Week 10 - Diabetes Flashcards
where is glycolysis carried out?
liver
what is the role of glycolysis?
extract energy from glucose
what is gluconeognesis?
synthesis of glucose from nonsugar precursors
where does gluconeogenesis mainly occur?
liver
and to a lesser extent the cortex of the kidney
what is glycogenolysis?
when glycogen breaks down into glucose
where does glycogenolysis occur?
hepatocytes and myocytes
what enzymes regulate glycogenolysis?
phosphorylase kinase and glycogen phosphorylase.
what is glycogenesis?
process of storing excess glucose as glycogen
which cells produce endocrine hormones?
islets of langerhans
pancreas
which cells produce glucagon?
alpha cells
what do alpha cells produce? (pancreas)
glucagon
which cells produce insulin?
beta cells
what do beta cells produce? (pancreas)
insulin
what do gamma cells produce? (pancreas)
pancreatic polypeptide
where are pancreatic polypeptides produced?
gamma cells
where are somatostatins produced?
delta cells
what do delta cells produce? (pancreas)
somatostatin
what do E-cells produce? (pancreas)
ghrelin
where is ghrelin produced?
E-cells
what is the function of glucagon?
increase blood sugar levels
what is the function of insulin?
decreases blood sugar levels
what is the function of somatostanins?
inhibits glucagon and insulin release
what is the function of pancreatic polypeptides?
regulates endocrine and exocrine secretion activity
list the microvascular complications that occur with diabetes?
retinopathy
nephropathy
neuropathy
what is non-proliferative retinopathy?
development of microaneurysms, venous loops, retinal hemorrhages, exudates (fluid that leaks out of blood vessels into nearby tissues).
what is proliferative retinopathy?
presence of new blood vessels, with or without vitreous hemorrhage. It is a progression of nonproliferative retinopathy.
what is seen on a fundoscopy of background retinopathy?
dots = microaneurysms
blots = small intraretinal haemorrhage
hard exudates = lipid
what is seen on a fundoscopy of pre-proliferative retinopathy?
cotton wool spots = ischaemia
intraretinal microvascular abnormalities
what is seen on a fundoscopy of proliferative retinopathy?
new vessel formation = very friable and have a high tendency to bleed
what is nephropathy?
Progressive deterioration in renal function resulting in end-stage renal disease, particularly glomerular sclerosis
how does diabetic nephropathy occur?
- Increased glomerular capillary flow with urine containing high glucose levels results in increased extracellular matrix production and endothelial damage
- The vascular damage to the glomerulus causes increased permeability to macromolecules, results in proteinuria (excessive protein loss in the urine). Specifically microalbuminuria, which is often the first sign of CKD.
- Causes mesangial expansion and interstitial sclerosis which can cause glomerular sclerosis.
- Also nonaluminium renal impairment due to unresolved episodes of acute kidney injury
what tests can be done to diagnose diabetic nephropathy?
- ARC (albumin to creatine ratio)
>3mg/mol- EGFR (glomerular filtration rate)
<60
BP
- EGFR (glomerular filtration rate)
what is neuropathy?
Heterogeneous condition associated with nerve pathology.
The condition is classified according to the nerves affected and includes focal, diffuse, sensory, motor, and autonomic neuropathy.
how does diabetic neuropathy occur?
- Diabetes is associated with dyslipidemia, hyperglycemia, and low insulin and growth factor abnormalities.
- These abnormalities are associated with glycation of blood vessels and nerves which causes structural nerve damage including: segmental demyelination, axonal atrophy and loss, and progressive demyelination.
- These effects causes a decrease in nerve sensitisation and also affect ANS function -> neuropathy.
- In addition, autoimmunity may affect nerve structure.
- Poor blood supply and nerve damage can also lead to the formation of ulcers seen often on diabetic’s feet.
what are the macrovascular complications of diabetes?
- Primarily diseases of the coronary arteries, peripheral arteries and cerebrovascular.
- Early macrovascular disease is associated with atherosclerotic plaque in the vasculature supplying blood to the heart, brain, limbs and other organs.
- Late stages of macrovascular disease involve complete obstruction of these vessels, which can increase the risk of MI, stroke, claudication and gangrene.
- Peripheral ischaemia causes poor skin healing and diabetic foot ulcers
how do macrovacular complications of diabetes occur?
Result from hyperglycemia, excess free fatty acid and insulin resistance -> increases oxidative stress, protein kinase activation and activation of glycine end products which act on the endothelium to cause:
* Increased vasoconstriction which causes hypertension and vascular smooth muscle cell growth
* Increased inflammation
* Thrombosis, hypercoagulation and platelet activation and decreased fibrinolysis
what is type 1 diabetes?
a condition where the pancreas stops being able to produce adequate insulin
Without insulin, the cells of the body cannot absorb glucose from the blood as use it as fuel.
The glucose levels in the blood keep rising, causing hyperglycaemia
what is thought to be involved in the onset of T1DM?
cold weather
viruses e.g. enteroviruses and coxsackie B
early diet - less common in breastfeeding
what age does T1DM usually present?
10-14
but can appear anytime before 40
what are the presenting symptoms of T1DM?
○ Polyuria (excessive urine)
○ Polydipsia (excessive thirst)
○ Weight loss (mainly through dehydration
May also present with diabetic ketoacidosis
what are the 3 key features of diabetic ketoacidosis?
Ketoacidosis
Dehydration
Potassium imbalance
why do each of the 3 symptoms of diabetic ketoacidosis occur?
ketoacidosis = liver produce ketones to fuel body. initially kidneys produce bicarb to counteract ketone acids but over time the bicarb is used up .: blood is acidic
dehydration = hyperglycaemia overwhelms the kidneys, glucose leaks into urine, water is drawn into urine by glucose .: polyuria .: dehydration
potassium imbalance = insulin normally drives K+ into cells .: no inulin = no K+ in cells .: high serum K+ .: total body K+ is low as its not stored in cells .: hypokalaemia which can lead to arrhythmias
what is the main cause of T2DM?
overweight and obesity, sedentary lifestyle and increased consumption of unhealthy diets containing high levels of red meat and processed meat, refined grains and sugar-sweetened beverages.
what are some non-modifiable factors of developing T2DM?
aging
black-african/carribean and south asian
family history
what are the presenting features of T2DM?
- Tiredness
- Polyuria and polydipsia (frequent urination and excessive thirst)
- Unintentional weight loss
- Opportunistic infections (e.g. oral thrush)
- Slow wound healing
Glucose in urine (on a dipstick)
how does T2DM occur?
Repeated exposure to glucose and insulin makes peripheral tissue resistant to the effects of insulin. More and more insulin is required to stimulate the cells to take up and use glucose (blood sugar).
Over time, the pancreas becomes fatigued and damaged by producing so much insulin, and the insulin output is reduced.
what is the defenition of hypoglycaemia?
Plasma glucose of <3.0mmol/L
what is the treatment of hypoglycaemia when the patient is conscious?
○ Administer glucose gel by mouth (e.g. GlucoGel)
○ Repeat capillary blood glucose after 10-15 minutes and if the patient is still hypoglycaemic, repeat administration of glucose gel a further 2-3 times
When the patient is fully alert, provide a longer-acting carbohydrate for the patient to eat (e.g. toast)
what is the treatment of hypoglycaemia when the patient is unconscious?
○ Administer intravenous glucose (e.g. 150-160 ml of 10% glucose)
○ If the patient then regains consciousness, switch to using oral glucose as above
If IV access is not able to be established rapidly, administer glucagon 1mg via the intramuscular or subcutaneous route. Glucagon stimulates the conversion of stored glycogen within the liver into glucose. As a result, glucagon is ineffective in patients with depleted glycogen stores (e.g. elderly patients with poor oral intake and patients with eating disorders)
how do you remember the treatment of DKA?
FIGPICK
* Fluids - IV fluid resuscitation with normal saline (1 litre in first hour, followed by 1 litre every 2 hours) * Insulin - fixed rate insulin infusion (e.g. Actrapid at 0.1 units/kg/hour) * Glucose - closely monitor blood glucose and add a glucose infusion when it is less than 14 mmol/L * Potassium - add potassium to IV fluids and monitor closely (e.g. every hour initially) * Infection - treat underlying triggers * Chart - chart fluid balance * Ketones - monitor blood ketones, pH and bicarbonate
what is the treatment of hypovolaemic shock?
- Fluid resuscitation
○ 500ml bolus of Hartmann’s solution or 0.9% sodium chloride (warmed if available) over 15 mins
○ Administer 250ml boluses in pts at increased risk of fluid overload (e.g. heart failure)
○ After each fluid bolus, reassess for fluid overload (JVP, auscultation of lungs)
○ Repeat administration of fluid boluses up to 4 times reassessing each time
○ Senior response if patient has negative response - increased chest crackled or pt not responding adequately to repeated boluses i.e. persistent hypotension
what is a hyperosmolar hyperglycaemic state?
- Characterised by hyperosmolality (water loss leads to very concentrated blood), high sugar levels (hyperglycaemia) and the absence of ketones, distinguishing it from ketoacidosis
what is the presentation of a hyperosmolar hyperglycaemic state?
polyuria, polydipsia, weight loss, dehydration, tachycardia, hypotension and confusion
what is the treatment of a hyperosmolar hyperglycaemic state?
IV fluids
replace electrolytes
blood glucose should normalise with fluids (insulin only given with senior advice)
careful monitoring
what is the long term management for T1DM?
Subcutaneous insulin
Monitoring dietary carbohydrate intake
Monitoring blood sugar levels upon waking, at each meal and before bed
Monitoring for and managing complications, both short and long term
what is the basal-bolus regime for insulin?
Background, long-acting insulin injected once a day
Short-acting insulin injected 30 minutes before consuming carbohydrates (e.g., at meals)
what is lipodystrophy?
Injecting into the same spot can cause lipodystrophy, where the subcutaneous fat hardens. Areas of lipodystrophy do not absorb insulin properly from further injections.
what is an insulin pump?
small devices that continuously infuse insulin at different rates to control blood sugar levels. They are an alternative to basal-bolus regimes. The pump pushes insulin through a small plastic tube (cannula) inserted under the skin. The cannula is replaced every 2 – 3 days, and the insertion sites are rotated to prevent lipodystrophy and absorption issues.
what are the advantages and disadvantages of using an insulin pump?
ADVANTAGES
better blood sugar control, more flexibility with eating and less injections.
DISADVANTAGES
Difficulties learning to use the pump
Having it attached at all times
Blockages in the infusion set
A small risk of infection
what is the difference between tethered and patch insulin pumps?
Tethered pumps are devices with replaceable infusion sets and insulin. They are usually attached to the patient’s belt or around the waist with a tube connecting the pump to the insertion site. The controls for the infusion are on the pump itself.
Patch pumps sit directly on the skin without any visible tubes. When they run out of insulin, the entire patch pump is disposed of, and a new pump is attached. A separate remote usually controls patch pumps.
what is a HbA1c test?
An HbA1c test is the main blood test used to diagnose diabetes. It tests your average blood sugar levels for the last two to three months
what HbA1c level diagnoses diabetes?
48mmol/mol or above
what HbA1c level indicates someone is pre-diabetic?
between 42 and 48mmol/mol
what is a random blood glucose test?
If you have severe symptoms of diabetes, you may have a random blood test at any time of the day. This is a quick test, through a finger prick or a vein in your arm
what random blood glucose level would indicate diabetes?
11mmol/l or more
what is a fasting blood glucose test?
fasting is required for 8 hours before blood glucose testing
what fasting blood glucose indicates diabetes?
7mmol/l or more (126mg/dL or above)
what test is routinely done when diagnosing gestational diabetes? what levels would diagnose gestational diabetes?
oral glucose tolerance test
a fasting glucose blood sample is taken and then a sugary drink is given. Two hours later another blood sample is taken.
If you are pregnant you have gestational diabetes if:
Fasting glucose is 5.6mmol/l or more
2 hour glucose is 7.8mmol/l or more
what tests help distinguish between T1 and T2 diabetes?
checking for autoantibodies which are common in type 1
The presence of ketones — byproducts from the breakdown of fat — in your urine also suggests type 1 diabetes, rather than type 2.
why isn’t a urine test used to diagnose diabetes?
It will show your doctor if there is any sugar in your urine, not how much or the possible cause.
what is bolus insulin?
short or rapid acting insulin taken at or before mealtime to control blood sugar levels
what is basal insulin?
intermediate or long acting insulin taken to keep blood sugar levels steady between meals and overnight
how can diabetic patients control what they eat in order to manage their diabetes?
- Patients need to eat regularly, three meals a day at the same time each day.
- Patients should not skip meals
- Eat meals consisting of starchy complex carbohydrates like whole grains, potatoes and brown rice.
- Avoid refined sugar4
- Avoid sugary drinks
- Use caution when eating fruit as some of them are deceptively sugary, like bananas.
Ensure at least 30 minutes of moderate activity per day, ideally after meals. This will help to regulate blood sugar. Ideally this will be a short brisk walk.
what are the symptoms of hypoglycaemia?
- Headache
- Anxiety
- Hunger
- Shaking
- Weakness or feeling faint
- Dizziness
- Sweating
Dry mouth
what are the target blood sugar levels in T2 diabetes before meals and 2 hrs after eating?
4-7mmol/l
<8.5mmol/l
what are the target blood sugar levels in T1 diabetes before meals and 2hours after eating? adults vs children
If you’re a child with type 1 diabetes
* when you wake up and before meals: 4 to 7mmol/l
* after meals: 5 to 9mmol/l
If you’re an adult with type 1 diabetes
* when you wake up and before meals: 5 to 7mmol/l
before meals at other times of the day: 4 to 7mmol/l
what are the target blood sugar levels for someone with gestational diabetes?
If you have gestational diabetes
* Fasting: below 5.3mmol/l
One hour after meals: below 7.8mmol/l
when would a biphasic insulin routine be used?
In type 1 diabetes, a twice daily regimen is suitable in people who have a consistent day to day routine.
when is a once daily insulin routine used?
- Suitable for those Type 2 diabetics taking insulin.
Usually ultra long acting insulin with no peak of activity - mimicking the background levels in a healthy person.
what is the first line therapy in T2DM?
metformin
what are the advantages of metformin?
- No weight gain.
- Has cardiovascular-protective effects= reduces risk of MI and death
- Does not usually cause hypoglycaemia.
- Cost-effective & long-term evidence
what is the dosage of metformin?
starting dose is 500mg daily & needs to be titrated up gradually over a period of weeks
NEEDS TO BE TAKEN WITH MEALS
how does metformin work?
- reducing hepatic glucose production
- inhibiting intestinal absorption of glucose
- increasing glucose utilisation by enhancing the action of insulin at peripheral receptors
increasing glucose uptake by muscles
when should metformin be used cautiously?
chronic stable heart failure
with drugs that impair
renal function
eGFR < 45
AVOID IF eGFR <30
what is a contraindication for using metformin?
acute metabolic acidosis including lactic acidosis and diabetic keto acidosis
what are some side effects of metformin?
GI upset
abdo pain
lactic acidosis
when should metformin be stopped?
before elective surgery for 48hrs
what is the target HbA1c when taking metformin alone?
<48mmol/l
give some examples of sulfonylureas?
Short acting: gliclazide
Long acting: glimepiride, glibenclamide.
what type of drug is gliclazide?
sulfonylureas
when is a sulfonylurea a first line drug in T2DM?
patients who are not overweight
if metformin is contraindicated
rapid response to therapy is requires because of hyperglycaemic symptoms
what is the dosing of gliclazide?
started at 40-80mg OD
gradually increased until blood sugar is controlled
take with meals
how do sulfonylureas work?
- stimulating insulin secretion by acting directly on pancreatic beta cells
- increasing tissue sensitivity to insulin
requires residual beta cell function
- increasing tissue sensitivity to insulin
which type of drugs stimulate insulin secretion by acting directly on pancreatic beta cells, increase tissue sensitivity to insulin and require residual beta cell function?
sulfonylureas
when are sulfonylureas used cautiously?
overweight people
elderly
G6PD defiencey
what is a contraindication to sulfonylureas?
severe renal/hepatic impairement
what are the side effects of sulfonylureas?
Weight gain
GI disturbances.
Liver function impairment
Increased risk of hypoglycaemia
what should be tested before sulfonylureas are started?
renal and hepatic function
give examples of DPP4 inhibitors
gliptins
linagliptin, saxagliptin, sitagliptin, vildagliptin, alogliptin
linagliptin is the only renal friendly gliptin and is licensed for monotherapy
what are the advantages of using DPP4 inhibitors?
✓Low risk of causing hypoglycaemia
✓Weight neutral
what is the action of DPP4 inhibitors?
Inhibiting dipeptidylpeptidase-4 which acts on the GLP1 pathway to increase insulin secretion & lower glucagon secretion
when should DPP4 inhibitors be used cautiously?
with a history of pancreatitis
what are the side effects of DPP4 inhibitors?
- Generally well tolerated
- Small risk of pancreatitis + liver toxicity
- Hypoglycaemia can occur
- Pts may experience GI upset, headaches, nasopharyngitis or peripheral oedema
what is a contraindication of DPP4 inhibitors?
pregnancy and breastfeeding
give examples of GLP1 antagonists
exenatide, liraglutide, lixisenatide, semaglutide
what are some advantages of GLP1 antagonists?
promotes weight loss
Good option for crtain occupations (HGV drivers as they lose licence if they go onto insulin = reduces chances of them having to go on insulin)
what is the action of GLP1 antagonists?
Binds to and activates the GLP-1 receptor.
* Increases insulin secretion
* Decreases glucagon secretion
Slow gastric emptying
when should GLP1 antagonists be used cautiously?
Renal impairment pts
Diabetic retinopathy (in patients treated with insulin)
history of pancreatitis
severe congestive heart failure (no information available)
what is a contraindication of GLP1 antagonists?
diabetic ketoacidosis
what are some side effects of GLP1 antagonists?
- Appetite decreased; burping; cholelithiasis; constipation; diarrhoea; dizziness; fatigue; gastrointestinal discomfort; gastrointestinal disorders; hypoglycaemia (in combination with insulin or sulfonylurea); nausea; vomiting; weight decreased
Rare: Pancreatitis, stop if symptoms occur
give some examples of thiazolidinediones
glitazones
e.g. pioglitazone
when should Thiazolidinediones be used?
- 2nd or 3rd line. if a patient has not tolerated or had a poor response to the DPP-4 inhibitors.
- may be useful if hypos a concern (e.g. driving, falls, occupational hazards)
combination therapy (with metformin and/or sulphonylurea)
- may be useful if hypos a concern (e.g. driving, falls, occupational hazards)
what is an advantage of Thiazolidinediones?
low hypoglycaemic risk
what is the action of Thiazolidinediones?
Agonist of a receptor called PPAR-gamma which enhances the action of insulin on liver, fat and skeletal muscle by:
* increasing glucose uptake into muscle cells
* reducing insulin resistance
decreasing hepatic glucose production
what are the contraindications for Thiazolidinediones?
HF
active bladder cancer
hepatic/renal impairment
pregnancy/brestfeeding
what are the side effects of Thiazolidinediones?
- Fluid retention
- Weight gain
- ↑ risk of fractures – v common
- Increased risk of infection, numbness, visual impairment
what should be monitored during use of Thiazolidinediones?
Liver toxicity- monitor LFTs
* Pioglitazone should only be continued if HbA1c concentration is reduced by 0.5 percentage points within 6 months of starting treatment.
give some examples of SLT2 inhibitors
“flozins”-
dapagliflozin, canagliflozin, empagliflozin.
what is the action of SGLT2 inhibitors?
- Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2)
- reduces glucose re-absorption
increases urinary glucose excretion
when should SGLT2 inhibitors be avoided?
breastfeeding
eGFR<15
what are some side effects of SGLT2 inhibitors
dizziness
hypoglycaemia
back pain
UTI
a patient who has CVD/HF is diagnosed with T2DM. what is there management?
first line is metformin
then once settled add an SGLT2 inhibitor
also consider this if they have a QRISK >10
when should T2DM management be metformin followed by an SGLT2 inhibitor?
cardiovascular disease
heart failure
consider it if QRISK is >10
a patient with T2DM is on metformin. the second drug added is a sulfonylurea. when would this not happen?
if patient has cardiovascular disease/heart failure
maybe if QRISK >10
what are the 3rd line options for T2DM management?
Triple therapy with metformin and two of the second-line drugs
Insulin therapy (initiated by the specialist diabetic nurses)
