
Q
what is the new technologies of measuring glucose level
A
Finger prick testing but more and more patients are able to use new technologies instead of having to do a finger prick testing and getting test strips etc
For example:
Dexcom G6 is a glucose sensor which goes into your abdomen and you have a little PDA that will tell you what your blood glucose levels are but now you attach it and sync it with your phone/smartwatch. Improves quality of life and has alarms which will tell you if you are hypoglycaemic. Removes worry from parents if the child is hypoglycaemic as it sets off an alarm so no need to worry whether or not a child will go into a diabetic coma.
Another example is the freestyle libre
- Are a glucose sensor and syncs it to a phone
17
Q
give an example of an artificial pancreas
A
New technologies
For example, Medtronic is like an artificial pancreas
Links together the glucose sensor on an insulin pump to give patients a completely free pancreas. The pump adapts to insulin and avoids complications
18
Q
what are some of the procedures for diabetes
A
- Thinking of ways to replace insulin-producing cells
- Islet transplants and the challenges of immunosuppressants. In the syringe, there are isolated human islets of Langerhans from a donor and they’re injected into the patient.
- Viacyte- little pouches you can put cells into and transplant them into the abdomen. No need for immunosuppressants because the cells are protected from the immune system.
o You have your little pouch and you’ve got your insulin-producing cells. Some of these are stem cells some of them are donated cells
o They can release insulin out and glucose can come in.
o There is newer tech that allows the cells to be modified so that the blood supply can go inside the little pouch
o So you get a replacement pancreas in the form of a little pouch that’s vascularised and will be able to respond to changes in your blood glucose - This tech is used in the form of CRISPR tech- Gene editing. Being able to modify the contents of the cells by slicing tiny sections of DNA. The aim is to try and avoid the immune response in T1D that destroys the insulin-producing cells
19
Q
what are some of the Challenges to understanding the immunology of T1D
A
- Monoclonal antibodies- the first drug to treat the immunology of T1D
- In T1D, the islet doesn’t show a lot of insulin-producing cells
- The green cells are the alpha cells (glucagon-producing cells) and there is a hollow bowl where the insulin-producing cells used to be
- Once the beta cells started to die there was no way of slowing the process down
20
Q
how to overcome these challenges of the immunology of T1D
A
- Monoclonal antibody Tzeild: Teplizumab which slows down the progression of T1D
- When the disease starts there is a period where you see the loss of beta cell function and you start to see a loss of first phase insulin release-like pre-diabetic (hard to detect it)
- Now we know there are which antibodies to test for and make a monoclonal antibody to slow down the process.
- Helps slow down the beta loss of insulin-producing cells.
21
Q
list the signs and symptoms of diabetes
A
- Polydipsia- an increased thirst to try to flush out high glucose
- Polyuria- increased urination caused by hyperglycaemia
- Polyphagia- Increased hunger. Not getting the energy from what you are eating. If you don’t have insulin can use the glucose which becomes stored as energy
- Blurred vision- can be one or both eyes occurs by changes in osmotic pressure in the eye from living in high concentrations of glucose
- Dizziness- dehydrated and low bp due to high level of glucose
- Fatigue- lack of energy if you don’t have insulin working properly don’t have energy, you can’t, burn glucose as energy it can take up into your muscles you as cant store glycogen in the liver don’t have the energy to complete tasks
Symptoms that are more common in adults
- Genital itchiness from yeast infections and general infections and thrush in a short period of time as you are peeing out high glucose levels
- Slow wound healing- nerve damage, infections
22
Q
what are the 3 diagnostic tests for diabetes
A
- A random plasma glucose concentration of >11.1mmol/l should be around 4-6mmol/l
- Fasting plasma glucose concentration of >7mmol/l should be around 4mmol/l
- The plasma glucose concentration of >11.1mmol/l 2 hours after oral glucose tolerance. Should be around 4-6mmol/l after 2 hours
23
Q
how do you do the random blood glucose test
A
- Can do them at your GP/hospital/pharmacy
- Can come in and do a finger prick test or draw blood and have a full analysis of them
- If it comes over 11.1mmol/l = diabetic
24
Q
how do you do the fasting plasma glucose test
A
- No food or drink 8-12 hours
- Take a blood test sample again
- If over 7mmol/l the = diabetic
25
how do you do The plasma glucose concentration of >11.1mmol/l 2 hours after oral glucose tolerance.
- No food or drink 8-12 hours prior to the test
- Have a glucose drink of 75g of glucose
- Take a blood test 2 hours later if still above 11.1mmol/l = diabetic
26
what is the final diagnostic test and what does it show us
HbA1c level (glycosylated haemoglobin)
If it has a lot of sugar molecules stuck to the haemoglobin then diabetic
- Tells us how your glucose regulation over the last 3 months
27
what are the steps you need to do before insulin injecting
Everyone's journey is different because the metabolism is different
Have to manage your metabolism by injecting insulin if not controlled then get complications
finger prick test
calculate carb count
inject insulin
28
what is insulin
- All insulin in UK is 100iu/ml
- Human – genetically engineered in yeast or E.coli you know how active it is so there is stability
- Range of activities, different combinations
29
what are the different regimens of insulin
Once daily injection – a mixture of very long and very short-acting analogues
- Twice daily injections – a mix of short and long-acting insulins (morning and evening)
- Multiple daily injections (before meals) of short-acting insulin and one daily injection of long-acting insulin (Basal Bolus)
-Insulin pump – short-acting insulin only
30
list the different types of insulin injections
- Short Acting – Lispro, Aspart, Novorapid, Glulisine
- Intermediate – NPH/isophane (pre-mix of NPH/regular)
- Long acting – Glargine, Detemir, Lantus, Levimir
31
what are the two factors when considering which injection to give to someone
speed of onset and duration are the key factors to consider when giving insulin
32
what is Tresibar
Smooth onset of action
Approx. 25 hours half life
42 hours duration of action
33
what do you have to consider when injecting insulin
When you are injecting insulin your body doesn’t know that the insulin is already there
Have to consider how long the long-acting insulin before injecting short-acting because might give too much insulin and get hypoglycaemia which means that blood glucose is low and can drop into a diabetic coma
34
what type of regimen do you start when you are first diagnosed with diabetes
When first diagnosed with diabetes get onto the basal-bolus regimen
35
what conditions should a child/young person not be offered the basal bolus regimen
- All children and young people should be offered a basal-bolus regime from the time they are diagnosed
Except:
- If a child needs such a small dose of insulin that it is too difficult to get the dosing right
- If it is felt inappropriate to expect a child <5yrs to have 4 or more injections a day
36
how do you calculate how much insulin to give
Insulin Injections: How much insulin?
10g of carbohydrate = 1 unit of insulin
10g of carbohydrate
= 1 carbohydrate portion (CP)
= 1 unit of insulin
Carb count- a handbook which guides new diagnosed T1D how to calculate their carb count
37
what is DAFNE
Online
- Helps us see patterns over the course of weeks and then can do trial and error
- Need to use a mixture of long and short to try and adjust the blood glucose level
38
what is mysugr
- Helps the user also keep a record of the glucose blood sugar level concentration
- Has got a gamification element as it allows users to collect points and set personal goals
39
what is glucose buddy
- A network where you talk with other types 1 diabetic to share their experience and they can come up with recipes or what things that they are doing that works/ doesn’t work for them
40
Finger Prick BG Monitoring
38 meters on the market
-Minimum of 5 tests per day
-More frequent testing with exercise or illness
If you are on the basal-bolus regime then you may have to take more finger-prick tests approx. 10-15 finger pricks
41
Finger pricks BGM: Advantages
- Helps determine which foods are best for individual control
- Helps inform patients and doctors re injection regimes
- Increases understanding and reduces anxiety about hypos
- Vitally important for undertaking dangerous tasks (driving, operating machinery etc)
42
Finger pricks BGM: Disadvantages
Requires willingness and commitment
- It hurts
- Expense to the NHS
- Anxiety about blood glucose control and general health
- can cause higher risks of infection
43
Continuous Glucose Monitoring Systems
There are 3 type of continuous blood glucose monitoring
- Real time Continuous Glucose Monitors
- Retrospective Continuous Glucose Monitors
- Flash Glucose Monitors
Continuous Glucose Monitoring Systems
- Originally to PDA but now to a phone/smartwatch
- Shows you continuous reading
- When you are in the red zone will alarm you and will let you know you are hypo
- The trend arrows move all the time showing where your glucose is going either up/down. - - Want the arrow flat
- Can link to other people's phones eg useful for parents w a child
44
An Example is Dexcom G6
No PDA
- Done on your phone
- Painless procedure
- Work for 10 days and gives reading every 5 mins
- Abdomen back of your arm or lower back region
- Can get it on prescription
Simple Auto-applicator
Slim, water proof 10 day sensor
High, low and “Urgent, low soon” alerts
3 options for sensor placement
Use in pregnancy
Indicated for two years or older
45
CGMS: Advantages
- All the advantages of SMBG, without the pain!
- Hypo alarms for safety
- Linked to parents’ phones/devices for safety
- Downloadable data for both patients & health teams
46
Continuous glucose monitoring systems
Recommended for children and young T1D who have
- Frequent severe hypoglycaemia
- Impaired awareness of hypoglycaemia
- Inability to recognise, or communicate about, symptoms of hypoglycaemia
47
Symptoms of hypoglycaemia include:
- Dizzy
- Clammy
- Confused
If you have had hypoglycaemia for a long time you may become desensitized to the symptoms so there is a risk of you falling into a diabetic coma so it may be strongly advised to get continuous glucose blood monitoring
48
When would you consider to go on Consider ongoing real-time CGMS for:
- Neonates, infants and pre-school children
- Children or young people undertaking high levels of physical activity
- Children and young people with comorbidities (e.g anorexia), or receiving treatments e.g. corticosteroids) that can make BG control difficult
49
What are the challenges of CGMS:
Not currently funded by the NHS for most patients
- Expensive to buy privately
- Time delay between interstitial and blood glucose levels
- Provides large amounts of data
50
what is flash glucose monitoring
- A sensor that goes into your phone and syncs it to your phone
- Scan the phone on the patch area and will give you the reading
51
An example of flash glucose monitoring
Abbot Freestyle Libre sensor
- 14-day sensor, scanned by a handheld reader
- Partial funding support in some areas of the NHS
- Does not have hypo alarms
The latest flash glucose monitoring is freestyle libre 3
- Linked to smartphones
- Reading every minute (CGMS)
- More affordable
- Smallest, thinnest sensor
- Accurate 14-day sensor life
- Now has hypo alarms
52
Insulin pump therapy
Adults and children >12 yrs provided that
- Attempts to achieve target HbA1c with MDI (basal/bolus) result in disabling hypoglycaemia
- If HbA1c levels remain greater than 8.5% (69 mmol/mol) on MDI despite a high level of care
When is the insulin pump advised
Children under the age of 12 yrs when:
- MDI therapy is considered impractical or inappropriate
- Young children on pumps would be expected to trial MDI Between the ages of 12-18yrs.
53
What are the advantages of insulin pump
Avoiding insulin injections
- Greater freedom and flexibility
- Fewer large swings in blood glucose
- Improvements in HBA1c
54
Insulin pump disadvantages
Checking blood glucose every 3-4 h
- Changing infusion site every 48-72 h
- Know your carbs!
- May take several months to optimise
55
An example of an insulin pump is Medtronic (minimed 670G System) features
Artificial pancreas system
-Advanced insulin pump
- Sensor talks to the pump
56
Features of smart guard tech
- Variable personalised rate of insulin 24 hours a day
- Automatically adjust insulin delivery and corrects blood glucose levels every 5 minutes
- Automatically corrects highs and suspends when low
- Anticipates blood glucose changes and adjusts insulin delivery automatically
- Advanced Bolus WizardTM
57
Features of guardian 4 tech
- Seven-day continuous wear
- No finger pricks required
- 94% of users prefer this system to their previous device
58
name other devices of insulin pump
Other examples are tandem, camdiab, CamAPD FX, omnipod
59
what are the follow-ups after a pancreas transplant
> 90% are simultaneous pancreas and kidney transplant
> Lifelong immunosuppressant therapy
> Cyclosporine/tacrolimus/sirolimus, Azathioprine/mycophenolate mofetil
> Corticosteroids- to dampen down the immune system to avoid rejection
60
what is islet transplantation and what do you need
Lifelong immunosuppressant therapy
- Steroid free immunosuppression to allow beta cell to function
- tacrolimus/sirolimus
- Alemtuzumab, monoclonal antibodies
61
Islet transplantation advantages:
- Improved HbA1c
- Improved quality of life
- Loss of fear of hypoglycaemia
- Zero instances of hypoglycaemia
62
Islet transplant Disadvantages
- Islets are in desperately short supply
o New sources of insulin-producing cells are required.
- Transplanted cells run out of steam
o Enhance and protect the function of transplanted cells
63
what is viacyte
Is like a pouch where it keeps the islet cells which contain the beta cells which are insulin-producing cells which are implanted near the abdomen underneath the surface of the skin and this device allows it to act like a normal pancreas. It is kept in a pouch to avoid the immune system from attacking the beta cells containing the insulin.
64
what is viacyte mad up of
A key component of ViaCyte’s devices is composed of a medical-grade plastic called expanded polytetrafluoroethylene (ePTFE)
- it is a polymer that can control the pore size at a molecular level and the insulin-producing cells are stored in a semi-permeable membrane and the blood vessels sit outside if the pouch
65
what are the three type of viacyte pouches available
- PEC-ENCAP is for T1D
- PEC-Direct is for uncontrolled high risk T1D
- PEC-QT is for insulin-dependent diabetes
66
what is the features of PEC-ENCAP- ALL TYPE 1 DIABETES
- Semi-permeable barrier- just small molecules such as insulin, oxygen, exchange gases can go through the pouch not blood vessel as it is too big
- No immunosuppressants
- Stem cell-derived
- Pancreatic precursors
67
what are the features of PEC-DIRECT- Type 1 patients with the highest risk of acute, life-threatening complications
- Permeable barrier
- Allows blood vessels to enter
- Improved, rapid engraftment
- Requires immunosuppressants
- Quicker then PEC-ENCAP
68
what People who are suitable for PEC-DIRECT
those who are:
- Hypoglycaemic unawareness
- Extreme glycaemic lability
- 140,000 USA and Canada waiting
- Unlimited, consistent supply-strength
69
what are the features of PEC-QT- All patients with Type 1 and insulin-dependent Type 2 Diabetes
-Experimental technology
-CRISPR-modified cells
- Permeable barrier
- Immune Evasive
70
PEC-QT Patients:
- T1D
- Insulin-dependent Type 2
- CRISPR technology
71
CRISPR Technology: Gene Editing
- Changes the original stem cells
- Uses Cas9 enzyme to find the sequence and uses gene editing
72
what are the features of PEC-QT
- Gene-edited pluripotent human stem cell line
- Differentiated into pancreatic endoderm cells
- Specifically engineered to avoid destruction by the patient’s immune system
- The same type of device is used for PEC-Direct
73
Viacyte approaches to overcoming limitations of islet transplantation by :
- Unlimited source of cells (from stem cells
- Physical barriers (PEC-Encap)
- Permeable barriers with immunosuppressants (PEC-Direct
- Permeable barriers without immunosuppressants (PEC-QT)
74
what are the benefits of a pharmacy
* Everyone lives within 20 mins of a pharmacy
* No appointment needed
* Healthcare professional is present alongside trained support staff
* Long opening hours
* Private room for consultations
= a very accessible, convenient setting to deliver routine care to the public
75
what programmes are put in place to advance a pharmacist role
* The NHS Long Term Plan (2019): significantly extend the role of pharmacists, taking advantage of all the benefits listed above for:
– Routine management/monitoring chronic disease
– Screening and diagnostics
– Risk assessment and referral pathways for disease prevention
– Prevention of hospital admission
76
what are the current status of a pharmacist role
* NICE – recommends community pharmacies should be risk assessing and offering to test
* Particular emphasis placed on hard to reach groups who GP might miss
* Pharmacy ideally placed within a smaller geographic area, can provide targeted promotion to their communities
77
what risks groups are associated with diabetes
* All adults over 40yrs (excludes pregnant women)
* Adults aged 25-39 from high risk ethnic groups (South Asian, Chinese, African-Caribbean, black African)
* Adults with conditions putting them at increased risk: obesity, HT, stroke, PCOS, previous gestational diabetes, mental health disorders
78
what recommendations are implemented for those who have diabetes
* NHS Health checks delivered via community pharmacy
* Use a validated diabetes risk assessment questionnaire
* If high risk – encourage GP appointment for testing, refer as necessary
* Provide advice/leaflets on weight loss, healthy eating, physical activity, refer as necessary
* Keep records of risk assessments, monitor and follow up, re-assess later
79
What else can pharmacists do?
* Be on alert for patients describing signs/symptoms of diabetes
* Repeated minor infections
* Repeatedly seeking candida treatments
* Seeking minor foot ailment treatments
* Know your local population – are there high risk or hard to reach groups?
* Signposting to relevant websites for support - Diabetes UK - Know diabetes. Fight diabetes. | Diabetes UK
80
what is meant by National Diabetes Prevention Programme (DPP)
* Non-diabetic hyperglycaemia ‘pre-diabetes’
* Pharmacists can refer patients
* Fasting glucose 5.5-6.9mmol/L or HbA1c 42-47 mmol/mol
* A behavioural intervention programme to try and prevent T2DM and reverse the hyperglycaemia
81
DPP – what’s involved?
* Patients referred/invited following check for pre-diabetes
* Take part in group sessions, set goals with support for:
– Healthy weight achievement
– Dietary recommendations
– Physical activity recommendations
* Evidence based to prevent T2DM
82
Glucose monitoring in T2D
* No need for routine self-monitoring of blood glucose (SMBG) for T2D patients on antidiabetic medication alone
* SMBG is required for T2D patients on insulin, but this is individualised, there’s no standard recommendations
83
treatment aims for T2D
* NICE published new guidelines in Feb 2022!
* Local Sussex-wide Diabetes Treatment Guidelines
* Core principles: individualise therapy and glycaemic control targets
* Consider – co-morbidity, contraindications, weight, preferences, risks, adherence etc
* NICE Algorithm: NG28 Visual summary (full version: choosing medicines for first-line and further treatment) (nice.org.uk)
84
list the T2D therapies
* Biguanide (metformin)
* Sodium glucose co-transporter inhibitors (SGLT-2i)
* Dipeptidylpeptidase inhibitors (DPP-4i)
* Thiazolidinidiones (pioglitazone)
* Sulfonylureas
* Glucagon-like peptide agonists (GLP-1 RA)
85
how to choose therapies for T2D
* At baseline, establish HbA1c, cardiovascular risk and renal function
* Metformin always first (after diet/lifestyle measures)
* Next steps depend on whether patient has/ is at high risk of cardiovascular disease (CVD). Includes chronic heart failure, atherosclerotic CVD or QRISK-2 of 10% or higher
* Add other classes for dual or triple therapy
* > 3 agents not recommended
86
what are Biguanide
* Metformin
* Inhibits gluconeogenesis, increases peripheral insulin sensitivity
* Significant GI disturbance, titrate slowly. Lactic acidosis in renal impairment
* If GI disturbance a problem – switch to MR preparation before trying other classes
* First line monotherapy in all cases
87
what are SGLT-2 Inhibitors
* ‘…flozin’ family
* Inhibit renal sodium glucose co-transporter that’s responsible for renal glucose reabsorption
* Cause hypos, nausea, fluid loss, UTIs. Rare risk of DKA
* Lots of recent evidence shows benefit in CVD – reduction in mortality and major CV events
* Add to metformin in CVD/high QRISK patients
* Alternative 1st line ONLY if pt has CVD/high QRISK
88
what are incretins and Dipeptidylpeptidase
* Incretins: gut hormones glucaon-like peptide (GLP-1) and gastric inhibitory peptide, stimulate beta cells to release insulin
* Dipeptidylpeptidase (DPP-4): enzyme that breaks down incretins
89
what are DPP-4 Inhibitors
* ‘…gliptin’ family
* Inhibit incretin breakdown therefore increase insulin release
* Cause GI upset, headaches. Rare pancreatitis
* Different kinetics in the class useful for individualising therapy e.g. renal/hepatic impairment
* Add to metformin in non-CVD patients (equal option with SU, pioglitazone)
* Alternative 1st line in non-CVD patients
90
what are Sulphonylurea
* Gliclazide, glibenclamide, glipizide, glimepiride
* Close K+ channels which leads to more insulin secretion
* Cause hypos, weight gain and can accumulate in renal impairment (esp if long acting e.g. glibenclamide)
* Add to metformin in non-CVD patients (equal option with DPP-4i, pioglitazone)
* Alternative 1st line in non-CVD patients
91
what are Thiazolidinidione
* Pioglitazone only now
* Block gluconeogenesis, increase insulin sensitivity
* Cause GI upset, weight gain
* List of safety warnings – heart failure, bladder cancer, bone fractures, hepatotoxicity
* Add to metformin in non-CVD patients (equal option with SU, piloglitazone)
* Alternative 1st line in non-CVD patients
92
what is meant by GLP-1 agonists (mimetics)
* ‘…tide’ family
* Incretin receptor activation causes insulin secretion
* Cause GI upset (nausea/diarrhoea), suppress appetite (induce weight loss)
* Mostly injectable form
* Some recent cardioprotection evidence
* NICE – only where triple therapy fails, switch one drug for GLP-1 RA (specific circumstances document)
* Sussex – add to metformin/SLGT-2i in CVD/high QRISK
93
what is meant by medicines optimisation
* Improve patient understanding, enable shared decision making
* Improve adherence and empower the patient to self-manage
* Identify and address ADRs
* Prevent hospital admission or re-admission
* Each review with patient should address and issues
94
name 2 Opportunities for support that pharmacists can do
* New medicine service (NMS) – people prescribed new treatment for specific conditions, includes diabetes
* Discharge Medicines Service - patient digitally referred to community pharmacist when discharged from hospital, for medicines reconciliation
95
what are the most ADRs from diabetic drugs
* Most common ADRs from diabetes drugs:
– hypoglycaemia
– GI upset (various)
– Toxicity if renally impaired
96
what is required General ADR monitoring
* Knowledge of type A (expected, relate to pharmacology) and type B (unexpected, usually more serious) ADRs
* Timeline is important – patients initiated on new treatments require close monitoring for ADRs
* Assess patient risk factors and vulnerability e.g. elderly, co-morbidities
97
what is meant by AKI
* 20-40% people with diabetes have background CKD
* 60% cases start in community
* Lots of hospital admissions are ‘acute on chronic’, background CKD carries high risk of AKI
* Very frequently drug-induced
98
Think kidneys
* Beware of acute illnesses causing fluid loss (D&V)
* Medicines review – anything causing fluid loss, lowering BP, impacting the RAAS, direct nephrotoxins or drugs that become toxic in renal impairment
https://www.thinkkidneys.nhs.uk/aki/resources/pharmacists/
99
what drugs causes AKI
Diabetes and AKI prevention
* Metformin
* Sulphonylureas
* Diuretics
* ACE-I
* A2RBs
100
what is the pharmacists role
* Review patients medicines – although MURs, routine clinical screening
* Apply ‘think kidneys’ guidance, be aware of risky drugs
* Educate patients about risks, awareness of hydration and acute illness etc
* Assist with managing ADRs e.g. slow-release metformin, advise prescribers on alternative therapy options
101
what are the risks and complications related to in cardiovascular mechanisms
♦ Glycemic exposure as measured as A1c over time
- Proven
♦ Genetic risks
- Clearly true, but little understanding
♦ Glycemic variability
- Supported by most but not all studies
102
what is meant by cardiovascular
* Endothelial dysfunction
* Cardiomyopathy
* Increased risk of heart attack and stroke
– Diabetics have 3-5 fold increased risk of a death from cardiovascular disease.
103
what is the relationship between Hyperglycaemia and angiotensin
* High glucose increases production of angiotensinogen
* Angiotensinogen is the precursor of angiotensin II
* Hyperglycaemia amplifies expression of renin
* Increased levels of angiotensin II linked to increased risk of hypertension
- Recommended to go on Ace inhibitor
104
Diabetic complications: mechanisms
- The various pathways can lead to oxidative stress
- Hyperglycaemia can induce oxidative stress by auto-oxidation
- The glucose can become auto oxidise which increases intracellular oxidative stress
- Hyperglycaemia can also cause AGEs where glucose-modified proteins
- Hyperglycaemia can also activate PKC and hexosamine pathway and also the polyol pathway
- Hyperglycaemia feeds into mitochondrial respiration because this is where your glucose goes to make cellular ATP- your own energy source. However, under high glucose conditions, this can become disrupted and can lead to increase oxidative stress
- Oxidative stress can lead to cell dysfunction and can also change the genome of your cell and therefore can activate specific genes and activate transcription factors such as NFkB which are able to change proteins that are actually expressed inside the cell
105
How does oxidative stress damage cells?
- Lipids can cause lipid oxidation can damage the membrane by making it less fluid and therefore make it harder for receptors to pass through the bilayer. In the cardiovascular system, lipid oxidation causes it harder for blood vessels to dilate
- Can oxidise proteins by changing their activity by inhibiting and hence damaging the enzymes. Can also disrupt the protein structure of the 2nd and 3rd structures of proteins which causes damage to the actual cell inside as the proteins will try to fold but will undergo endoplasmic reticulum stress which leads to cell death.
- Reactive oxygen species can affect DNA by either altering gene expression by activating transcription factors but also by directly damaging your DNA to activate DNA repair enzymes such as PARP and this leads to increase DNA cellular damage which leads to cell death
- Can bind to macromolecules by changing their function
- Also linked to sugars such as AGE products leading to cellular damage
- Can disrupt calcium control and is fatal in some cells especially cardiac cells as impairs the contraction of the heart and can lead to cell apoptosis. Also, affect nitric oxide production.
106
how is glycolysis and the krebs cycle linked to the different pathways
- shows the metabolism of glucose through glycolysis. Has a series of reactions until it enters the Krebs cycle at the end of the chain reaction
- Coming off the glycolysis pathway you can see an increase in hyperglycaemia because there is more glucose going in and so there are more intermediate steps
- At the end of the chain reaction of glycolysis, oxidative stress can inhibit GAPDH- the enzyme at the end of glycolysis
- So oxidative stress causes the GAPDH enzyme to be inhibited and therefore this will lead to an increase of the substrates of the intermediate steps
- The glucose can be converted to the polyol pathway to sorbitol to then fructose and increase oxidative stress because it involves the Glutathione pathway
- Fructose can be converted through the hexosamine pathway
- And G3P can be converted to methylglyoxal which can act on proteins to increase the amount of AGEs products and G3P can be converted to DHAP and then converted to DAG which is the intracellular messenger for activating PKC through the protein kinase pathway
107
Mitochondrial respiration
How does it cause an increase in oxidative stress?
- Under normal conditions, you have glycolysis and the Krebs cycle where the goal is to create ATP for energy for the cells
- Does this by NADH and FADH where it gets pushed into the mitochondria where they travel through the electron transport chain
- At the electron transport chain complex 1, the hydrogens are taken from the NADH which returns it to NAD and the hydrogen is pumped into the gap in the mitochondria. Hydrogen ions are positive and therefore you are left with an electron which gets passed from complex 1-4 before it is added to oxygen to make water
- The hydrogen that’s moved into the gap through a couple of places from FADHII moves through the complexes. The hydrogen ions build up in the gap of the mitochondria which turns the mitochondrial space potential positive
- At the end, the hydrogen ions get moved back into the mitochondria from the membrane through ATP synthase. When they get moved back, it creates an electrical force because they are positively charged ions.
- The electrical force converts ADP and phosphate into ATP which is needed for energy for the cells
- To get rid of the hydrogen ions in the mitochondria, you add it to oxygen to make water
108
what happens in mitochondrial respiration under hyperglycaemic conditions
- During hyperglycaemia, there is a build-up of NADH so therefore you have much more glucose that you are metabolising so you are creating for the glycolysis and the Krebs cycle more NADH and FADH
- More hydrogen ions are going into the membrane gap so the mitochondrial membrane potential is increasing
- When it increases this inhibits complex 3 from the electron transport chain
- When you inhibit complex 3, the electron can’t be moved to complex 4 so it starts getting stuck in complex 2
- It starts to be put into oxygen but there is no hydrogen to make water so the electron is being put into oxygen which makes O2- which is a superoxide which is a free radical.
- The mitochondria know that this can happen and that electrons can get in the way so there is a possibility of superoxide being built up. This is why the mitochondria have manganese superoxide dismutase which is an antioxidant which protects against the superoxide radicals as it converts the superoxide back into the water so it can be reused
- The problem with hyperglycaemia is that there is an overload of superoxide which can undergo a series of reactions that produce other radicals by adding more electrons and can cause cellular damage.
109
Mitochondrial respiration- easier explanation
* Hyperglycemia increases the production of electron donors from the TCA cycle (NADH and FADH2)
* Increased mitochondrial membrane potential because protons are pumped across the mitochondrial inner membrane in proportion to electron flux through the electron transport chain
* Inhibition of complex III by the increased membrane potential increases the half-life of free radical intermediates of co-enzyme Q
* Co-enzyme Q can reduce oxygen to superoxide
110
how are Advanced glycation end products (AGEs) produced
* Formed from the reaction of glucose with proteins, non-enzymatically at 37 degrees
* They are irreversibly formed
* Have specific cell receptors (RAGE)
* Increase superoxide formation by immune cells causing NF-kB activation and subsequent release of cytokines and growth factors
* Quench nitric oxide- key for vasorelaxation
* Affect matrix molecules such as type I collagen affecting vessel elasticity
111
describe the age pathway in a macrophage
- This is a macrophage that floats in your immune cell and blood cell and can react with AGE products which increase reactive species which activate NF-kB and release cytokines and growth factors
- AGE product receptor cells are also found in endothelial cells which can affect the superoxide and transcription factors. Does this by increasing inflammatory proteins expression inside of the endothelial cell and can cause an increase in oxidative stress which causes damage to cells
- AGE products can also end up in the matrix and collagen and therefore affect the elasticity of blood vessels
112
what is the Aldose Reductase and Polyol Pathway
Aldose reductase increased glucose which is converted to sorbitol
- Converts NADPH to NADP. Also depleting cells of NADPH
- Glutathione reductase converts glutathione to reduced glutathione which isn’t a superoxidant defence enzyme so there is a depletion of glutathione so oxide radicals build up leading to oxidative stress
113
what is the Protein Kinase C (PKC)
* Activated by hyperglycemia-induced DAG formation via increased de novo synthesis
* Increases:
– ET-1- causes blood vessels to contract so they constrict and this increases hypertension
– VEGF- growing blood vessels- overproduction of blood vessels can cause them to harden for example in the retina light wouldn’t be able to pass through
– TGF-ß- generated in the matrix
* Collagen- will affect vessel elasticity hard for blood vessels to relax
* Fibronectin
– Plasminogen activator inhibitor (PAI)-1
* Decreases fibrinolysis- decreases the breakdown of clots can lead to heart attack and strokes
– NF-kB- a pro-inflammatory transcription factor that can affect protein
– NADPH oxidases- cause an increase in cellular oxidative stress
* Oxidative stress
* Decreases:
– eNOS- decreases nitric oxide formation from endothelial cells so less likely to relax in the first place. Causes an increased risk of hypertension
114
what do endothelial cells produce
Single layer of endothelial cells line innermost portion of arterioles. Increased pressure stimulates release of endothelial-derived relaxing factor (EDRF) or nitric oxide (NO) causing vasodilation.
115
explain the Vasorelaxation Of Diabetic Aortic Rings experiment
- In an experiment where the rats are made diabetic for 8 weeks
- After 8 weeks removed the aorta and cut it into rings and put it in an organ bath
- When you put the aortic ring in can make it pre-contract by using the alpha-1 receptor of the adrenergic receptors of the sympathetic system.
- Pre-contract the ring by using phenothrin which activates the alpha-1 receptors causing them to contract
- The function of the endothelial cells and the key function is to make nitric oxide to cause vasodilation
- Want to add a substance to the pre-contracted aortic rings as you increase the concentration, that substance will increase nitric oxide from the endothelial cell so that you can measure the endothelial cell function. We use AcH which affects the muscarinic receptors on the endothelial cells and causes them to contract by opening the calcium channels and the activation of eNOS to make nitric oxide and cause vasodilation
- In the control animal aortic ring, as you increase AcH, you get an increase in relaxation.
- In the diabetic ring of 8 weeks, as you add AcH, there is relaxation but the curve is shifted to the right so it is less sensitive to AcH. There is a loss of endothelial cell function and they are not making much nitric oxide. As you get to the higher concentrations you see a contraction because of the effect of AcH on the smooth muscle cells causing contraction as it overwhelms the nitric oxide that is being released. There is functional impairment
116
describe Endothelial Nitric Oxide synthase
- Nitric oxide synthase and the co-factors involved. It is a haem requiring enzyme
- Requires tetrahydro bartron also requires FMN and FAD
- One of the key co-factors is NADPH- which gets depleted in the sorbitol pathway
- The co-substrate for nitric oxide synthase to make nitric oxide is the amino acid arg
117
Inhibition of nitric oxide action- why are we getting an impairment in function in the endothelial cells is it due to…
* Quenching of nitric oxide
– With superoxide to form peroxynitrite
* Decrease in nitric oxide production
– Direct inhibition of enzyme
– Reduction in enzyme co-factors
118
describe the different tests for diabetes
- Nitrotyrosine is residues in protein of nitrate (nitrated version of nitric oxide) only happens if you form peroxynitrite
- In the diabetic- Nitrotyrosine box there is evidence that the nitric oxide is being quenched
- In DNA strand breaks- diabetic box there is an increase in DNA strand breaks which will stimulate the activation of DNA repair enzymes (PARP)
- In the PARP-diabetic box, you can see an increase in activity in diabetic rings in response to the increase in DNA strand breaks
- PJ34 was the first PARP inhibitor and is water soluble
- In diabetics with PJ34- and nitrotyrosine you still see an increase in nitrotyrosine. Inhibiting PARP doesn’t affect oxidative stress and the formation of nitrotyrosine
- In diabetics with PJ34- and DNA breaks box it isn’t protecting against the strand breaks it is still the same. Still getting DNA breaks. Not blocking the oxidative stress or the DNA repair enzymes
- diabetics with PJ34 and PARP activity there is inhibition
119
how is PARP activated
- PARP is activated by a single-strand break in the DNA such as ONOO-, S-mustard (chemical weapon), UV, H2O2, alkylating agents and ionizing radiation
- When PARP become active, it used NAD as a substrate which breaks down NAD and puts this ribose group onto the proteins around your strand break. The proteins around your strand break are the histones which act like a flag because your other DNA repair enzymes can’t tell that your DNA is damaged
- PARP ribosylates the histone proteins next to the actual DNA strand breaks and creates a long chain of polymers which acts like a flag and so other repair enzymes come in and can repair the break.
120
what happens to PARP under hyperglycaemic conditions
- Hyperglycaemia causes damage to DNA which causes the strand to break. This causes an overproduction of PARP. This causes a depletion of NAD and decreases the production of ATP which causes the cell to undergo necrosis and also causes depletion of NADH. No nitric oxide is made as a result
121
describe Vasorelaxation Of Diabetic Aortic Rings experiment when diabetic and treated with PJ34
- In the black triangle and black circle, we treated the normal and diabetic rats with PARP (PJ34) which is an antagonist of PARP. It inhibits the activity of poly-ADP polymerase
- If you inhibit the activity of DNA repair enzymes, you get a restoration of endothelial cell function. Back to normal
- The PARP inhibitor is protecting against the loss of endothelial cell function. PARP is using NAD as a substrate
122
describe the Reversibility of diabetic vascular NAD and NADPH levels by PARP inhibition
- The top graph is non-diabetic animals and using HPLC can measure NAD and NADPH level
- The middle graph shows the endothelial cell from diabetic animals. There is no endothelial function. Depletion of the cells of NAD, NAD and NADPH. This is because PARP activation is depleting the cells of NAD
- In the bottom graph, the endothelial cells from diabetic animals that have been treated with PJ34, you get endothelial function again. NADPH increase a little and the NAD increase a lot and the NADP also.
Why have they come back preferentially?
Because it is the function f the endothelial cell to make nitric oxide. So that’s what happens when you put a PARP inhibitor in, you get the NADPH back first which is why you get the function back because the cells can now make nitric oxide
123
how else can PARP be expressed other than DNA repair
PARP and PJ34 also mediated in gene expression
The adhesion molecules and if expressed on endothelial cells mean that the immune cells can stick to them
Good if you have an infection as the immune cells can deal with that
Nut in terms of hyperglycaemia and diabetics increases the risk of atherosclerosis
With the first two adhesion molecules, there is an increase with high glucose and get an even bigger increase with high/low glucose but PJ34 reverses it and PARP is involved in gene transcription as well as DNA repair
124
summarise part 1
* Hyperglycemia leads to oxidative stress
* Oxidative stress leads to peroxynitrite formation in endothelial cells
* Resulting DNA strand breaks leads to PARP activation
* PARP activation depletes cellular NAD/NADPH impairing eNOS activity
* PARP activation has a pro-inflammatory effect on gene expression increasing risk of atherosclerosis
125
how is methylglyoxal linked to glycolysis pathway
- Methylglyoxal levels goes up because you have hyperglycaemia and increases the components of the intermediate steps in the glycolysis pathway
- Methylglyoxal is an alkylating agent and linked to an increase in AGE products formation
126
what is Methylglyoxal
* -↑ MG in diabetic patients and in models of diabetes
* Highly reactive dicarbonyl
* Potent glycating agent so an increase in the formation of AGE products
- Comes from the glycolysis pathway
- Goes up with ageing so the suggestion that diabetic accelerate ageing
127
There are 2 ways to get rid of Methylglyoxal
1st way:
- GLO-1 which is converted to lactoylglutothione
- And GLO-2 which is then converted to D-lactate which is then converted to pyruvate and fed back into the citric acid cycle
2nd way:
Methylglyoxal reductase which can be converted to lactaldyhde and rhen converted to L-lactate to be converted to pyruvate and passed back into the citric acid cycle
128
Does Methylglyoxal damage endothelial cell function?
- Exposed aortic rings at different lengths of time to increase the concentration of Methylglyoxal
- The red line looking for a shift to the right because that shows there is impaired endothelial cell function because not making nitric oxide
- As time goes on you see endothelial cell impairment as the red line shifts to the right
129
how can you measure oxidative stress by NBT reduction
- can measure oxidative stress by NBT reduction and as you expose the endothelial cells for 1,2 4 hours you can see an increase in oxidative stress
- Oxidative stress in terms of endothelial cells causes damage to DNA activation and activation of poly-ADP ribose polymerase
- Can see an increase in PARP activation at 1mM at 2 and 4 hours
- NADPH depletion levels inside of cells and eNOS being the co-factor at 2 and 4 hours at 0.3 and 1 mM there is a decrease in NADPH level
130
what is the effect of IL-8 on Methylglyoxal
- Methylglyoxal can increase IL-8 (inflammatory mediator and releases the mediators through NK-kB
- Linked to the increase in PARP activation
131
describe summary 2
* ↑ glucose
* MG
* Oxidative stress
* Endothelial cell viability
* Endothelial dysfunction
* Diabetic vascular disease
- Methylglyoxal directly causes endothelial cell dysfunction, increased oxidative stress, over-activation of PARP and cellular depletion of NADPH
- Methylglyoxal also increases endothelial cell production of IL-8
132
describe IL-8 (decrease TIMP-1 ) and the cardiovascular system
* IL-8 is highly expressed by endothelial cells, smooth muscle cells and macrophages in atherosclerosis
* Induces firm attachment of monocytes to the endothelium expressing E-selectin in early stages of atherogenesis. Promotes attachment of monocytes
* Inhibits TIMP-1 ( enzymes that regulate extracellular matrix) activity which may make plaques more unstable as there is an imbalance between MMP:TIMP activity
133
what is meant by Resveratrol- protects against it
* Natural phenol produced by several plants including grapes (not very much in red wine)
* Has various biological actions including
– Anti-aging effects
– Anti-diabetic effects by lowering blood sugar
– Cardiovascular protective effects
– Cancer prevention
– Neuroprotective effects
– Anti-inflammatory effects
134
does Resveratrol have an effect on NBT
- in NBT there aren’t any antioxidant effects or oxidative stress that seems to be happening in the presence of Resveratrol. Does have an effect inhibiting PARP activity and protecting NADPH level
135
what is the MoA of Resveratrol
* Mechanism of action
– SIRT-1- increase
– Increase Anti-oxidant increasing MnSOD expression, reducing mitochondrial superoxide production
– NF-kB inhibition
– Estrogen receptor modulator- has relaxant effect on blood vessels
– AMPK activation
– Increase Glyoxalase-I expression
136
what is SIRT
* SIRT 1-7
* NAD-dependent deacetylases
– 1st step NAD is cleaved to nicotinamide
– 2nd step the acetyl group is transferred from the substrate to the ADP-riobose moiety
* Nicotinamide is an endogenous inhibitor of sirtuins
* SIRT-1 also has ADP-ribosyltransferase activity
137
what is SIRT-1 function
* Transcriptional control through chromatin modification by deacetylating histones
* Regulates a variety of metabolic processes
– Increases gluconeogenesis
– Increases cholesterol efflux
– Inhibits PPAR-gamma
– Increases insulin secretion
* Inflammation and stress response
– Inhibits NF-kB
– Increases Heat Shock protein expression
138
what other functions does SIRT-1 have?
* Cardiovascular disease
– Increases expression of eNOS
– Increases activity of eNOS
– Decreases ANG II receptor expression
– Enhances MnSOD expression
– Reduces senescence
– Inhibits PARP activity
139
SIRT-1 and PARP Interaction
- B) cross modification is the most likely for PARP inhibition
140
summarie part 3
* Resveratrol protects against MGO-mediated endothelial cell dysfunction
* Prevents PARP activation and NADPH depletion
* May not be through an anti-oxidant action but may be through direct inhibition of PARP
141
what is meant by Glyoxalase I
* Present in all human tissues
* Breaks down methylglyoxal
* Expression decreases in aging and diabetes
* Increasing expression can protect cells from hyperglycaemia-mediated damage.
142
GLO-I expression-the future
* 2016 study demonstrated Resveratrol and Hesperetin decreased plasma MGO levels, improved vascular dilation, reduced vascular
* inflammation as well as improved glucose sensitivity in overweight and obese individuals
– Resveratrol and hesperetin synergistically increase GLO1 expression and activity
143
what is meant by diabetic foot in diabetes
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
Diabetic foot is defined as any foot pathology that results directly from diabetes or its long term complications
144
what are the statistics of people who have diabetes
One of the most common diseases in the UK and is increasing
Most people in the UK have type 2 diabetes 85%
In England the number diagnosed has increased between 2006 and 2022, from 1.9 million to 4.9m
13.6 million people are now at increased risk of type 2 diabetes in the UK
850,000 people are currently living with type 2 diabetes but are yet to be diagnosed
75% die of macrovascular complications
145
what is the Epidemiology of people who have diabetes
Lesions of the feet affect ~10% of people with diabetes will have a foot ulcer at some point in their life.
An associated amputation rate 15 fold higher than non diabetics
Foot ulcerations are the commonest cause of hospital admission in people with Diabetes
Diabetic Foot Ulcerations are the most common cause of non-traumatic lower limb amputations.
Up to 80% of these amputations are thought to be preventable
146
After a first amputation, people...
with diabetes are twice as likely to have a subsequent amputation as people without diabetes.
Mortality rates after diabetic foot ulceration and amputation are high, with up to 70% of people
dying within 5 years of having an amputation and around 50% dying within 5 years of developing a
diabetic foot ulcer.
147
what does it cost the NHS to deal with diabetes
The cost of diabetes to the NHS is over £1.5m an hour or 10% of the NHS budget for England and Wales. This equates to over £25,000 being spent on diabetes every minute.
In total, an estimated £14 billion pounds is spent a year on treating diabetes and its complications, with the cost of treating complications representing the much higher cost.
Click here to see a breakdown of costs in 2012
148
what are T2D risk factors
You’re at risk if you:
Have prediabetes.
Are overweight.
Are 45 years or older.
Have a parent, brother, or sister with type 2 diabetes.
Are physically active less than 3 times a week.
Have ever had gestational diabetes (diabetes during pregnancy) or given birth to a baby who weighed over 9 pounds.
Are an African American, Hispanic or Latino, American Indian, or Alaska Native person. Some Pacific Islanders and Asian American people are also at higher risk.
If you have non-alcoholic fatty liver disease.
(CDC 2022)
149
Why is Foot assessment necessary?
Around 5% of people with diabetes may develop a foot ulcer in any year
Of ulcerated persons:
45% have peripheral vascular disease (PVD)
Ischaemia – 15%
NeuroIschaemia – 30%
55% of people with diabetes have sensory neuropathy
Of all non-traumatic lower limb amputations 85% are due to diabetic foot ulcerations
150
what do NICE guidelines recommend for diabetics who have a risk of diabetic foot
When examining the feet of a person with diabetes, remove their shoes, socks, bandages and dressings, and examine both feet for evidence of the following risk factors:
Neuropathy
Limb Ischaemia
Ulceration
Callus
Infection / inflammation
Deformity
Gangrene
Charcot Arthropathy
151
how do you classify the Ulceration risk status
Active Ulceration / Charcot
Critical limb Ischaemia / Necrosis
Neuropathic Pain
Previous Ulceration
Previous Amputation
Renal replacement
>1 risk factor
1 risk factor – Ischaemia / Neuropathy / Deformity with Callus
No Risk factors
152
what are the Factors leading to development of diabetic foot:
Diabetic macroangiopathy – peripheral arterial occlusive disease
Diabetic microangiopathy – thickening of basement membranes
Diabetic polyneuropathy
Diabetic osteoathropathy –
abnormal foot biomechanics
Reduced resistance to infection
Delayed wound healing
Reduced rate of collateral
vessel formation
153
what are the 2 Vascular Assessment
Palpate pulses: Posterior Tibial:
- The Posterior tibial pulse comes from the posterior tibial artery and can be found just behind the medial malleolus
Dorsalis Pedis:
-The dorsalis pedis pulse comes from the anterior tibial artery and is located on the dorsum of the foot often close to the extensor tendon of the big toe
154
what are the 6 P's for neurovascular assessment are
pain, poikilothermia, paresthesia, paralysis, pulselessness, and pallor.
155
what are 3 types of neuropathies
Sensory
- Loss of touch and pain sensation can occur.
- There is large and small nerve fibre involvement.
Autonomic
- A disease of the non-voluntary, non-sensory nervous system. Affects CV, erectile dysfunction, bladder and digestive systems.
Motor
- Damages nerve supply to muscles, causing small muscle atrophy.
156
how does the autonomic neuropathy cause ulceration
Autonomic neuropathy causes increased capillary pressure, this leads to micro vascular sclerosis and therefore a lack of nutrients to the skin, this can result in ulceration.
Motor neuropathy can cause prominent metatarsal heads, clawing of the toes and anterior displacement of metatarsal fatty padding = altered gait pattern
Glycation In collagen leads to limited joint mobility
157
what are the different effects of the sensory
Sensory neuropathy
Predominates
Large fibers - tactile and deep sensitivity
Small fibers - pain and heat sensitivity
Motor neuropathy
Weakness and atrophy of the intrinsic muscles of the foot-clawtoe
Loss of joint mobility
Secondarily, it contributes to loss of joint mobility, which is also due to conjunctive tissue glycosylation inducing fibrosis of the joint, soft tissue and skin
158
Symptoms of Neuropathy
Symptoms of Neuropathy
Tingling / Numbness
Loss of ability to detect temperature changes
Loss of co-ordination / Proprioception
Burning / shooting pains – can be constant and highly distressing
Glove and stocking distribution
Associated Deformity:
High arch feet
Bunions
Claw and hammer toes
Areas of heavy callus
Deformities due to past trauma/surgery
Past ulceration sites
Charcot foot
159
what are the most common deformities
Any deformity has the potential to cause problems, these are the most common:
Deformity may not necessarily be linked to motor or autonomic neuropathy.
Previous unproblematic deformity such as bunions could now be areas that are vulnerable due to poor circulation or higher pressure
Previous ulceration can cause areas of scarring or fragile thin skin
160
What might patients be buying?
Callus Creams – Urea Based – e.g. flexitol – Appropriate - Callus areas only
Bath Thermometers - Appropriate
Callus Files – Electric / Cheese Grater type – Avoid!
Corn Plasters – Contraindicated Salicylic Acid – Avoid!
Insoles - Caution
Padding – Felts – Caution
161
what are the Biomechanics of Ulceration
Loss of pressure and pain sensitivity leads to repeated local hyperpressure shear stress in the hyperkeratotic region
Under which effusion develops and exteriorizes into an ulcer
Mechanical, thermal or chemical wound may also lead to ulceration - diagnosed late due to the absence of associated pain
162
what is callus
- Callus increases pressure on the skin
- Pressure damages the skin underneath
- The skin breaks down, fluid becomes trapped
- An ulcer is present under the callus
- Ulcer only revealed once the callus is removed
163
what are the causes of ulcers
Poor tissue viability
Thin, fragile skin
Poor circulation
Neuropathic feet
High pressure / friction on margins of the foot
Consider pressure sore areas such as the heels
Oedema
Ill-fitting footwear
164
what are the causes of neuropathic ulcers
Mechanical
High plantar pressures
Chronic repetitive stress causes callus
When neglected breaks down vulnerable tissue underneath
Unsuitable footwear
Lack of hosiery
Worn out insoles
Traumatic
Acute injury
Unsuitable footwear
Thermal injuries
Walking barefoot
Puncture wounds
Inappropriate self care
Chemical
Salicylic Acid
Vaporub
Bleach
Drain cleaner
Battery Acid
165
what is meant by Lymphangitis
is an inflammation or an infection of the lymphatic channels that occurs as a result of infection at a site distal to the channel
If left untreated can lead to Lymphadenopathy and Sepsis
166
what is meant by cellulitis
Cellulitis is a common bacterial skin infection that causes redness, swelling, and pain in the infected area of the skin.
* is a potentially serious infection in the deeper layers of your skin.
* It can start suddenly and may become life threatening without prompt treatment.
167
what is meant by sepsis
Sepsis is a serious condition that can initially look like Flu, gastroenteritis or a chest infection.
Seek medical help immediately if the patient has any of the following:
Slurred Speech
Extreme Shivering
Passing no urine (in a day)
Severe Breathlessness
‘I feel like I might die’
Skin Mottled or discoloured
168
what features will a good footwear have
A good shoe will have the following features:
Sufficient room i.e. depth, length and width to accommodate toes
Fastening – lace, buckle or Velcro
Heel height – under 5cm
Smooth seamless lining
Wear socks or stockings
Trainers or ‘Hotter’ style shoe
169
list bad footwear types
Court shoes
Mules
‘Deck shoes’
Slip-ons
Slippers without fastening
Leather soled shoes
Rigid upper
Hospital slippers!
170
what is a common problem for people with finding good shoes when they have diabetic foot problems
A common problem with patients with diabetes is changing inappropriate footwear
Patients may need to change their style of footwear even if they don’t have any other risk factors
This reduces the risk of callus formation, friction and pressure
171
what are the different types of Orthoses / devices
Plantar orthoses - Insoles have a preventive and sometimes curative function
Silicones- are little molded silicone devices that protect areas of conflict with the shoe (notably at the toes)
Shoes - Shoes are essential to prevention
They may be adapted mass-produced models, semi-therapeutic or made to measure orthopedic shoes
Patient may be buying gel toe spacers and props – care if neuropathy present
172
what are some of the patient related products that a patient might buy
Patients might be trying to buy:
Dressings
Iodine / Povidone Iodine
Honey
Padding / Semi Compressed felt
Heel grips
Ankle supports
Enquire to any breaks in the skin
173
what is the difference in when to refer to a specialist when someone has a diabetic foot or ulcers
Ulcers should be referred within 24 hours
Diabetic foot wounds are different
Refer Immediately >24 hours
Off-load pressure
Cover the wound with a dressing
Allow gaseous exchange – No Granuflex please
Non-allergenic
Changed regularly
Changed when strike through occurs
Do not use adhesives on ischaemic/ neuroischaemic ulcers or fragile skin
174
Apart from the dressings we use other essential considerations are:
Metabolic control, what is the patients glycaemic control like? Is their blood pressure high?
Lifestyle? Do they smoke? What type of work do they do?
Footwear, do they need a DH boot or walker boot?
175
Charcot Foot:
Occurs in patients with neuropathy
Most commonly affects the medial border of the mid-foot
Sudden foot collapse / shape change
Can be triggered by trauma even just walking
Red, hot, swollen foot
Irreversible deformity
Leaves foot prone to ulceration due to altered plantar pressure
176
autonomic neuropathy always present
Not all symptoms – differential diagnosis
If you suspect Charcot Foot then you should refer the patient to the diabetic multidisciplinary foot clinic urgently or to the MAU for admission
177
what is the treatment of Charcot:
Assess:
Foot temperature
Swelling
Pain
History
Deformity
Refer or admit to A&E >24 hours
Advise patient to rest / not to weight bare
Need non-removable below knee cast and MRI
178
Prevention in at-risk feet
General measures
Optimal glycemic balance
Prevention of associated CVS risk
Smoking cessation
Specific measures
Podiatry
Orthoses
Adapted footwear
Patient education
179
what are the common problems with diabetes
Common problems with Diabetes
Slow healing cuts / sores - dressings
Itchy Skin – Groin area – Thrust treatments eg. Clotrimazole
Frequent fungal infections – Lamisil Once e.g. Terbinafine
Reduced Vision – Hazard self treating – Graters / nippers
Numbness and Tingling
Erectile Dysfunction
Be mindful if people are coming back regularly for the same product.
180
what can pharmacists recommend for diabetic foots
What can you recommend?
DO:
File nails – Not cut
File callus only if low risk – do not use the cheese grater type files.
Apply moisturising creams daily – not to broken skin
Only use Urea based creams on callus areas only.
Contact Podiatry or GP / Diabetes Nurse if they have problems / notice any colour changes, breaks in the skin etc.
Check inside shoes daily for objects
Check feet daily
Do Not:
Do not use corn / callus treatments – corn plasters
year 4
flashcards
Decks in class (5)
# Cards
