ICS - Endocrine Complete

Question 1

what is glomerulosclerosis?

Answer 1

Glomerulosclerosis is scarring of the filtering part of the kidneys. (glomerulus)

Question 2

Define Diabetes Mellitus

Answer 2

Syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both.

Question 3

What are normal levels of blood glucose?

Answer 3

Blood glucose levels should be between 3.5-8.0mmol/L under all conditions.

Question 4

What is the main organ involved in glucose homeostasis and what is its role?

Answer 4

LIVER

• Stores and absorb glucose as glycogen - in post-absorptive state
• performs gluconeogenesis from fat, protein and glycogen
• If blood glucose is HIGH the liver will make glycogen - GLYCOGENESIS - in the long term liver makes triglycerides (lipogenesis)
• If blood glucose is LOW the liver will split glycogen - GLYCOGENOLYSIS - in the longer term liver makes glucose (gluconeogenesis) from amino acids/lactate

Question 5

How much glucose is produced everyday?

Answer 5

• About 200g of glucose is produced and utilised each day
• more than 90% is derived from liver glycogen and hepatic gluconeogenesis and the remainder from renal gluconeogenesis

Question 6

Where is glucose utilised?

Answer 6

BRAIN is a major consumer. - function depends on its uninterrupted supply of this substrate.

Tissues eg muscle and fat have insulin-responsive glucose transporters and absorb glucose in response to postprandial (post-meal) peaks in glucose and insulin.

Question 7

Why is the brain so reliant on just glucose and no other energy forms?

Answer 7

brain cant use free fatty acids to be converted to ketones to be converted to acetyl-coA and used in Krebs for energy production because free fatty acids cant cross the blood brain barrier.

glucose uptake by brain obligatory and isn’t dependent on insulin and the glucose used is oxidised to co2 and h20.

Question 8

How is glucose utilised in muscles?

Answer 8

Glucose taken up by muscle is stored as glycogen or metabolised to lactate or co2 and h20.

Question 9

How is glucose utilised in adipose tissue?

Answer 9

• fat uses glucose as a substrate for triglyceride synthesis
• Lipolysis of triglyceride releases fatty acids + glycerol - the glycerol is then used as a substrate for hepatic gluconeogenesis

Question 10

What are the 2 main hormonal regulators of blood glucose levels?

Answer 10

Insulin
Glucagon

Question 11

Name some of the roles of insulin?

Answer 11

1. Supresses hepatic glucose output - decreases glycogenolysis and gluconeogenesis.
2. increases glucose uptake into insulin sensitive tissues:
   -muscle - glycogen and protein synthesis
   -fat - fatty acid synthesis

-suppresses: lipolysis, breakdown of muscles (decreased ketogenesis)

Question 12

What is meant by biphasic insulin release?

Answer 12

• B cells sense rising glucose levels and aim to metabolise it by releasing insulin - glucose levels are a major controlling factor in insulin release!

1st phase response: rapid release of stored insulin
2nd: if glucose levels remain high then more insulin must be synthesised.

Question 13

Name some roles of glucagon

Answer 13

• Increases hepatic glucose output - increases glycogenolysis and gluconeogenesis
• reduces peripheral glucose uptake
• stimulates peripheral release of gluconeogenic precursors eg glycerol and amino acids
• stimulates:
  1. muscle glycogenolysis and breakdown (increased ketogenesis)
  2. lipolysis

Question 14

Name some other counter-regulatory hormones that are involved in blood glucose regulation?

Answer 14

• adrenaline, cortisol and growth hormone

increase glucose production in the liver and reduce its utilisation in fat and muscle.

Question 15

How is insulin formed?

Answer 15

-coded for on chr11
-produced in beta cells of islets of langerhans of pancreas

• Proinsulin is precursor of insulin
  -It contains alpha and beta chains of insulin joined together by c peptide
• when insulin is being produced, it is cleaved by its c-peptide and then used to make insulin which is packaged into insulin secretory granules.
• when there is insulin release there will be a high level of c peptide in blood from cleavage of proinsulin from it.

Synthetic insulin have c peptide - if u have c peptide u know if insulin release is natural or synthetic
after secretion insulin enters portal circulation and is carried to liver - prime target organ.

Question 16

What are the main roles of insulin in a fed and fasting state?

Answer 16

FED: (POSTPRANDIAL) - PROMOTE GLUCOSE UPTAKE BY FAT AND MUSCLE

FASTING: REGULATE GLUCOSE RELEASE BY LIVER

Question 17

How does glucose get into the cells?

Answer 17

glucose-transporter proteins (GLUT) carry glucose through the membrane and into cells.

Question 18

How many glut are there?

Answer 18

4

Question 19

what is the function of glut 1 ?

Answer 19

enables basal non insulin stimulated glucose uptake into many cells.

Question 20

what is the function of glut 2?

Answer 20

found in beta cells of pancreas - transports glucose into the beta cell - enables these cells to sense glucose levels.

low affinity transporter - only allows glucose in when there is a high conc of glucose ie: when glucose levels are high and thus want insulin release.

beta cells are able to detect high glucose levels and release insulin in response.
also found in renal tubules and hepatocytes

Question 21

what is the function of glut 3

Answer 21

enables non insulin mediated glucose uptake into brain, neurones and placenta

Question 22

what is the function of glut 4

Answer 22

mediates much of peripheral action of insulin.

it is the channel through which glucose is taken up into muscle and adipose tissue cells following stimulation of the insulin receptor by insulin binding to it.

Question 23

What is the role of the insulin receptor in glucose transport?

Answer 23

its a glycoprotein, coded for on the short arm of chr 19 - straddles the cell membranes of many cells.

when insulin binds to the receptor it results in activation of tyrosine kinase and initiation of a cascade response - one consequence of which is the migration of glut-4 transporter to the cell surface and increased transport of glucose into the cell.

Question 24

What conditions might diabetes be secondary to?

Answer 24

1. pancreatic pathology eg total pancreatectomy, chronic pancreatitis, haemochromatosis
2. endocrine disease - acromegaly, Cushing’s disease
3. drug induced commonly by thiazide diuretics and corticosteroids
4. maturity onset diabetes of youth - autosomal dominant form of t2dm - single gene defect altering beta cell function.
   tends to present <25 yrs with a positive family history.

Question 25

Define T1DM

Answer 25

metabolic disorder characterised by hyperglycaemia due to ABSOLUTE DEFICIENCY OF INSULIN.

caused by autoimmune destruction of beta cells of the pancreas.

Question 26

Give some epidemiology of t1dm

Answer 26

typically manifests in childhood - peak incidence around puberty
younger under 30, lean, northern europe like finland.

Question 27

What is the aetiology of t1dm?

Answer 27

1. autoimmune - autoantibodies forming against insulin and islet beta cells - INSULITIS
2. idiopathic - uncommon form characterised by absence of antibodies
3. genetic susceptibility - HLADR3DQ2 or HLADR4DQ8
4. association found with enterovirus

Question 28

What are the risk factors for t1dm?

Answer 28

1. northern europe - finnish
2. fhx - hladr3dq2 or hladr4dq8 in >90%
3. associated with other autoimmune disease like autoimmune thyroid, coeliac, addisons (excess cortisol), pernicious anaemia
4. environmental factors: dietary constituents, enteroviruses like coxsackie b4, vit d deficiency, cleaner environment may increase t1 susceptibility

Question 29

What is the pathophysiology of t1dm?

Answer 29

Due to autoimmune destruction by autoantibodies of the pancreatic insulin-secreting beta cells in islets of langerhans.

• causes insulin def and thus continued breakdown of liver glycogen (producing glucose and ketones) -= glycosuria and ketonuria as more glucose is in blood.

in skeletal muscle and fats impaired glucose clearance:
- bg is increased - when it reaches 10mmol/L , body cant absorb anymore - you get thirsty and get polyuria

pts must have insulin - otherwise DKA -
due to reduced glucose supply to cells due to lack of insulin which drives formation of ketone bodies for use as a form of energy.

ketone bodies are strong acids and lower the ph of blood. effects - impair Hb ability to bind o2 , AKI

• Eventual complete beta cell destruction results in absence of serum c - peptide

present very late often with only 10% of beta cells remaining

Question 30

Key presentation of t1dm

Answer 30

pt generally leaner than pt with t2dm

Question 31

Signs of t1dm

Answer 31

• bmi typically <25kg/m^2
• glycosuria
• ketonuria
• failure to thrive in children : dropping off height and weight centiles
• glove and stocking sensory loss
• reduced visual acuity
• diabetic retinopathy
• diabetic foot disease: reduced peripheral pulses , calluses, ulceration, charcot joint

Question 32

Symptoms of T1DM

Answer 32

• Polydypsia
• Polyuria
• Nocturia
• Weight loss
• Lethargy
• Recurrent infections - e.g. pt complaining of balanitis or pruritis vulvae due to repeat candida infections
• Evidence of complications: Blurred vision or parasthesia

Question 33

1st line investigations for t1dm

Answer 33

random bg - any time of day >11 mmol/L is diagnostic
fasting bg - >7.0mmol/L
for both tests, one abnormal value is DIAGNOSTIC in symptomatic individuals. 2 abnormal values are required in asymptomatic individuals

for borderline cases:
hba1c - measures glycated haemoglobin. >48mmol/mol suggests hyperglycemia over the preceding 3 months.
ogtt - 75g glucose load - >11mmol/L 2 hrs after. 7.8-11mmol/L pre-diabetes.

Question 34

other investigations other than 1st line for t1dm

Answer 34

c- peptide: in atypical presentations like over 50 or over 25 bmi.
autoantibodies: if atypical features present, and if positive, suggest autoimmune beta-cell destruction. autoantibodies against the following may be found:
1. glutamic- acid decarboxylase,insulin, islet cell, islet antigens, zinc transporter (znt8)

• vbg - if concerned about dka, systemically unwell or vomiting , reveals metabolic acidosis.

Question 35

diagnostic criteria for t1dm

Answer 35

clinical features and hyperglycaemia evidence eg random bg over 11.1
nice states t1dm diabetics usually have 1 of the:
1. ketosis
2. rapid wt loss
3. age over 50.
4. bmi over25.
5. personal and/or family history of autoimmune disease

Question 36

What are the differentials for t1dm?

Answer 36

1. monogenic diabetes - maturity onset diabetes of the young - suspect in diabetes cases on non-obese, young pts (adolescence or young adult) with fhx od diabetes in 2 or more sucessive generations - cpeptide present, autoantibodies absent.
2. neonatal diabetes - under 6 months. - genetic testing with majority of mutations in the genes encoding the adenosine triphosphate-sensitive potassium channel and the insulin gene.
3. latent autoimmune diabetes in adults - over 30. non obese . initially respond to lifestyle changes and oral agents. production of insulin gradually decreases then insulin is required. low to normal initial c-peptide level. can be positive for at least 1 of 4 antibodies commonly found in t1dm pts.
4. t2dm - older , slow onset, obesity, strong fhx, no dka, initial response to oral anti-hyperglycaemic drugs. cpeptide present, autoantibodies absent.

Question 37

1st line management of t1dm

Answer 37

• multidisciplinary approach

lifestyle:
1. educate pt on disease and risk, maintain lean weight, stop smoking, take care of feat (reduce gangrene risk)
2. pts should be educated regarding carbs counting. a technique which allows the insulin dose to be matches to intake.

Question 38

1st line management of t1dm

Answer 38

• multidisciplinary approach

lifestyle:
1. educate pt on disease and risk, maintain lean weight, stop smoking, take care of feat (reduce gangrene risk)
2. pts should be educated regarding carbs counting. a technique which allows the insulin dose to be matches to intake.

insulin therapy -
basal-bolus regimen - 1st line
long acting - regularly (basal)
rapid acting - before each meal - bolus

basal: levemir (Determir) , 1st line given twice daily. lantus (glargine) once daily is alternative
bolus: humalog (lispro) or novorapid (Aspart) are example

Question 39

name some other options for t1dm treatment?

Answer 39

mixed insulin regimen - mix of short or rapid acting and intermediate acting insuloin. 2 times daily used in those who cant tolerate multiple injections.

continuous insulin infusion: if pt has disabling hypoglycaemia or persistently hyperglycaemix (hba1c >69) on multiple injection insulin therapy

Question 40

Name some complications of insulin therapy

Answer 40

• hypoglycaemia - most common (also caused by sulfonylurea - antidiabetic)
• injection site - lipohypertrophy
• insulin resistance - mild and associated with obestiy
• weight gain - insulin makes people feel hungry

Question 41

How to monitor t1dm?

Answer 41

hba1c - every3-6 months - <48mmol/mol

self monitor: 4 times a day - before meals and bed.
targets:
- on waking: 5-7mmol/L
-other times of day including before meals: 407mmol/L
- bedtime: this target should be personalised and depnds on timing of last meal

Question 42

explain the diabetic review

Answer 42

injection site problems, retinopathy, nephropathy: eGFR and albumin:creatinine ratio (Acr) , diabetic foot problems , cv rf: optimisation of bp, lipids, weight, smoking, thyroid disease

Question 43

What are the macrovascular complications of t1dm?

Answer 43

cv - ischaemic heart disease, heart faulire, peripheral vascular disease

cerebrovascular: stroke

Question 44

What are the microvascular complications of t1dm?

Answer 44

neuropathy: mononeuropathy, polyneuropathy (glove and stocking), amyotrophy: painful proximal lower limb muscle wasting. autonomic neuropathy: gastroparesis, erectile dysfunction, postural hypotension

renal: diabetic nephropathy and CKD

retinopathy: non-proliferative vs proliferative maculopathy

Question 45

Name some complications of t1dm?

Answer 45

dka
hypoglycaemia - complication of insulin treatment, especially insulin doses without meal.
diabetic kidney disease - glomerular mesangial sclerosis leading to proteinuria and progressive decline in glomerular filtration
retinopathy
peripheral or autonomic neuropathy
cvd - increase atherosclerosis risk, hyaline arteriolosclerosis

Question 46

Name the 3 main types of insulin

Answer 46

short-acting soluble - work within 30-60mins last for 4-6hrs. give 15-30mins before meal in pt on multiple dose regimen and by continuous iv infusion in labour during med emergency.
short-acting insulin analogues - human insulin analogues (aspart, lispro, glulisine) - faster onset, shorter duration than soluble insulin but overall no improvement on diabetic control. reduced carry over effect compared to soluble insulin and used with evening meal in pts prone to nocturnal hypoglycaemia.
longer acting insulin - insulin premixed with retarding agents (Either protamine or zinc) precipitate crystals. can be intermediate (12-24 hrs) or long-acting (more than 24hrs)

Question 47

what is Lada?

Answer 47

latent autoimmune diabetes in adults
slow burning - slow progression to insulin def occurs in later life.

diff from t2dm: leaner build, rapid progression to insulin therapy following an initial response to other therapies, and the presence of circulating islet autoantibodies.

Question 48

define dka

Answer 48

acute metabolic complication of t1dm.
characterised by absolulte insulin def.

Question 49

epidemiology of dka

Answer 49

more common in children under 10 and in non-white

Question 50

risk factors of dka

Answer 50

infection
undiagnosed diabetes
inadequate insulin or non-adherence to therapy
MI
Psychological stress eg trauma/surgery
other co-morbidities eg hypothyroidism and pancreatitis
drugs that affect carb metabolism - corticosteroids, diuretics and salbutamol

Question 51

Explain the pathophysiology of DKA

Answer 51

associated with triad of : hyperglycaemia, acidosis, ketonaemia = dehydration and electrolyte disturbance

lack of insulin = hyperglycaemia = increase in hepatic glucose production (glycogenolysis) and gluconeogenesis .
increase in counter-regulatory horjmone release = hyperglycaemia = drives alternative production.

lipolysis , increased serum free fatty acids. = used as alternative energy source through ketogenesis.
increased levels of ketone bodies (acetone, beta-hydroxybutyrate) within the blood = ketonaemia.

main ketone body in DKA is 3-beta-hydroxybutyrate. ketone bodies are weak acids, lead to significant acidosis and severe illness in creasing quantities.

raised plasma glucose = osmotic diuresis= profound hypovolemia exacerbated by vomiting.
major electrolyte derangements, reduced GCS, eventual death if not managed.

Question 52

Signs of dka

Answer 52

fruity acetone smell of breath
dehydration:
mild - only just detect it
moderate: dry skin and mucus membranes, reduced skin turgor
shock: tachycardia, hypotension , drowsiness, reduced urine output

Kussmaul respiration: deep,labored breathing trying to reverse the metabolic acidosis.

hypotension
abdo tenderness
reduced gcs/coma

Question 53

symptoms of dka

Answer 53

abdo pain
leg cramps
headache
nausea and vomiting
polyuria
polydipsia
weight loss
inability to tolerate fluids
lethargy
confusion

Question 54

1st line investigations for DKA

Answer 54

primary:
lab glucose >11mmol/L
vbg/abg: quickest way to get ph and hco level. abg used as initial blood gas sample for diagnosis, but later venous used. ph<7.3 or bicarbonate <15mmol/L

ketone testing: capillary blood ketone 3 or more or urinary ketones 3 or more.

Question 55

other investigations to diagnose DKA

Answer 55

urine dip: glycosuria and ketonuria
u+e: electrolyte derangement and aki due to dehydration
fbc and crp: raised inflammatory markers - underlying infection?
lfts
troponin
infection screen: trigger?
ecg
imaging : chest xray

Question 56

what is the diagnostic criteria for dka?

Answer 56

hyperglycaemia, acidosis and ketonaemia

glucose over 11 or already known
hco3 less than 15 and or venous ph less than 7.3
ketonaemia - 3 or more or 2+ ketones on dipstick

Question 57

what is the 1st line management for dka?

Answer 57

ABC :
IV FLUID 0.9% SALINE - dka pt deplete by 5-8 lts. slow fluid replace with younger pts 18-25 due to cerebral oedema risk and those with hf.

insulin infusion : 0.1 units/kg/hr. once glucose level <14 mmol/L add 10% glucose. dont stop long acting insulin

potassium replacement (KCL): even if serum potassium levels are normal, total body potassium is low.

if potassium level in first 24 hours is more than 5.5 do nothing, if 3.5-5.5 then 40 mmol/L of infusion solution, if less than 3.5 then HDU/ITU for replacement via central line.

anticoagulation: pts increased risk of VTE

Question 58

treatment targets for dka

Answer 58

ketones fall by 0.5 mmol/L/H
bicarbob: rise by 3.0 mmol/L/H
glucose: fall by 3 mmol;/L/H

Question 59

what are the complications of dka?

Answer 59

hypokalaemia - k+ moves out of cell, h+ moves into. lack of insulin = more k+ lost from cell. may cause arrhytmias
hypoglycaemia
cv: VTE
renal: AKI
iatrogenic (treatment) : cerebral oedema, pulmonary oedema, central pontine myelinolysis , hypokalaemia, hypoglycaemia: due to inappropraite fluid replacement

gi: gastric stasis
non-anion gap hyperchloremic acidosis: urinary loss of ketoanions needed for bicarbonate regeneration and also increased reabsorption of chloride secondary to intensive administration of chloride- containing fluids

Question 60

define t2dm

Answer 60

characterised by insulin resistance and less severe insulin deficiency.

Question 61

give epidemiology of t2dm

Answer 61

affluent life
older - over 30 now popular in teens
overweight around abdo
south asian, african, cqarribean
m>f

Question 62

give aetiology of t2dm

Answer 62

decreased insulin secretion +/- increased insulin resistance
associated with obesity, lack of exercise, calorie, alcohol excess
no immune disturbance
no hla distrubance but stronger genetic link
polygenic disorder

Question 63

rf of t2dm

Answer 63

fhx - 75% risk if both parent shave it
increasing age
obesity poor exercise
ethnicity
obesity
htn
dyslipidemia: especially with low hdl and/or high triglycerides
gestational diabetes
polycystic ovary syndrome
drugs: corticosteroids, thiazide diuretics

Question 64

key presentation for t2dm

Answer 64

pt generally overweight compared to t1dm

Question 65

signs of t2dm

Answer 65

acanthosis nigricans - black pigment nape of neck and axillae
glove and stokcing sensory loss
reduced visual acuity
diabetic retinopathy
diabetic foot disease - reduced peripheral pulses
caclluses
ulceration
charcot joint

Question 66

symptoms of t2dm

Answer 66

weight loss polyuria polydipsia lethargy
recurrent infections
evidence of complications eg: blurred vision or paresthesia.

Question 67

other investigations other than 1st line t2dm

Answer 67

fasting lipids: dyslipidemia
u+e: reduced eGFR may be seen due to nephropathy
urine albumin: creatinine ratio: nephropathy leads to protein leaking through the glomerular basement membrane

Question 68

diagnostic criteria for t2dm

Answer 68

requires elevated plasma glucose sample and/or hba1c on 1 occasion if symptomatic or 2 occasions if asymptomatic.

pre-diabetic phase which has ifg and igt

pts if impaired fasting glucose: raised fasting glucose and normal ogtt
pts if impaired glucose tolerance: raised ogtt, may or may not have raised fasting glucose

Question 69

explain the pathophysiology of t2dm

Answer 69

-associated with central obesity, htn, hypertriglyceridaemia, decreased hdl, disturbed homeostatic variables.

• insulin binds to its receptor- issue post-receptor.
• circulating insulin higher than non-diabetics and tend to rise further. - decline after months/yrs due to eventual secretory failure. - STARLING CURVE OF PANCREAS
  initial compensatory mechanism is hyperplasia and hypertrophy of beta cells to secrete more insulin. This is then exhausted and leads to hypoplasia and hypotrophy.

-at diagnosis, beta cell mass reduced to 50%
-amyloid deposition in islets of the pancreas at autopsy. when beta cells hypertrophy and undergo hyperplasia to release more insulin as a compensatory mechanism they also secrete more amylin.

• early sign - loss of biphasic response.
• circulating insulin higher than healthy - inadequate to control.
  hyperglycaemia and lipid excess are toxic to beta cells (Glucotoxicity) - further beta loss - further deterioration or glucose homeostasis.
• dont get dka - small amount of insulin halts fat and muscle breakdown into ketones.

Question 70

where is crh released from? (corticotropin-releasing hormone)

Answer 70

hypothalamus

Question 70

where is crh released from? (corticotropin-releasing hormone)

Answer 70

hypothalamus