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Diabetes Flashcards

1
Q

What is the features of T1D?

  1. cause
  2. age onset
  3. BMI
  4. onset time
  5. family history
  6. insulin level
  7. life expectancy
A
  1. cause - autoimmune insulin producing beta cell destruction
  2. age onset - young
  3. BMI - thinner
  4. onset time - sudden (days/weeks)
  5. family history - less influence as spontaneous in 85%
  6. insulin level - low
  7. life expectancy - reduced by 5-14 years
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2
Q

What is the features of T2D?

  1. cause
  2. age onset
  3. BMI
  4. onset time
  5. family history
  6. insulin level
  7. life expectancy
A
  1. cause - insulin resistance + beta cell defects
  2. age onset - older
  3. BMI - obese
  4. onset time - longer (months/years)
  5. family history - strong
  6. insulin level - high
  7. life expectancy - reduced by 6 years
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3
Q

What is your normal blood glucose level (in mmol/L)?

A

4-7 mmol/L

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4
Q

which cells are present in pancreas?

A

alpha and beta cells

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5
Q

what is produced in alpha and beta cells?

A

alpha - glucagon

beta - insulin

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6
Q

How is blood glucose level maintained or regulated?

A

The normal blood glucose level (BGL) is maintained by insulin and glucagon

  1. Insulin absorb glucose -> lowers BGL
  2. Glucagon secretes glucose -> glucose increases BGL
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7
Q

Which are the 3 main tissues that insulin acts on to lower blood glucose?

A

liver, adipose and muscle

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8
Q

How does glucagon secrete glucose?

A

converts glycogen to glucose

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9
Q

How does insulin mediate its inhibitory effect to lower the BGL?

A

Insulin mediates its inhibitory effect to lower the BGL by acting on:
1. Liver - prevents glucose production by stopping glycogen breakdown
2. Fat - inhibits lipolysis, therefore promoting lipogenesis
3. Muscle - increases the glucose uptake
Altogether, lowering the BGL

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10
Q

How does glucagon mediate its stimulatory effect to increase the BGL?

A

Glucagon mediates it stimulatory effect to increase BGL by acting on
1. Liver - promotes the glycogen breakdown to secrete glucose

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11
Q

Outline the insulin signalling pathway

A
  1. insulins binds the insulin receptor (TRK) on the plasma membrane + binding leads to dimerisation and auto-phosphorylation
  2. phosphorylation of adaptor protein (IRS1)
  3. the PIP2 converts to PIP3
  4. PIP3 then binds PKB/Akt
  5. the binding results in glut4 translocation to the plasma membrane
  6. the glucose molecules enter the cells of adipocytes and skeletal muscle through glut 4 via facilitated diffusion
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12
Q

Outline the glucagon pathway

A
  1. Acts on liver via glucagon receptor (GPCR) to increase cAMP and PKA
  2. the increase in cAMP and PKA leads to
    2a. inhibition of glycolysis and glycogenesis
    2ai. glycolysis - breakdown of glucose to pyruvate
    2aii. glycogenesis - formation of glycogen
    together, decreasing the glycogen formation
  3. stimulates gluconeogenesis and glycogenolysis
    3a. gluconeogenesis - formation of new glucose
    3b. glycogenolysis - breakdown of glycogen into glucose
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13
Q

where is insulin stored in beta cells?

A

in the granules of cytoplasm of beta cells

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14
Q

What is the response of insulin to glucose?

A
  • the response is marked against x and y axis i.e. the levels of insulin (pg/min/islet) for 11mM of glucose in 60 mins
  • it is essentially marked by two phases
    1. First phase/ transient phase - it is a rapid short lived spike in insulin level due to the insulin secretion probably from the granules adjacent to cell membrane representing the first spike at 10 mins on graph
    2. Second phase - if BGL is high, then the rise in insulin level continue, representing the plateau for 45 mins on graph
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15
Q

what nutrients/factors stimulate the insulin release?

A
  1. amino acids
  2. fatty acids
  3. GPR40
  4. GLP-1
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16
Q

how is insulin secreted in beta cells of pancrea?

A
  1. glucose is taken up by GLUT2
  2. post uptake of glucose, it is converted into pyruvate though glycolysis
  3. once pyruvate is formed in cytoplasm it gets converted into Acety CoA in the mitochondria
  4. Acetyl CoA enters the Krebs cycle in which ATP and H+ ions are release
  5. the K+ channels on plasma membrane are sensitive to ATP
  6. high levels of ATP leads to close of K+ channels resulting in depolarisation
  7. the depolarisation further then open the Ca2+ channels
  8. increase in Ca2+ levels leads to insulin release
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17
Q

what neuronal factors stimulate the insulin release?

A
  1. parasympathetic innervation

2. sympathetic innervation

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18
Q

how does parasympathetic innervation stimulate the insulin release?

A
  1. increases insulin
  2. by release Ach (acetylcholine)
  3. Ach acts on DAG -> PKC -> Ca2+ -> insulin release
  4. therefore, lower BGL
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19
Q

how does sympathetic innervation stimulate the insulin release?

A
  1. decreases insulin
  2. by inhibiting cAMP and therefore reducing PKA and ultimately reduce in Ca2+ levels
  3. resulting in decreased insulin release
  4. therefore, increases the BGL
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20
Q

what is glucokinase?

A
  1. member of hexokinase family (hexokianse IV or D)
  2. essential for glucose metabolism
  3. converts glucose to glucose 6 phosphate
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21
Q

what are the properties of glucokinase?

A
  1. sets the threshold for glucose stimulated/depedent insulin release
  2. phosphorylates glucose to form glucose 6 phosphate (glycolysis)
  3. hexokinase IV - low affinity for glucose (S0.5 8-10mM) - ensures insulin secretion only when glucose increases above the basal level
  4. lack of inhibition by product (like glucose 6 phosphate unlike other hexokinase)
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22
Q

how are beta cells specialised to allow glucose regulated insulin release?

A
  1. presence of glucokinase
  2. low affinity of Glut2 for glucose
  3. vascularised islets
  4. tightly controlled/highly static numbers of beta cells
  5. highly differentiated beta cells
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23
Q

what are the consequences of diabetes (secondary diseases)?

A
  1. macrovascular - myocardial infarction, stroke, peripheral gangrene
  2. microvascular - retinopathy, nephropathy (kidney failure), neuropathy or foot ulcers
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24
Q

what type of receptors do insulin and glucagon act on?

A
  1. insulin receptor - receptor tyrosine kinase (RTK)

2. glucagon receptor - G protein coupled receptor (GPCR)

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25
Define Diabetes Mellitus
Hyperglycemia (high BGL) due to insufficient insulin secretion
26
what is clinical definition of diabetes mellitus?*
fasting BGL over 7mmol/L (normal BGL 6mmol/L)
27
Is diabetes monogenic or polygenic?
diabetes is caused by single gene defects (beta cell defect) therefore, it is is monogenic
28
what are the common mutations found in neonatal diabetes?
KCNJ11 and ABCC8 - mutations in K+ channels
29
how are K+ channels involved in blood glucose regulation?
K+ channels are significantly involved in blood glucose regulation via depolarisation of the membrane resulting in Ca2+ influx which ultimately releases insulin
30
what is MODY?
Maturity Onset Diabetes of the Young
31
which are the six genes that account for 87% of UK MODY?
1. HFN1A 2. HFN1B 3. HFN4A 4. IPF1 (PDX-1) 5. NEUROD1 6. Glucokinase
32
10% of people have T1D and 90% of people have T2D? A. True B. False
A. True
33
Define T1D and T2D wrt to insulin and glucose
T1D - low insulin + high glucose | T2D - high insulin + high glucose
34
Define T2D
Hyperglycaemia (high BGL) due to insufficient insulin secretion
35
Why there is low insulin secretion despite of high levels of insulin in T2D?
1. increased (peripheral) insulin resistance | 2. beta cell defects
36
In T2D, there can be very high levels of insulin secretion but due to insulin resistance BGL remains high? A. True B. False
A. True
37
what are the defects in blood glucose regulation of T2D due to insulin resistance?
1. Pancreas - stop releasing insulin 2. Liver - glucose production is increased 3. muscle - reduced glucose uptake 4. fat - lipolysis promoted, forming fatty acids
38
what are the symptoms of T1D?
``` The 4T's 1. Toilet 2. Thinner 3. Tired 4. Thirsty + ketoacidosis ```
39
what is ketoacidosis?
high levels of ketones in blood (symptom of T1D)
40
what are the symptoms of T2D?
1. hunger, thirst and polyuria (due to high BGL) 2. oral and vaginal thrush 3. periodontal disease (infections of teeth e.g. gums) 4. sleepiness 5. change of behaviour
41
what are the treatments for T2D (insulin resistance)?*
1. Diet/exercise - low calorie diet with carbs and proteins 2. Drugs - to improve insulin resistance (metformin + pioglitazone) 3. Drugs - to stimulate insulin secretion (GLP-1 + sulphonylureas) 4. Drugs - to promote glucose excretion via kidney (gliflozins) 5. insulin injections
42
what are the drugs used in T2D? 1. to improve insulin resistance 2. to stimulate insulin secretion 3. to promote glucose excretion via kidney
1. to improve insulin resistance - metformin, pioglitazone 2. to stimulate insulin secretion - GLTP-1 agonists, sulphonlyureas 3. to promote glucose excretion via kidney - gliflozins
43
Define T1D
Hyperglycaemia (high BGL) due to autoimmune destruction of insulin producing beta cells of pancreas
44
what are the treatments for T1D (autoimmune insulin destruction)?
1. insulin replacement therapy - injections or insulin pumps 2. blood glucose monitoring - regularly 3. exercise - carbohydrate count to track glucose levels 4. transplant - islets or pancreas (rarely done)
45
which transporter is used to allow glucose entry into muscles and adipose tissues?
Glut 4
46
which transporter is used to allow glucose entry into liver/pancreas ?
Glut 2
47
what is glycolysis?
the breakdown of glucose into pyruvate in the cell membrane and pyruvate converts into acetyl CoA in mitochondria
48
does insulin secretion promote glycolysis (breakdown of glucose)? A. Yes B. No
A. Yes
49
does glucagon secretion promote glycolysis? A. Yes B. No
B. No, glucagon inhibits glycolysis since its role is to increase BGL and glycolysis is the breakdown of glucose
50
``` which component in beta cell sets the threshold for glucose stimulated insulin secretion? A. Glut2 B. Glucokinase C. Krebs cycle D. K+ ATP channel ```
Ans: B. Glucokinase
51
how does glucokinase set the threshold for glucose stimulated insulin secretion?
- low affinity towards glucose - due to low affinity it will start the conversion of glucose to glucose 6 phosphate when the amount of glucose is above its normal range resulting in glycolysis/Krebs cycle etc. - lack of inhibition by substrate
52
glucokinase has low affinity for glucose A. True B. False
A. True, its affinity if S0.5 8-10mM
53
glucokinase is not inhibited by a product A. True B. False
A. True, due to this property it sets a threshold for glucose stimulated insulin release
54
Glucose is only molecule that can moderate insulin secretion A. True B. False
B. False | GLP1, A.A, F.A, GRP 40, para and sympathetic innervation can also moderate insulin secretion
55
``` which second messenger does GLP-1 increase in beta cells to promote insulin secretion? A. FA- acyl CoA B. IP3 C. DAG D. cAMP ```
Ans. cAMP -> PKA -> Ca2+ release A. Fatty acids activate receptor on membrane releasing FA-acyl CoA entering the Krebs cycle C. parasympathic innervation releases acetylcholine -> DAG -> PKC -> Ca2+ release
56
what are the new advances in beta cell replacement therapy?
the use of 1. embryonic stem cells (ESC) 2. induced pluripotent stem cells (iPSCs)
57
how is insulin cell generated from ESC?
1. fusion of sperm and egg 2. embryo develops into blastocyst in 5-7 days 3. remove the inner cell mass in blastocyst 4. grow the inner cell mass in a dish 5. subjective the inner cell mass culture to various conditions to stimulate the cells to differentiate into variety of cells like skin cells, skeletal muscle cells, neural cells etc
58
what are the challenges in using ESC for treating diabetes?*
1. heterogeneity of ESC progeny - unacceptable in clinical settings 2. use of virus, transcends and genetic modifications - risk of cancer 3. replication - difficult to generate fully functional insulin producing cells similar to mature beta cells in vivo - full maturation can be achieved?? (i.e. glucose stimulated insulin secretion) through transplantation of stem cell progeny in vivo 4. ethical issues
59
what are the medical applications/advantages for iPSC based insulin cells generated?*
1. research - disease/ mutation specific beta cells 2. personalised treatment - since cells are taken directly from a person 3. replacement therapies 4. genetic defects - correcting them 5. removes the reliance on immunosuppressants (unlike islets/pancreas transplants)
60
what are the challenges in using iPSC for treating diabetes?*
1. time/cost 2. use of virus - increasing the risk of mutations 3. teratoma formation - potential presence of pluripotent cells 4. clinical relevance - creating clinically relevant numbers of mature beta cells
61
what is theracyte?
it is a device for maturation and immunoprotection of stem cell progeny
62
what are the advantages of islet transplants?*
1. improved BGL control 2. reduces the need for insulin injections 3. reduces hypoglycaemic events 4. improved hypoglycaemic awareness
63
what are the disadvantages of islet transplants?*
1. High levels of cell death 2. several donors - required to achieve insulin independency 3. insulin independency - may not last for long 4. immunosuppressants - requirement of immunotherapy to prevent rejection 5. site of injections - problems may arise
64
outline the steps in an islet transplant
1. consists of a donor and receiver 2. islets are isolated from the pancreas of donor 3. the isolated islets are transferred into the portal vein (liver) of recipient with T1D
65
what are the alternatives to the islet transplants protocols?*
1. whole pancreas transfer 2. animal model islets 3. alternate site for injection of islets instead of portal vein in liver 4. improved islets culture before
66
what are the new technologies for monitoring BGL?* A. invasive B. non-invasive
A. Invasive 1. finger prick test 2. continuous glucose monitor (GM) 3. flash glucose monitor (cheaper than GM) 4. HbA1c (Glycated Hb = blood +sugar, as an indicator for diabetes control (gives avg. BG over last 3ms) B. non-invasive
67
how is the insulin processed within the beta cell?*
1. pre-pro insulin in RER cleaves into pro-insulin 2. pro-insulin translocates to Golgi and forms secretory granules 3. pro-insulin is cleaved into equimolar concentrations c-peptide and insulin
68
name the insulin analogues for* 1. rapid acting insulin 2. long acting insulin
1. rapid acting (has the most relative insulin effect) - aspart, glulisine and lispro 2. long acting insulin (has the insulin effect for the longest time) - glargine, determir
69
what is the action of mechanism for* 1. rapid acting insulin 2. long acting insulin
1. rapid acting insulin - changes in AA sequences to disrupt the dimerisation - faster absorption and rapid onset of action 2. long acting insulin - changes in AA to shift isoelectric point - sustained, basal rate of insulin throughout the day
70
why do we need insulin analogues?*
regular human insulin forms hexameter around Zn2+ ions and has slow absorptions of glucose
71
how does glargine and determir work? (LAI)*
1. glargine - two additional arginine residues and asparagine replaces glycine -> shifts the isoelectric point -> reduced solubility at physiological pH -> slower release of insulin -> longer acting 2. determir - myristic acid binds to lysine B29 -> promises self-association and albumin binding
72
what are the other alternatives methods to injections for insulin delivery?*
1. insulin pumps 2. inhaled insulin 3. smart insulin
73
what are the disadvantages of non-direct methods of glucose monitoring?*
1. more expensive (glucose strips are cheaper than glucose monitor) 2. accuracy
74
what are the features of insulin pump?
- it is a battery operated device attached to the skin that delivers insulin throughout the day - delivers insulin through a small tube called cannula inserted under the skin - the pump needs to be replaced every 2-3 days - the insulin delivery increases while eating, called the 'bolus dose'
75
what are the features of inhaled insulin?
- administrated before meals using a dry powder inhalation device - formulated with novel carrier (fumarole diketropiperazine) that dissolves instantly in lungs - rapid absorption of insulin - disappearance time is shorter than subcutaneously administered RAI - causes a rapid drop in glucose levels which return to normal in a shorter time than subcutaneously administered insulin - lower incidence of hypoglycaemic reactions
76
what properties would a SMART insulin need, to be effective?*
1. be inactive when BGL is low/normal 2. rapid activation when BGL rises 3. rapid inactivation when BGL falls (to prevent hypoglycaemic events)
77
what is microneedle array patches?
a patch has many tiny micro-needles on one surface to project onto the skin
78
what does the needle consist of in micro needle array patches?
the needle consists nano-particles that consists of 1. insulin 2. glucose oxidase that converts glucose into gluconic acid and oxygen is consumed in this process 3. hypoxic responsive polymer that disassembles under hypoxic conditions the nanoparticles are released/burst. under high glucose concentration
79
what is the modified insulin molecule in smart insulin?
consists of albumin binding and glucose sensor - insulin released from albumin when glucose levels are high
80
what does the artificial pancreas consists of?
consists of three components 1. continuous glucose monitor 2. insulin pump 3. an algorithm
81
why is it hard to write an algorithm to connect glucose monitor to the insulin pump?*
because insulin deposited just under the skin takes too long to begin working
82
what is Medtronic's minimum 670G hybrid close loop system? what are its features?*
it is the first automated insulin delivery system for T1D approved by FDA its features are - adjusts insulins with no/little input from the user - checks the BGL every 5 mins and automatically administers or withholds insulin - predicts a persons BGL drop and prevent the low in first place and also corrects high BGL
83
why is a hybrid better than fully closed loop system?
1. users will still need to direct when they are about to eat 2. estimate the carbohydrate count of food 3. then the device can calculate the additional amount of insulin needed
84
what is the role of auto-antibodies and auto reactive cells in T1D ?
the presence of auto antibodies and auto reactive T-cells are directed against islets cells or their antigenic constituents e.g. insulin, GAD-65, IA-2
85
aspart than hormone what other factors regulated your BGL ?
1. exercise 2. illness 3. stress
86
the introduction of which factors into liver cells are sufficient to transform them directly into beta cells?*
1. Ngn3 (neurogenin-3), Pdx-1 (it is an insulin promoting factor) and MafA 2. Pax 4 mediated conversion of alpha to beta cells 3. GABA
87
explain transdifferentiation
a. Adenoviruses are used to deliver Ngn3, Pdx-1 and Mafa to pancreas b. WT pancrea is predominantly an exocrine tissue with insulin beta-cells in the islet c. One month after infection with a combination of Ngn3, Pdx1 and Mafa viruses (pAd-M3), numerous insulin cells appear outside of islets
88
explain the pax-4 mediated conversion of alpha cells to beta cells
1. the misexpression of pax-4 in glucagon+ cells converts these into functional beta cell 2. the resulting glucagon shortage provokes a compensatory Ngn-3 dependent conversion of duct lining cells into glucagon+ cells 3. however, these are again converted into beta-cells upon pax-4 misimpression 4. this cycle of neogenesis and differentiation leads to oversized islets mainly composed of beta cells 5. the latter then display most characteristics of true beta cells and can reverse streptozocin - induced diabetes in vivo
89
how can the transdifferentation research be translated into treatment for T1D in humans?
1. Long term GABA administration induces alpha cell mediated beta cell neogenesis in vivo 2. the beta cell there by generated are functional and can replace endogenous beta cells 3. GABA also converts human and rat alpha cells into beta like cells
90
what is the evidence for beta cell regeneration possibility in patients with T1D?
1. Some patients with type 1 diabetes for over 50yrs still have detectable levels of c-peptide 2. Willcox et al 2011 - found increased proliferation of beta-cells in recent on-set type 1 diabetes cases. 3. Several signals can increase beta-cell proliferation. E.g. hepatocyte growth factor, insulin-like growth factor I, exendin-4 placental lactogen and adenosine 4. Fasting mimicking diet promotes beta-cell regeneration
91
how does fast mimicking diet promote beta cell regeneration?
fast mimicking diet promotes Ngn3 which drives the beta cell regeneration to reverse diabetes
92
How do fatty acids stimulate insulin secretion?
1. By increasing DAG 2. By increasing ATP 3. Binding to GRP40
93
When might you suspect a diagnosis of Type 1 diabetes in children might not be correct?*
1. a diagnosis of T1D before 6 months 2. family history of diabetes with an affected parent 3. evidence of endogenous insulin production outside the 'honeymoon' phase (after 3 years of diabetes) with detectable C-petide when glucose >8mmol/L 4. absence of pancreatic islet auto-antibodies, especially at diagnosis
94
When might you suspect a diagnosis of T2D in adults might not be correct?*
1. not marked obese or diabetic family members who are normal weight 2. no evidence of insulin resistance with fasting C peptide within the normal range 3. ethnic background with a low prevalence of T2D race (or in the family) e.g. European caucasian 4. Acanthosis nigricans not detected (darkening of skin specially armpits, groin and neck)
95
In monogenic diabetes >80% of cases a molecular genetic diagnosis can be made by DNA testing A. True B. False
A. True

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