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Endo > Diabetes mellitus > Flashcards

Diabetes mellitus Flashcards

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

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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

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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.

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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
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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%

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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

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7
Q

What type of hormone in insulin?

A

anabolic

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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

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9
Q

What can be used as a measure of endogenous insulin secretion?

A

C-peptide

exogenous insulin - no c-peptide

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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

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11
Q

In most cells - what transporter does insulin increase the activity of?

A

GLUT 4

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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)
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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

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14
Q

What does sick day rules mean?

A

need to increase insulin when sick even if not eating as much

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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

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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

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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

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18
Q

Metabolic syndrom

A 
central obesity
High BP
High triglycerides
low HDL-cholesterol
insulin resistance
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19
Q

What are endocrine causes of diabetes mellitus?

A

Acromegaly

Cushings syndrome

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20
Q

What are antagonists of insulin?

A

GH
Cortisol
Adrenaline

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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
Q

Neuroglycopenic symptoms of hypogylcaemia

A 
confusion
drowsiness
difficulty speaking
odd behaviour
incoordination
transient hemiplegia
coma
cardiac arrhythmia
sudden death
26
Q

How may hypogylcaemia present in:

  • children
  • elderly
A

children - behavioral changes

elderly - neurological symptoms - may mimic stroke, hemiparesis

27
Q

What is the risk of repeated hypoglycemic episodes?

A
  • reduced ability to recognize hypos
28
Q

Morbidity of hypos

A

CNS - coma, convulsions

  • vascular event - TIA, stroke
  • cognitive impairment (children)
  • brain damage (rare)

cardiac - arrhythmias, MI

29
Q

Hypo diagnosis triad

- must have 2 of 3 of what?

A

typical symptoms
biochemical confirmation
symptoms resolve with carbohydrate

30
Q

hypo management

  • mild
  • severe
  • long acting insulin/on SU
A

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
Q

Driving advice in drivers with insulin-treated diabetes

A
  • 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
Q

Main causes of DKA and HHS

A

THINK FOUR I’s

Insufficient insulin (unidentified diabetes, inadequate treatment)
Infection (UTI, resp etc)
Infarction (MI, stroke)
Intercurrent illness

33
Q

Diagnostic criteria of DKA

A

Diabetes -Hyperglycaemia: cap blood glucose >11mmol/L or known diabetes

Ketones – 
Urinary ketones (acetoacetate) ≥2 on dipstick 
Capillary ketones (3-HOB) >3 mmol/L

Acidosis: venous pH <7.3 and/or bicarbonate <15mmol/L or H>50nmol/l

34
Q

Pathogenesis of DKA

A

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
Q

DKA presentation

A

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
Q

DKA investigations

A

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
Q

DKA management

A

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

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

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
Q

After DKA event, what needs to be done?

A

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
Q

HHS

  • key signs
  • symptoms
A 
Marked hyperglycaemia (>30mmol/l)
raised osmolality (>320mosmol/kg)
hypovolaemia 
mild/no ketoacidosis (<3mmol/l)
  • Insidious onset (happens gradually)
  • Profound dehydration (9-10L deficit)
  • Hypercoagulability (exclude CVA, DVT, PE)
  • Confusion, coma, fits
  • Gastroparesis, N&V, haematemesis
Polyuria, polydipsia (may be absent)
Weakness, cramps, visual disturbance 
Neuro symptoms – acute stroke/ Focal weakness/ hemisensory loss
Seizures (25%)
Nausea/ vomiting
Coma – 10%

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
Q

HHS diagnosis

A

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
Q

What blood gases would you check in DKA and HHS?

A

DKA - VBG

HHS - ABG

42
Q

HHS management

A

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
Q

HHS complications

A

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
Q

Sulphonylureas

  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

BIGUANIDE

  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

GLUCOSE PRANDIAL REGULATORS 


  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

Alpha-GLUCOSIDASE INHIBITORS

  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

Thiazolidinediones

  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

Incretin mimics

  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

Gliptins

  • examples
  • mechanism of action
  • indications
  • SE
A

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
Q

Glucuretic

  • examples
  • mechanism of action
  • indications
  • SE
A

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 
Cons
Cannot be used if eGFR<45 or eGFR>60
Polyuria – care with hypovolaemia/ loop diuretics
Genital infections
Cannot be given >85 years

Endo (4 decks)

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