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Med Sci 4930 > Midterm lectures 2-4 > Flashcards

Midterm lectures 2-4 Flashcards

1
Q

pathophysiology of T1DM

A

autoimmune destruction of beta cells
leads to insulin deficiency and hyperglycaemia

etiology is largely unknown but involves genetic predisposition, environmental components and distinctive metabolic changes

primary clinical systems are associated with acute hyperglycaemia and ketoacidosis

genetics and environment interact
autoantigens form on beta cells, activate T cells and you get Abs
-> can detect Abs before diabetes develops

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2
Q

how much beta cell function is left by the time you have symptoms of T1DM?

A

10%

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3
Q

2 Abs we can measure clinically for T1DM development

A

insulin and glutamic acid decarboxylase ( within islet cell)
can measure and predict likelihood of developing T1DM

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4
Q

how many Abs can be measured in research for T1DM development?

A

5

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5
Q

annual increase in incidence of T1DM in children

A

3.4%

annual incidence is 0.2% of children under 18

prevalence is 1 in 600 school children

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6
Q

does T2 or T1 have a greater genetic component?

A

T2 - about 50%

T1 only about 15% will have first degree relative with it

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7
Q

why is there an increase in T1 and T2 around puberty?

A

probably because at this time there is an increase in insulin resistance

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8
Q

criteria for diagnosis of T1DM

A

polyuria and polydipsia
glycosuria and ketonuria
random blood glucose > 11.1 mol/L

only need to do fasting plasma glucose if random was 6-7

don’t usually need to do OGTT or A1C

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9
Q

early presentation of T1DM

A

polydipsia
polyuria
weight loss

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10
Q

late presentation of T1DM

A 
diabetic ketoacidosis 
vomiting 
dehydration
abdominal pain 
hypovolemic shock 
hyperventilation due to acidosis 
drowsiness 
coma
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11
Q

what is DKA?

A

a life threatening complication due to insulin deficiency

insulin deficiency leads to increased counter regulating hormones - glucagon, cortisol, catecholamines and growth hormone

which then leads to increased lipolysis, ketogenesis and acidosis

causes decrease in pH of the blood which is what causes the morbidity or mortality (not the level of blood sugar)

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12
Q

what are the clinical manifestations of DKA?

A

dehydration
tachypnea (deep, singing (Kussmual) respiration)
nausea, vomiting and abdominal pain
confusion, drowsiness, progressive obtundation and loss of consciousness

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13
Q

diagnosis of DKA

A

blood glucose > 11 mmol/L
venous pH < 7.3 or bicarbonate < 15 mmol/L
ketonemia and ketonuria

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14
Q

what is a major concern with DKA in children?

A

increased risk of cerebral edema
(0.7-3% of cases)
have high morbidity (21-35%) and mortality (21-24%)

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15
Q

how to manage T1DM?

A

insulin administration
blood glucose monitoring
dietary counselling
education

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16
Q

what kind of education is needed after a child is diagnosed with T1DM?

A 
prevention, detection and treatment of hypoglycemia 
insulin action and administration 
dosage adjustment 
blood glucose and ketone testing
sick-day management 
prevention of DKA
nutrition and exercise
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17
Q

what is blood sugar normally?

A

between 4 and 6 mmol/L

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18
Q

what is target A1C for ppl with T1DM? what is this equivalent to?

A

under 7% for children
equivalent to blood sugar of 8

(<7.5 for youths, <7.0 for adolescents)
7.0 for adults, 7.5 healthy older adults, 8 complex/intermediate, 8.5 very complex/poor health

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19
Q

what did DCCT show?

A

clearly demonstrated that intensive therapy and control of DM delayed the onset and slowed progression of complications

also showed “metabolic memory” - i.e. early control is better
long-term influence of early metabolic control on clinical outcomes
ie intensive group continued to have slower complications even after A1Cs converged

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20
Q

bolus insulin

A

the amount of insulin required to cover the food eaten

required to maintain euglycemia during absorption of a meal

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21
Q

basal insulin

A

small amount of insulin continuously released to cover the body’s non-food related insulin needs
required to maintain euglycemia during fasting and prevent excess formation of ketoacids

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22
Q

currently used rapid onset insulin

A

lispro and aspart
onset of action is 10-15 min
peak of action is 1-2 hours
duration of action is 3-5 hours

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23
Q

currently used slow onset insulin

A

detemir and glargine
onset is 2-3 hours
detemir has 6-8 hour peak
duration of action is 24 hours

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24
Q

describe rapid analog insulins

A

humalog, novorapid, apidra

rapid onset and short duration of action
reduced risk of hypoglycaemia
need to take 10-15 min before eating
increased dose does not increase duration of action

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25
Q

what are the target BG levels in T1DM patients?

A

4-7

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26
Q

describe basal analogue insulins

A

lantus, levemir, basiglar
prolonged action
onset about 2 hours, duration 22+/- 4 hours
no peak
rate of absorption at different sites doesn’t differ
not recommended to mix in a syringe with other insulins

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27
Q

basal-bolus insulin

A

4 shots a day
1 basal before bed, 3 bolus at each meal
this doesn’t include snack, only need bolus if more than 15 g carbs in a snack

basal is always the same (with pump you can change)

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28
Q

describe insulin pumps

A

basal rates are pre-programmed but can be varied
basal is infused 24/7 to cover the body’s non-food needs

burst of insulin used to meet requirements of food intake
used to correct high BG reading as entered by user
ie covers body’s food and correction needs

rapid-acting analogue insulin is in a cartridge and is delivered through a cannula implanted in subcutaneous tissue
need to change site every 3 days using a need

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29
Q

benefits of insulin pump therapy

A

modest improvement in A1C
reduces glucose variability
reduces hypoglycemia (nocturnal, exercise and assisted)
reduced insulin requirements
prevents “dawn phenomenon” - blood sugar increasing at 5am
improves quality of life bc it is more flexible, can sleep in, have snacks etc

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30
Q

requirements for a pump in london

A

BG testing 4 times daily
complete records
use abdomen
count carbs
communicate with team frequently and attend 3 or 4 a year
carry emergency supplies and wear medic alert
be able to work pump
financial - ontario gov pays, need to pay an extra 250 a month for supplies

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31
Q

what is glucose monitoring

A
  • 4 times a day (before meals and at bedtime) plus occasional nocturnal values
  • every 2-3 hours when sick
  • whenever you have symptoms of hypoglycaemia

prick finger with BG meter

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32
Q

continuous glucose monitoring

A

glucose sensor is inserted into subcutaneous tissue and reads interstitial glucose (so about 20 min delay)
is attached to transmitter which sends values to pump
need to calibrate 3 times a day with meter glucose

facilitates glucose pattern recognition and alerts when out of range or expected to be

sensors last about a week

using sensor improves A1C (remember 1% A1C improvement can decrease complications by 40%)

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33
Q

what is the definition of hypoglycaemia?

A 
development of autonomic or neuroglycopenic symptoms 
low BG (<4 mmol/L if on insulin)
response to carb load
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34
Q

autonomic symptoms of hypoglycemia

A 
trembling
palpitations
sweating 
anxiety 
hunger
nausea
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35
Q

neuroglycopenic symptoms of hypoglycaemia

A 
difficulty concentrating 
confusion 
weakness 
drowsiness 
vision changes 
difficulty speaking 
dizziness
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36
Q

mild hypoglycemia

A

autonomic, self treat

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37
Q

moderate hypoglycemia

A

autonomic and neuroglycopenic, self treat

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38
Q

severe hypoglycemia

A

autonomic and neuroglycopenic, need help, unconsciousness may occur
plasma glucose usually <2.8

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39
Q

steps to address hypoglycaemia

A

recognize symtoms and confirm by testing BG (<4) if possible
treat with 15g fast sugar
retest in 15 min and retreat if needed
then eat normal snack/meal at that time of day with 15g carbs plus protein

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40
Q

what is 15g of glucose?

A 
tablets
3 packets sugar 
3/4 of juice or soft drink 
6 lifesavers
tablespoon of honey
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41
Q

overall what are the goals of T1DM management?

A 
normal growth and development 
normal home and school life 
good diabetic control through knowledge, technique and self-reliance 
avoidance of hypoglycemia 
prevention of long-term complications
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42
Q

what is unique about managing T1DM in children and adolescents?

A

physical and psychological growth and development
caloric and insulin requirements, target levels, education strategies change with age
going from parents treating to doing it yourself
needs to be flexible

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43
Q

diagnosis of T2DM

A

clinical criteria

  • presentation can be similar to T1 i.e. polydipsia and polyuria, but usually isn’t acute i.e. occurs over months
  • may be asymptomatic
  • also look at demographics

biochemical criteria are the same as T1
RPG >11.1 or FPG >7.0

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44
Q

epidemiology of T2DM in children under 18

A

incidence in Canada is 1.54/100 000

but has important regional variation i.e. in manitoba was 12.45

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45
Q

clinical features of T2DM at diagnosis

A

1/3 asymptomatic
2/3 acanthosis nigrans - reflection on insulin resistance
95% obese
ketosis and DKA (used to think this was just T1)
PCOS - associated with insulin resistance
dyslipidemia, hypertension
liver and kidney involvement
i.e. sometimes already have complications at presentation if there was a long asymptomatic period

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46
Q

ethnicity of children with T2DM

A

44% were aboriginal
asian, hispanic are also more prone

8% of total diagnosed were under the age of 10

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47
Q

what is the most significant risk factor for children to have T2DM?

A

obesity ie BMI above 95th percentile for their age and gender

48
Q

risk factors for T2DM

A 
obesity 
member of high-risk ethnic group 
family history of T2 and/or exposure to hyperglycaemia in utero 
high or low birth weight 
symptoms of insulin resistance 
puberty 
gender (more girls than boys) 
visceral fat - directly correlates with insulin resistance
49
Q

what are symptoms of insulin resistance?

A 
acanthosis nigricans 
hypertension 
dyslipidemia 
PCOS
NAFLD (ALT > 3X ULN or fatty liver on ultrasound)
50
Q

BMI classes

A

healthy < 85th
overweight is 85-95
obese is over 95

if a 5 yr old has above 95th there is an 80% chance they will be obese as an adult also
if its an adolescent is a 90% chance

51
Q

who should be screened for T2DM with fasting plasma glucose every 2 years?

A
  • non-pubertal and 3 or more risk factors
  • pubertal and 2 or more risk factors
  • if they have impaired fasting glucose or impaired glucose tolerance
  • if they are on atypical antipsychotic medications

if they also have a BMI >99th and/or multiple risk factors should also do OGTT every 2 years

52
Q

what is the target A1C for kids with T2DM?

A

7 or less

53
Q

what are some lifestyle changes recommended for children with T2DM? is this usually enough?

A

60 min moderate to vigorous physical activity a day
less than 2 hours of screen time a day

less than 10% achieve BG goals through lifestyle alone

54
Q

when should oral antihyperglycemic therapies be used in children with T2DM?

A

if glycemic targets aren’t achieved in 3 to 6 months give metformin, glimepiride or insulin

metformin can be used at diagnosis if A1C is >7%

(don’t usually use glimepiride bc it may cause weight gain)

55
Q

what does metformin do?

A

insulin sensitizing agent
reduces hepatic gluconeogensis, increase GI absorption and improves insulin action
with diet/lifestyle can cause weight loss or at least prevent weight gain

56
Q

what is kids have sever metabolic decompensation at diagnosis? what is this?

A

DKA, A1C>9, symptoms of sever hyperglycemia

give them insulin, can be weaned after targets are achieved though

57
Q

pathogenesis of T2DM

A

genetics and environment contribute to insulin resistance
when you have insulin resistance need to produce more insulin to maintain BG because the insulin isn’t working as well

go from insulin resistance to impaired glucose tolerance to T2DM so there is an opportunity to intervene early

58
Q

what do you do to assess risk of T2DM in obese adolescents?

A

fasting insulin and glucose

59
Q

what is impaired glucose tolerance?

A

do an OGGT, have normal fasting glucose but then 2 hours later fasting is 7.8 or higher

60
Q

how does BMI change in insulin resistant kids at risk for T2DM with lifestyle and metformin?

A

lifestyle alone no change
metoformin and lifestyle BMI decreases
standard care BMI increases

61
Q

what is glumetza?

A

extended release metformin, given once a day instead of 2 or 3 and has fewer side effects

62
Q

what were the results of lifestyle and glumetza in children who were obese?

A

all groups decreased % body fat at 3 months

only glutmetza groups decreased BMI and % body fat at 6 and 12 months (placebo did not)

insulin resistance, FPG, HDL and leptin improved in all groups at 6 and 12 months

ie moderate ve intensive exercise didn’t make a difference

63
Q

what is z score?

A

basically takes into account age and gender

64
Q

what is HOMA? what is high?

A

surrogate measure of insulin resistance higher than 4 in adolescents is indicative of insulin resistance

65
Q

differences between mouse and human islets and impact

A

human islets are more variable i.e. have alpha and delta cells throughout them

there is feedback between insulin and glucagon so these mechanisms may be different in humans and mice

66
Q

how does the vascularization of islets relate to the rest of the pancreas? why?

A

about 3x the vessel density i.e. richly vascularized
is so BG can be detected and insulin can be released into the blood stream
beta cells and blood vessels are very close to each other

67
Q

how is insulin synthesized?

A

preproinsulin starting in the cytosol then goes to ER
in ER signal sequence is cleaved during translocation
proinsulin is created by folding and forming DSBs between A and B and within A chain
then goes to golgi and then into granules
in granules convertases 1 and 2 cleave out c peptide and it become insulin
assemble into hexamers with Zn ion
granules condense (ie lose water) and acidify to 5.5-6 and insulin crystallizes
then sits there until there is a stimulus

68
Q

describe proinsulin structure

A

is folded, had 3 DSBs

A and B chain are connected by DSBs

69
Q

describe the structure of insulin

A

after c peptide is cleaved out there are 2 DSBs between A and B (and other is just A chain)
they are then assembled into hexametric structures and stabilized by a Zn ion

70
Q

insulin granules

A

very electron dense core with halo around it, then granule membrane
(dense bc they exclude water)

71
Q

are all islet hormones stored in granules?

A

yes

72
Q

glucagon granules

A

charcoal grey all the way to the edge

73
Q

somatostatin granules

A

electron dense, but don’t have the halo around the outside

74
Q

what is in insulin secretory granules besides insulin?

A

Zn transporter
proton exchanger
VAMPs (vesicle associated membrane proteins) - also called synaptobrevin

75
Q

what is the SNARE hypothesis?

A

a protein assembly-disassembly path that is used for exocytosis

76
Q

what proteins are involved in insulin release and where are they?

A

VAMP/synaptobrevin are on the granule membrane
syntaxin is on the plasma membrane
SNAP-25 is on plasma membrane but is associated by a lipid modification

synaptotagmin is on the PM

NOTE: syntaxin and SNAP-25 are on the inner leaflet of PM

77
Q

explain insulin release

A

docking - VAMP/synaptobrevin approaches PM
at the same time calcium binds to synaptotagmin 7 and it acts as a switch allowing the other proteins to interact

priming - VAMP interacts with syntaxin and SNAP-25
fusion occurs and exocytosis happens

78
Q

can fusion happen in insulin release without calcium?

A

no

insulin secretion is calcium dependent (i.e. need influx of Ca)

79
Q

describe the neuropeptide Y reporter and what was found using it

A

designed reporter with neuropeptide Y fused to GFP so that it only fluoresces at high pH
neuropeptide Y is in granules bc it is a hormone and granule is acidic so it doesn’t fluoresce until exocytosis occurs

saw individual vesicles fusing normally, not a lot

found that when islets were exposed to high glucose insulin isn’t all released at once, it occurs in patches randomly around the islet (i.e. no pattern)

80
Q

what regulates insulin secretion?

A

nutrients - glucose, fatty acids and amino acids

hormones - glucagon (suppresses) and GLP-1 (increases)

neurotransmitters - NE

drugs - sulfonylureas and diazoxide

81
Q

explain glucose-regulated insulin secretion

A

glucose high in blood
gets transported into beta cells via GLUT2
glucose is metabolized and results in ATP production
ATP interacts with an ATP-sensitive K+ channels, binds and closes it
causes depolarization
depolarization activates voltage-dependent Ca channels
get an influx of Ca
waiting insulin granules are then released with the waves of Ca influx

82
Q

what is ZnT8?

A

Zn transporter on granules

autoantigen for it is found in T1DM

83
Q

what are PC1/PC2?

A

converting enzymes, mutations in them predispose to obesity and insulin resistance

84
Q

what CPE?

A

enzyme that assists in conversion of proinsulin to insulin

mutations predispose to obesity and diabetes

85
Q

what do mutations in ATP-sensitive K+ channel cause?

A

permanent neonatal diabets

86
Q

describe C69Y mutation

A

mutation in proinsulin that causes misfolding and activates ER stress
this impair GSIS and beta-cell apoptosis
get eventual development of T1DM

87
Q

what do mutations in the insulin gene near the DSB sites cause?

A

improper folding, retention in ER

then get improper processing and trafficking and impairment of GSIS

88
Q

what kind distribution to alpha cell granules have?

A

gaussian

->important bc it means they come in different sizes and shapes

89
Q

how does islet cell mass change during diabetes?

A

up to 80% of beta cell mass is gone before onset of fasting hyperglycaemia (in mice aren’t hyperglycemic until about 10% left)

there is also a concurrent increase in alpha cell mass

so decreased beta cells = blood sugar stays high and increased alpha cells = more glucagon so blood sugar even higher

90
Q

what are preclinical and clinical imagining modalities used in vivo?

A

preclinical fluorescence (imaging development) and bioluminescence (beta cell mass changes during diabetes)

clinical are PET (detecting decreased beta cell function) and MRI (detecting transplated islets)

91
Q

what is fluorescence?

A

have a fluorophore, hit with an excitation wavelength of light, it changes energy state and will emit light at a different wavelength

detect through microscopy (wide-field, confocal, super-resolution)

molecule is unchanged

92
Q

what is bioluminescence?

A

in the presence of oxygen and ATP luciferin is converted to oxyluciferin and light by luciferase (i.e. photons are released)

need a charge-coupled device camera to detect - must be cooled and put in an airtight container so there is no contamination from other light sources

93
Q

describe an experiment that used fluorescence to look at islet development in neonatal mice

A

made transgenic mouse that expressed RFP in the promoter of insulin gene
so RFP is only in beta cells in the mouse pancreas
isolated the pancreas and imaged, used computer algorithm to model

found that in 7 day old mice islets were all connected
ie islets started out as elongated large structures
by day 21 were more circular and uniform of size
ie islets form as interconnected structures and then cells connection them undergo apoptosis and result in discrete structures

94
Q

strengths and weaknesses of fluorescence imaging

A

very sensitive - can detect minute concentrations
high spatial resolution - can detect sub cellular structures (100 nm)
quantitative

autofluorescence in metabolically active tissues (normally in green wavelength) can give some contamination
low depth of penetration - i.e. need to use think tissue slices because signal is lost due to tissue scatter/absorption

95
Q

describe an experiment that used bioluminescence to look at beta cell mass in mice

A

transgenic mice that expressed luciferase in the insulin promoter
were non obese diabetic (NOD) mice that spontaneously develop T1DM
so luciferase is in the beta cells, inject the mice with luciferin and then can take pics of the mice
took a series of photos from 5-35 weeks (the time period the mice develop diabetes over)

were able to show in whole mice that decrease in beta cell mass occurred before the onset of fasting hyperglycaemia (signal decreased as beta cell mass decreased)

96
Q

strengths and weaknesses of bioluminescence

A

very sensitive - can detect minute concentrations
low background (bs not natural in mice)
cost-effective

need to engineer cells to express luciferase
not very quantitative - relative signal intensities (not absolute)

97
Q

What is PET?

A

positron emission tomography
uses radioactivity to detect ongoing processes in the body

create images from emission of gamma rays or positrons that have been injected, ingested or inhaled and are in specific tissues in the body

highly sensitive

98
Q

what is a positron?

A

a positive electron, very unstable particle, also called a beta+ particle

travels a short distance, binds to an electron resulting in annihilation which emits gamma rays in opposite directions (511 keV)

99
Q

what are some positron-emitting isotopes?

A

C11 - 20 min
N13 - 10 min
O15 - 2 min
F18 - 110 min

(F18 is most common in clinical imaging)

100
Q

how are PET images taken?

A

data must be acquired and corrected and then images are reconstructed from the data

reconstructed images can then be quantified to show precise amount of radioactivity in tissues

101
Q

static vs dynamic PET data acquisition

A

static - inject tracer, wait an hour for uptake then scan for 10-30 min, get one image at the end i.e. data from one time point

dynamic - inject tracer and immediately start scanning, scan for an hour, get many images
get a time-activity curve, can see initial rapid increase and then a plateau once tracer is retained in target tissues and washed out of others

102
Q

What is the only clinical PET tracer?

A

FDG - deoxyglucose labelled with F18
gets transported like glucose normally does and then hexokinase phosphorylates it to G6P
metabolism stops here so it gets stuck in the tissues - this is where you get the plateau

103
Q

how are PET images quantified?

A

find the standardized uptake value (SUV)

calculates the amount of tracer in a given regions and corrects for the amount of tracer given and body weight

104
Q

What is LAT1? How is it being used int PET imaging?

A

protein on the surface of beta cells, transports AAs into them, mostly Trp

Trp is made into serotonin and put in granules
one group tagged a Trp analogue with C11
it gets transported in, made into serotonin and then goes into granules via VMAT
it will stay until it is secreted with insulin

other islets will take up Trp but won’t make it into serotonin so it doesn’t stay in the cell

105
Q

describe the study that used C11 tagged Trp analogues (C11-HT) too look at beta cell mass and function

A

it was mostly taken up in the rat pancreas and its uptake was decreased in diabetic rats (fewer beta cells)

its uptake also correlated with number of beta cells and changes in their mass i.e. more uptake for more beta cells

it may also report function i.e. blood glucose levels, but the correlation wasn’t as good

strongest correlation was between mass and uptake

106
Q

explain the clinical study that looked at C11 5-HTP uptake in T2DM patients

A

retrospective study of patients who had T2DM
saw that the tracer did go to the pancreas in humans (control)
in patients with T2DM there was very little pancreas signal
tracer uptake correlates with beta cell mass in humans too

could see the progressive decrease in beta cell mass with T2Ds which is interesting because usually just associated with insulin resistance (i.e. there is an insulin secretion issue as well)

107
Q

explain the clinical study that looked at C11 5-HTP in T1DM patients

A

dynamic scans
can see that in T1D there isn’t a signal in the pancreas bc of autoimmune destruction of beta cells
in healthy ppl still have pancreas signal after an hour

108
Q

what is F18 FEHTP? what did it show?

A

another Trp analogue, this time tagged with F18

tracer uptake was significantly decreased in mice that had spontaneously developed diabetes

109
Q

strengths and weakness of PET imaging for islets

A

very sensitive
tomographic (ie 3D)
both preclinical and clinical
quantitative

low spatial resolution - i.e. cannot detect individual islet, just the mass
high background due to uptake from non-target tissue (kidney and liver eliminating tracer)
ionizing radiation

110
Q

what is signal transduction?

A

any process by which a cell converts one kind of signal or stimulus into another

involves an ordered sequence of biochemical reaction inside the cell

usually rapid i.e. millisecond for ions, minutes for kinases, but some can take hours or days i.e. altering gene expression

111
Q

name 5 known transmembrane signalling mechanisms

A

lipid soluble signal cross PM and binds to intracellular receptor

bind to extracellular domain of a receptor that activates enzymatic reaction

bind to ECD of a TM receptor bound to a spare protein tyrosine kinase

bind to and directly regulate ion channel opening

bind to cell surface receptor linked to effector enzyme by a G protein

112
Q

what organs do complications from DM affect?

A 
CV system 
kidneys 
eyes
peripheral NS
limbs 
immune system
brain

all of them have signal transduction pathways that are affected

113
Q

non-modifiable risk factors for CVD

A

age (BP increases with age)
genetic
sec (men have higher risk)
race

114
Q

modifiable risk factors for CDV

A 
diet (high Na and high fat increase BP)
smoking 
alcohol (lots of it increases BP) 
weight (obesity increases BP) 
environment (stress increases BP)
115
Q

what are some diseases that diabetes is a significant risk factor for?

A 
hypertension 
cerebrovascular disease 
coronary artery disease 
congestive heart failure 
renal failure 
peripheral vascular disease

Med Sci 4930 (2 decks)

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