Diabetes mellitus Flashcards
(51 cards)
1
Q
Pancreatic islet
- where are the Beta cells aggregates in relation to the alpha cells?
A
Beta cells aggregate in centre of islets.
Alpha - around periphery
2
Q
How does glucose pass into the beta-cell?
A
GLUT 2 transporter
rate of transport is determined by the diffusion gradient - so determined by concentration of glucose in blood
3
Q
What is glucose converted to? what enzyme does this?
A
glucose converted to G6P
G6P may be fed into glycolysis pathway and Krebs cycle - to make ATP
glucokinase is needed.
4
Q
What cellular changes lead to release of insulin
A
high intracellular ATP blocks K channels in cell membrane Depolarising cell membrane Causing opening of Ca channels Ca rushes into cell Ca causes exocytosis of granules containing pre-manufactured insulin
5
Q
What do each of these islet cells secrete? What percentage of the islet is taken up by each cell? Alpha Beta Delta PP
A
Alpha - glucagon - 11%
Beta - insulin - 85%
Delta - somatostatin - 3%
PP - pancreatic polypeptide - 1%
6
Q
What are the phases of insulin secretion?
A
Biphasic response of insulin secretion
1st phase - in response to meal - rapid insulin secretion
= stored insulin is released
2nd phase - sustained insulin secretion until blood sugar levels are normalised
7
Q
What type of hormone in insulin?
A
anabolic
8
Q
How is insulin synthesized?
A
As pro-hormone - beta-cell peptidases cleave c-peptide
pro-insulin is converted to c-peptide and insulin in equimolar amounts
9
Q
What can be used as a measure of endogenous insulin secretion?
A
C-peptide
exogenous insulin - no c-peptide
10
Q
Once insulin is released, where does it go/act?
A
portal circulation = goes to liver first
- promotes formation of glycogen from glucose in liver
then passes into systemic population - adipose and skeletal tissue
Prevents breakdown of fat and muscle protein
11
Q
In most cells - what transporter does insulin increase the activity of?
A
GLUT 4
12
Q
Actions of insulin
A
increased glucose uptake in fat and muscle
increased glycogen storage in liver and muscle
increased amino acid uptake in muscle
increased protein synthesis
increased lipogenesis in adipose tissue
decreased gluconeogenesis from 3-carbon precursors decreased ketogenesis (in liver)
13
Q
What is the normal fasting glucose levels? post-prandial?
A
fasting - 3.5-5 mmol/l
post-prandial - 5.5-7 mmol/l
14
Q
What does sick day rules mean?
A
need to increase insulin when sick even if not eating as much
15
Q
In diabetes, what would you expect each of these results to be? fasting plasma glucose 2hr plasma glucose in OGTT random plasma glucose HbA1C
A
fasting plasma glucose - >7.0mmol/l
2hr plasma glucose in OGTT - >11.1 mmol/l
random plasma glucose - >11.1mmol/l
HbA1C - >48 mmol/mol
16
Q
HbA1C
- What does it reflect?
- what would the expected results be - normal, pre-diabetes, diabetes
- when should it not be used?
- what does it allow the evaluation of?
A
- glycated hemoglobin - reflects integrated blood glucose concentrations during life span of erythrocyte (120 days)
- reflects degree of hyperglycemia over past 3 months
Normal - <41mmol/mol
pre-diabetes 42-47 mmol/mol
diabetes >48mmol/mol
Should not be used as diagnostic test, or in conditions where red cell survival may be reduced (haemaglobinopathy, haemolytic anaemia, severe blood loss, splenomegaly, antiretroviral drugs), increased red cell survival (splenectomy), renal dialysis
Efficacy of treatment
Patients adherence to treatment
risk of developing diabetes complications
17
Q
Oral glucose tolerance test
A
Used to assess state of glucose tolerance
75g oral glucose load
No restriction/modification of carbohydrate intake for preceding 3 days; Fast overnight
Test is performed in morning – seated, no smoking
Blood samples for plasma glucose taken at 0hrs and 2hrs or at 30min intervals
Results:
Diabetes - exaggerated glucose response
Acromegaly - GH fails to suppress normally
Hyperglycaemia normally suppresses GH
18
Q
Metabolic syndrom
A
central obesity High BP High triglycerides low HDL-cholesterol insulin resistance
19
Q
What are endocrine causes of diabetes mellitus?
A
Acromegaly
Cushings syndrome
20
Q
What are antagonists of insulin?
A
GH
Cortisol
Adrenaline
21
Q
Kussmauls respiration
A
increased rate of deep breathing
greater total expiration of CO2
reduces level of dissolved CO2 in blood
increased blood pH
22
Q
MODY
- inheritance
A
early onset not-insulin diabetes AD inheritance obesity unusual gene defect altering beta-cell function
1-2% of type 2 diabetes
23
Q
What is the definition of a severe hypo episode?
A
require external assistance
24
Q
Autonomic symptoms of hypogylcaemia
A
2.5-4mmol/l
sweating shaking palpitations hunger mood swings
25
Neuroglycopenic symptoms of hypogylcaemia
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confusion
drowsiness
difficulty speaking
odd behaviour
incoordination
transient hemiplegia
coma
cardiac arrhythmia
sudden death
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26
How may hypogylcaemia present in:
- children
- elderly
children - behavioral changes
elderly - neurological symptoms - may mimic stroke, hemiparesis
27
What is the risk of repeated hypoglycemic episodes?
- reduced ability to recognize hypos
28
Morbidity of hypos
CNS - coma, convulsions
- vascular event - TIA, stroke
- cognitive impairment (children)
- brain damage (rare)
cardiac - arrhythmias, MI
29
Hypo diagnosis triad
| - must have 2 of 3 of what?
typical symptoms
biochemical confirmation
symptoms resolve with carbohydrate
30
hypo management
- mild
- severe
- long acting insulin/on SU
Mild - alert – give sweet drink (lucozade/dextrose tablet)
- Oral fast-acting carbohydrate (10-15g)
- Recheck glucose 10 mins later
- If still <4mmol/l, repeat above
- Only once glucose >4mmol – give long acting carb (10g)
Severe - not alert
- IV dextrose 20-30g - 20% dextrose iv (or hypostop, polycal) / 200ml 10% dextrose over 5 mins
- If cant get iv access – give 1mg IM glucagon plus sweet drink (not effective in alcoholic hypo/starvation – as depend on hepatic breakdown of glycogen)
- Follow up rapid acting carbs with slow release carbs - Oral therapy – buccal glucose gel, jam, honey
10% glucose infusion if long acting insulin or SU
- Oral hypogylcaemics (gliclazide/glipizide) –long half life (8 hrs)
- Accidental OD of long-acting insulin
- Alcohol excess
- New renal failure
31
Driving advice in drivers with insulin-treated diabetes
- Carry glc meter and rescue carbohydrate
- Check glc before driving
- Test every 2hr on long journeys. Regular snacks advised
If glc <5mmol/l – take a snack
If glc <4mmol/l – do not drive
Carry ID saying diabetic in case of accident
If have hypo while driving
- Stop vehicle as soon as safe
- Switch off engine and remove keys from ignition
- Get out drivers seat
- Wait 45 mins after blood glc normal before driving
Drivers must inform DVLA
- >1 severe hypo within last year
- If feel at risk of developing hypo
- Develop impaired hypo awareness
- Suffer hypo while driving
- Any of above – can result in loss of licence for 1 year
2 severe hypos in 1 year – licence revoked for a period of time
32
Main causes of DKA and HHS
THINK FOUR I's
Insufficient insulin (unidentified diabetes, inadequate treatment)
Infection (UTI, resp etc)
Infarction (MI, stroke)
Intercurrent illness
33
Diagnostic criteria of DKA
Diabetes -Hyperglycaemia: cap blood glucose >11mmol/L or known diabetes
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Ketones –
Urinary ketones (acetoacetate) ≥2 on dipstick
Capillary ketones (3-HOB) >3 mmol/L
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Acidosis: venous pH <7.3 and/or bicarbonate <15mmol/L or H>50nmol/l
34
Pathogenesis of DKA
Severe insulin deficiency –> increased counter-regulatory hormone secretion (catecholamines, cortisol) -> lipase
Increased gluconeogenesis and decreased glucose uptake
Fat broken down to fatty acids -> Acetyl CoA production exceeds oxidative capacity of Krebs cycle -> ketones
Combo of ketosis + renal failure (due to dehydration – not enough water -> kidneys unable to control acid-base balance and excrete ketones) -> ketoacidosis
Osmotic diuresis due to hyperglycaemia saturation SGLTs
Renal loss: Na, K, Cl, Ca PO4
HyperK
- Na/K ATP intracellular transporter
- H/K transporter
HypoNa
- Component dilutional
1. profound insulin deficiency, reduced peripheral glucose use
- muscle proteinolysis -> lactate and arginine -> gluconeogenesis -> glucose rises further
- FFA mobilisation -> KB production -> ketonuria and metabolic acidosis
- high glucose, ketonuria and metabolic acidosis leads to osmotic diuresis and hypovolemia - reducing GFR - more glucose remains in blood
35
DKA presentation
polyuria, polydipsia, dehydration
lethargy
hypovolemia (reduced JVP, low BP, increased HR, reduced urine output)
- 5L fluid deficit
- may lead to hypotension and tachycardia
Abdo pain, nausea, vomiting
Kussmauls resps (deep rapid breathing, trying to breathe off CO2, raise pH of blood)
ketotic breath
muscle cramps
drowsiness and coma
36
DKA investigations
Finger prick glucose
Bloods – FBC, U&E, HCO3, glucose (blood cultures, amylase)
Venous gas (no need for arterial) – for acid/base status
Serum osmolality
Anion gap – expect raised
Urine – ketones, glucose, dipstick, +/-MSU (infection?)
ECG (if hyperK – flattened p waves, prolonged QRS segment, tall peaked T waves, and sign wave (severe)
CXR - if potential problem/ infection in chest
37
DKA management
THINK VIP – volume, insulin, potassium
ABC
IV Fluid replacement: initially fast then slower to rehydrate
- 1L 0.9% saline per hours for 1st 2h, then 1l over 2h
- Risk of cerebral oedema if fluid replaced too quickly
IV insulin: switch off ketone body production
- 6 units/h
- If blood drops below certain level – give dextrose.
- Important to continue giving insulin as it will clear the ketosis
Monitor potassium: metabolic acidosis shift K+ to extracellular space.
- K can be high/normal/low at presentation
- As you give insulin, K+ moves into the cell and K+ falls
- Usually K will fall and need to be replaced
- Never give K IV faster than 10mmol/h
If K<3.5mmol/l initially do not start insulin, fluids only
NG tube if vomiting/gastroparesis
Antibiotic if infection suspected
- High WCC not helpful unless >25x109/l
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Protocol driven
1st hour
- Confirm diagnosis
- Start rapid iv fluids
- Start iv insulin
1-4 hours
- Review K
- Add 10% glucose once blood glucose 14 or less
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Monitor patient closely – hourly capillary blood glucose, hourly capillary ketones, and frequent vital signs and U&Es
Seek precipitant – commonly infection and errors/omissions
Start fluid balance chart
Prescribe low molecular weight heparin prophylactically (high risk of venous thromboembolism)
38
After DKA event, what needs to be done?
Continue with long acting throughout treatment
Give usual short-acting insulin once eating even if still on IV insulin
Can stop IV insulin once biochemically normal & patient eating
Overlap sliding scale and sc insulin by 1 h
39
HHS
- key signs
- symptoms
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Marked hyperglycaemia (>30mmol/l)
raised osmolality (>320mosmol/kg)
hypovolaemia
mild/no ketoacidosis (<3mmol/l)
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- Insidious onset (happens gradually)
- Profound dehydration (9-10L deficit)
- Hypercoagulability (exclude CVA, DVT, PE)
- Confusion, coma, fits
- Gastroparesis, N&V, haematemesis
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Polyuria, polydipsia (may be absent)
Weakness, cramps, visual disturbance
Neuro symptoms – acute stroke/ Focal weakness/ hemisensory loss
Seizures (25%)
Nausea/ vomiting
Coma – 10%
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Signs:
Dehydration – tachycardia, hypotension, decreased skin turgor
General examination – look for cause (pneumonia, MI)
Focal/global neurological dysfunction
Acute abdominal pain – paralytic ileus/ gastroparesis – usually settles
40
HHS diagnosis
Hyperglycaemia (>30mmol/l, often 60-90mmol/l) - much higher than that seen in DKA
Hypovolaemia
- Secondary to osmotic diuresis -> significant dehydration
Pre-renal failure common
- Serum osmolality >320mmol/kg
- No/mild ketoacidosis
41
What blood gases would you check in DKA and HHS?
DKA - VBG
| HHS - ABG
42
HHS management
Management as for DKA but:
- Slower, prolonged rehydration (IV – 0.9% Na Cl)
- Gradual reduction in Na+
- Gentler glucose reduction (not as great emphasis on IV insulin as in DKA)
- Prophylactic sc heparin
- Seek precipitant (infection, MI etc.)
ABC
IV fluid replacement – usually 1L over first hour
- Slower if cardiac failure, faster if SBP <90mmHg
- 0.9% Na Cl
- Osmolality reduced by 3-8 mOsm/kg per hour
- Only use 0.45% Na Cl if osmolality not decreasing despite +ve fluid balance
- Plasma Na should not drop by >10mmol/L (cerebral oedema risk)
Insulin replacement – often not required initially as fluid replacement will lower BG
- Plasma glucose reduced by 1-5mmol/L per hour aiming for a target range of 10-15 mmol/L
- Add in insulin when BG not decreasing by 5mmol/L despite +ve fluid balance
K replacement as for DKA
High dose prophylactic LMWH
Antibiotics if needed
Assess GCS regularly (1-2h)
If in shock/coma – may require inotropes / ventilation
43
HHS complications
Embolic – ischaemia, infarction of any organ (brain, heart, gut) / VTE
HypoKa, Cardiac failure, cerebral oedema
Foot ulcers
Multi-organ failure/ ARDS
Death rates up to 58% in studies
44
Sulphonylureas
- examples
- mechanism of action
- indications
- SE
E.g. glipizide, gliclazide
Stimulate secretion of endogenous insulin
- Close K-ATPase channel
- non-obese patients (may be insulin-deficient)
- monotherapy or in combination with metformin, glitazone or insulin
- Used in combination in obese
Choice of sulfonylurea is based on duration of action and method of elimination
SE: promote weight gain
- Main adverse effect = hypoglycaemia
Reduce dose in renal impairment
Avoid in hepatic failure
45
BIGUANIDE
- examples
- mechanism of action
- indications
- SE
E.g. metformin
Decreases hepatic glucose production
Increases insulin sensitivity in muscle
Encourages weight loss
Effective as monotherapy or in combination with sulfonylurea, glitazone or insulin
SE: GI common - nausea/ diarrhea
Contraindicated in renal impairment (risk of lactic acidosis) stop if eGFR<30
46
GLUCOSE PRANDIAL REGULATORS
- examples
- mechanism of action
- indications
- SE
Glinides
Repaglinide (MEGLITINIDE)
Nateglinide (AMINO ACID DERIVATIVE)
Insulin secretagogues – direct effect on beta cells
Stimulate rapid endogenous insulin release when given with meals
Side-effects: weight gain and hypoglycaemia
Lower risk of hypoglycaemia than sulfonylureas
47
Alpha-GLUCOSIDASE INHIBITORS
- examples
- mechanism of action
- indications
- SE
e.g. Acarbose; Miglitol
Delay digestion of carbohydrate and slow down postprandial absorption of glucose
No weight gain
Limited efficacy; can be used in combination
GI SE common - bloating / flatulence
48
Thiazolidinediones
- examples
- mechanism of action
- indications
- SE
E.g. pioglitazone
Activates PPAR gamma nuclear receptors (adipose tissue)
- PPAR (Peroxisome proliferator-activated receptors) = family of nuclear transcription factors regulating expression of genes involved in lipid and carbohydrate metabolism
Reduces insulin resistance in liver and muscle
- Lowers plasma FFA
- Increases adiponectin
Enhances actions of endogenous insulin
Effective, rare hypo, sustained improvements in HbA1C
Potential benefit in fatty liver
Slow onset of action – take 2-3 months to achieve maximal effect
Promote weight gain – redistributed body fat to reduce visceral depot
Contraindicated in congestive cardiac failure, hepatic impairment
May cause fractures
49
Incretin mimics
- examples
- mechanism of action
- indications
- SE
Glucagon-like peptide 1 (GLP-1)
- Potent isulinotropic hormone (incretin) is released in response to meals
- Rapidly degraded in plasma by enzyme dipeptidyl peptidase (DPP-4)
- Plasma GLP-1 is lower in people with impaired glucose tolerance (IGT) and T2DM compared to healthy, non-diabetic subjects
GLP-1 effects: stimulate glucose-dependent insulin secretion, suppresses glucagon secretion, slows gastric emptying, reduces food intake, improves insulin sensitivity
Exenatide, Liraglutide,
Must be injected
Promote weight loss
Combination with either metformin or sulfonylurea
SE: nausea
- Hypo rare unless given with SU
- Risk of pancreatitis
50
Gliptins
- examples
- mechanism of action
- indications
- SE
DDP-4 inhibitors
DDP4 breaksdown GLP-1 -> inhibits enzyme -> get more endogenous GLP-1
Inhibit degradation of incretin hormones -> enhance their actions
Oral route
Combination with metformin
Produce modest reduction in HbA1C
Weight neutral
Safe in renal impairment
Few SE: minimal hypo
51
Glucuretic
- examples
- mechanism of action
- indications
- SE
Empaglifozin, canglifozin, dapaglifozin
Act at kidney to prevent glucose resorption
- Glucosuria, polyuria
- Na-glucose cotransporter 2 (SGLT2) inhibitors
Moderately effective (7mmol/mol)
```
Pros:
Weight loss
BP reduction
Not associated with hypos
CV mortality improved
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Cons
Cannot be used if eGFR<45 or eGFR>60
Polyuria – care with hypovolaemia/ loop diuretics
Genital infections
Cannot be given >85 years
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