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BMS336 - Modelling Human Disease and Dysfunction > 3. Metabolic Disease 1: Animal Models > Flashcards

3. Metabolic Disease 1: Animal Models Flashcards

1
Q

How does T1D lead to hyperglycaemia?

A
  • Pancreas makes little/no insulin due to immune system attacking B cells
  • Little insulin in bloodstream means glucose cannot enter cells and therefore accumulates in bloodstream
  • Leads to hyperglycaemia
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2
Q

How does T2D lead to hyperglycaemia?

A
  • Pancreas make insulin which enters bloodstream
  • Due to insulin resistance of peripheral cells glucose cannot enter and therefore accumulates in bloodstream
  • Leads to hyperglycaemia
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3
Q

How can T1D and T2D be similar?

A

Both T1D and late-stage T2D show B cell depletion despite early mechanistic differences

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4
Q

Describe the natural history of T2D.

A
  • Before metabolic defects that lead to T2D, fasting and post-meal glucose levels are similar and constant
  • As T2D develops, insulin resistance increases over time, leading to compensatory increases in insulin secretion t prevent blood glucose levels rising
  • Eventually insulin resistance peaks and stabilises whilst insulin secretion continues to increase
  • At crisis point, B cells become depleted/dysfunctional and so insulin secretion cannot match insulin resistance leading to hyperglycaemia
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5
Q

What is thought to be a major risk for T2D?

A

There is a strong correlation between obesity and T2D

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6
Q

Why is it unclear how obesity leads to T2D?

A

So many tissues are involved in glucose homeostasis and they all interact with one another therefore hard to understand cause vs consequence

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7
Q

What is the relationship between obesity, insulin resistance and dyslipidemia?

A
  • Central obesity is associated with an increase in free fatty acids (FFA) and insulin resistance (unclear whether increased FFA causes insulin resistance or vice versa)
  • These 2 effects stimulate increased hepatic apolipoprotein B and hepatic lipase activity (catalyse removal of lipids from HDLs)
  • This leads to hypertriglyceridemia, increased small, dense LDLs and decreased HDLs
  • These abnormal lipid patterns increase risk of developing plaques in the CV system and therefore increases the risk of co-morbidity
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8
Q

What is co-morbidity?

A

Having more than 1 recognised disease

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9
Q

What is the cause of hyperglycaemia in T2D?

A

3 major body metabolic defects:

  • Increased hepatic glucose production
  • Decreased pancreatic insulin secretion
  • Increased peripheral insulin resistance
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10
Q

How have animal models been used to study how obesity can trigger T2D?
What is the problem with this study?

A
  • Obesity characterised by accumulation of excess fat in ectopic sites (liver and skeletal muscle) instead of accumulation in adipocytes - this is associated with insulin resistance and T2D
  • Hypothesis: Adipocytes are critical to prevent T2D
  • Genetically-engineered mice lacking adipocytes show hyperphagia, insulin resistance and T2D
  • However, due to lack of adipocytes these mice are leptin-deficient - leptin’s primary effects are on the brain therefore primary trigger may be brain dysfunction
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11
Q

How can transgenic reporter lines be used in the study of T2D?

A

Allow us to analyse specific tissues involved in glucose homeostasis in real time and space:

  • In healthy animals
  • In animals with genetic mutation (to study impact of human genetic variation)
  • In animals subjected to different environmental conditions (e.g. high fat diet)
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12
Q

What is a future idea for a study to understand triggers in T2D?

A
  • Cross 3 reporter lines to make fish that reports pancreas, liver and adipose tissue
  • Feed fish high fat diet and observe which tissue is affected first
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13
Q

What is a reporter line used to specifically visualise B cells?

A

Tg(ins:Kaede)

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14
Q

Describe a technique for analysing proliferation.

A

EDU labelling

  • EDU is an analog of Thymidine that has been modified to allow visualisation of proliferation
  • Incubate cells with EDU
  • EDU is incorporated into DNA during active DNA synthesis that occurs prior to cell division
  • Incorporated EDU in DNA can then be detected with click chemistry procedure which makes nucleus fluoresce
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15
Q

What is the current treatment for diabetes?
What is wrong with this?
What is a potential new treatment?
What must be known for this to be possible?

A
  • Insulin injections
  • Does not increase life expectancy or decrease morbidity
  • Restore B cell numbers
  • Need to know what controls B cell number in development and regeneration
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16
Q

What 2 things shape development of an embryo?

A
  • Gene/Chemical signals (e.g. Wnt, Shh)

- Environmental cues (e.g. signals from nearby bacteria)

17
Q

What did the Hill et al (2016) paper on B cell development show?

A

Certain gut bacteria (specifically a protein they secrete) are necessary for the pancreas to populate itself with a robust number of B cells

18
Q

What did rearing fish conventionally and in microbe-free environments show?

A
  • In conventionally-reared fish, number of B cells increases steadily between 3-6dpf
  • In microbe-free-reared fish, number of B cells remains the same during this period
19
Q

What effect did the lower number of B cells in fish reared in microbe-free environments have?

A

Lower number of B cells means less insulin secretion resulting in increased blood glucose levels

20
Q

What could restore the normal number of B cells in fish reared in microbe-free environments?

A

Exposing fish to specific bacteria (aeromonas)

21
Q

What did the bacteria that restored the normal number of B cells in fish reared in microbe-free environments have in common?
How does this increase B cell numbers?

A
  • They all secrete a protein - BefA which is sufficient to restore normal number of B cells
  • Using EDU labelling they showed BefA increases B cell numbers by inducing proliferation
  • BefA has homologs produced by bacteria in humans which were also sufficient to restore normal number of B cells
22
Q

What future studies did Hill et al (2016) suggest?

A

Investigate the mechanism by which proteins affect B cell development and if they have the same effect in humans

23
Q

What shows that the pancreas has the capacity to regenerate?

A

Experimental ablation of B cells by chemical treatment/partial pancreatectomy in rodents is followed by significant recovery of B cell mass

24
Q

What is the stumbling block for using regeneration of B cells to treat diabetes?

A

Intrinsic transcriptional cascade that regulates B cell formation is well known, but the extrinsic signals regulating B cell regeneration in unclear

25
Q

What transgenic fish line was used by Andersson et al (2012) in their screen to identify enhancers of B cell regeneration?

A

Double transgenic fish:

- Tg(ins:Kaede); Tg(ins:CFP-NTR)

26
Q

Explain how conditional genetic ablation works.

A
  • Identify cell-specific promoter for cell to be ablated and clone coding sequence of Nitroreductase (NTR) downstream
  • NTR catalyses the conversion of MTZ into cytotoxic product
  • NTR will only be expressed in the cells expressing the cell-specific promoter
  • When MTZ is added it will be only be converted to cytotoxic product in cells that express NTR resulting in their ablation
27
Q

How was the screen performed by Andersson et al (2012)?

A
  • Fish were treated with MTZ and then transferred to 96-well plates
  • Each well contained 1 of 7000 small molecules and fish were left to recover for 2 days
  • Looked if any compound enhanced B cell regeneration by measuring fluorescence
28
Q

What were the results of the high-throughput screen by Andersson et al (2012)?

A
  • Hit compounds that enhanced B cell regeneration converged on the Adenosine signalling pathway, including exogenous agonists and compounds that inhibit degradation of endogenous adenosine
  • Most potent enhancer of B cell regeneration was NECA (adenosine agonist) which increased B cell proliferation and accelerated restoration of normoglycemia
29
Q

What did treatment of diabetic mice with NECA show?

A
  • B cell regeneration and glucose-lowering effects were seen
  • Suggests an evolutionary conserved role for adenosine signalling in B cell regeneration

BMS336 - Modelling Human Disease and Dysfunction (14 decks)

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