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BIOL31571 > Lecture 5 - T2DM > Flashcards

Lecture 5 - T2DM Flashcards

1
Q

Diabetes risk genes: how many loci have been identified, what do the genes cause, and what are some examples?

A

More than 80 loci identified

Genes identified so far mainly affect β-cell function or βcell mass and not insulin resistance

Examples include:
* TCF7L2 – decrease incretin signalling – most important gene so far
* KCNJ11 – kATP channel
* SLC30A8 – Zn²⁺ transport in insulin granules via ZnT8
* HHEX – transcription factor for pancreas development
* CDKN2A/B – cell cycle regulation

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2
Q

Polymorphism

A

The presence of different variant forms of a gene

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3
Q

Diabetes stats: how many people are affected in the UK and globally and how many are caused by T2DM?

A

> 830 million people globally (WHO (2022))
5.6 million in the UK (Diabetes UK (2024))

Likely much higher - undiagnosed

T2DM accounts for 90% of cases

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4
Q

Epigenetics in diabetes: what is historical example and what is a current day example?

A

Low birth weight is associated with insulin resistance and diabetes in offspring (e.g. Dutch Famine 1944-45)

BUT babies born to mothers with diabetes are also at high risk - modification of genes associated with β-cell function, epigenetic changes may be
inherited

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5
Q

Environmental factors in diabetes formation

A

Physical inactivity - exercising for 30 mins or more per day halves
risk of developing T2DM

  • Obesity:
  • Total adiposity and distribution
  • Increased waist circumference = increased risk
  • Subcutaneous vs visceral fat (visceral = higher risk)
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6
Q

Insulin resistance: what is the molecular mechanism behind it and what is an example?

A

Chronic low grade inflammation arises from adipose tissue in response to over-nutrition – e.g. TNFα, IL1, IL6, CRP, leptin, adiponectin, etc

Cytokines and other factors can interfere with different aspects of insulin receptor signalling:
* At the level of the insulin receptor
* Downstream signalling pathways

  • e.g. cytokines activate stress
    kinases which inhibit IRS-1
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7
Q

At what point is nutrient overload?

A

Effects of nutrient overload
dependent on:
* Genetic predisposition
* Epigenetic programming
* Multifactorial

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8
Q

os: what is it?

A

oxidative stress (damage)

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9
Q

Gestational diabetes: what is one way it may occur?

A

Islet cell expansion doesn’t occur as weight increases - one way it occurs

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10
Q

Types of type 2 diabetes drugs

A
  • Insulin secretagogues
  • Incretin therapies
  • Reduce glucose supply
  • Insulin sensitizers
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11
Q

Insulin secretagogues: what do they do and what are some examples?

A

Act on kATP channels to release insulin despite glucose presence

  • Sulphonylureas
  • Meglitinides
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12
Q

Incretin therapies: what do they do and what are some examples?

A

Utilise GLP-1 pathway to increase its effect - Ideal drug choice for people with diabetes and high risk factors for CVD and renal disease

  • GLP-1 receptor
  • GIP receptor agonists
  • DPP-IV inhibitors
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13
Q

Reduce glucose supply: what do they do and what are some examples?

A

Reduce/slows glucose absorption in the GI tract

  • α-Glucosidases
  • Amylin analogues
  • SGLT2 inhibitors
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14
Q

Insulin sensitizers: what do they do and what are some examples?

A

Reduce circulating FFA and their intrinsic insulin resistance inducing effects

  • Thiazolidinediones (TZDs)
  • Biguanides
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15
Q

Sulphonylureas and meglitinides: what type of diabetes medication are they and what do they do?

A

Insulin secretagogues

bind to SUR1 subunit of kATP, causing activation despite glucose presence

leccy

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16
Q

GLP-1/GIP receptor agonists and DPP-IV inhibitors: what type of diabetes medication are they and what do they do?

A

Incretin therapies

Promote:
* Beta cell proliferation
* Neogenesis
* Augmentation of secretion
* Enhanced cAMP production
* Activation of PKA and Epac

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17
Q

DPP-IV inhibitors: what type of diabetes medication are they and what do they do?

A

Incretin therapies

Dipeptidyl peptidase-4 (DPP-4) degrades both GIP and GLP-1, its inhibition results in an increase in their action

Less change than GLP1-RA but still does what it does

18
Q

GLP-1 receptor agonists: what type of diabetes medication are they and what do they do?

A

Incretin therapies

Bind to GLP-1 (glucagon-like peptide) receptor, mimicing the effect of GLP-1:
* Increases insulin secretion
* Decreases glucagon secretion
* Increases insulin-sensitivity in both alpha cells and beta cells
* Increases beta cells mass (?) and insulin gene expression and post-translational processing
* Inhibits acid secretion and gastric emptying in the stomach
* Decreases food intake by increasing satiety in brain
* Decreases body weight
* Lowers blood pressure, improves lipid profile
* Anti-inflammatory and antioxidant properties too

19
Q

GIP receptor agonists: what type of diabetes medication are they and what do they do?

A

Incretin therapies

Bind to GIP (glucose-dependent insulinotropic polypeptide) receptor, mimicing the effect of GIP

20
Q

Thiazolidinediones: what type of diabetes medication are they and what do they do?

A

Pioglitazone - insulin sensitisers

Prevent damage, and improve function (reduces free fatty acids):
* Agonists of PPARγ nuclear receptors in adipose tissue
* Alter gene regulation of lipid and glucose metabolism
* Reduce circulating free fatty acids
* Increase HDL cholesterol, reduce LDL density
* Enhance insulin-receptor signalling in muscle and adipose tissue and therefore reduce insulin resistance
* Inhibit hepatic gluconeogenesis
* Reduced lipotoxicity and glucotoxicity of β-cells

21
Q

Biguanides: what type of diabetes medication are they and what do they do?

A

Metformin - insulin sensitisers

  • Reduces circulating free fatty acids
  • Acts via activation of AMP kinase, with further downstream effects on SREBP-1 and acetyl-CoA carboxylase; precise mechanism
    not fully elucidated
22
Q

Incretin effect: what is it

A

The phenomenon where the body produces more insulin when glucose is consumed orally than when it is consumed intravenously

This is due to the release of the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)

23
Q

Metformin: what are the medications

A

Biguanides - insulin sensitisers

24
Q

GLP-1: what is it, when is it released, what gene is it produced by, what is it degraded by, and what is it responsible for?

A

Glucagon-like peptide-1

Released from intestinal L-cells in response to nutrients

Produced from the same gene as glucagon but processed differently

Degraded by Dipeptidyl peptidase 4 (DPP-4)

Responsible for the incretin effect

25
Q

GLP1-RAs: what are they and what do they do?

A

GLP1 receptor agonists - good for CVD and renal failure as well as the effects below

  • Increases insulin secretion
  • Decreases glucagon secretion
  • Increases insulin sensitivity in both alpha cells and beta cells
  • Increases beta cells mass (?) and insulin gene expression and post-translational processing
  • Inhibits acid secretion and gastric emptying in the stomach
  • Decreases food intake by increasing satiety in brain
  • Decreases body weight
  • Lowers blood pressure, improves lipid profile
  • Anti-inflammatory and antioxidant properties too
26
Q

Renal tubular glucose reabsorption: what is it controlled by?

A

Sodium-glucose transporter 2

27
Q

SGLT2: what is it, what does it do, and how may it work in T2DM?

A

Sodium-glucose transporter 2

Low-affinity glucose binding - reabsorbs ~80% of glucose filtered by the kidneys

SGLT2 is possibly overexpressed in T2DM

28
Q

SGLT2 inhibitors: how do they work and how is hypoglycaemia prevented?

A

Inhibit SGLT2, allowing more glucose to be excreted in the urine

SGLT1 isn’t inhibited - it has high-affinity glucose binding

29
Q

α-Glucosidases: what is it also known as, what type of diabetes medication are they, and what do they do?

A

Acarbose

Drugs that reduce glucose supply

Inhibits α-glucosidase in the brush border of the small intestine – these enzymes hydrolyse disaccharides to monosaccharides which slows glucose absorption

30
Q

Amylin analogues: what is it also known as, what type of diabetes medication are they, and what do they do?

A

Pramlintide

Drugs that reduce glucose supply

Amylin is co-secreted with insulin but reduced in patients with type 2 diabetes:
* Inhibits glucagon secretion
* Delays gastric emptying
* Increases satiety

31
Q

Bariatric surgery: what is it, what patients are eligible for it, what are the main types, and what does it do?

A

Surgery to reduce the intake of glucose

Eligible patients (NICE 2006, amended 2014):
* BMI>35 kg/m2 + diabetes
* BMI 30-34.9 with recent onset type 2 diabetes

  • Bariatric surgery for diabesity
  • Roux-en-Y gastric bypass - adjustable gastric band

Substantial weight loss and “remission” of type 2 diabetes

32
Q

Bariatric surgery: what does it result in?

A
  • Weight loss (up to 60% of body weight)
  • Reduced insulin resistance (hepatic and peripheral)
  • Attenuated appetite, altered food
    references
  • Changes in homeostatic mechanisms of energy balance (not fully understood)
  • Better β-cell function (reduced lipotoxicty and glucotoxicity)
  • Enhanced incretin secretion / sensitivity
  • Changes to gut microbiota (not fully understood)
  • Could lead to further developments in pharmacological treatment e.g. GLP-1 axis is already exploited in newer treatments
  • Research ongoing into gastrointestinal devices/surgery
33
Q

How is diabetes treatment changing?

A

Treat the whole patient - comorbidities (CF, CVD, CKD, etc) arise from diabetes complications, treating those is helpful

34
Q

How is diabetes treatment changing? (ER)

A

Treat the whole patient - comorbidities (CF, CVD, CKD, etc) arise from diabetes complications, treating those is helpful

This idea is supported by a study that found that there is a ~50% increased risk of dementia and alzheimers in T2DM, which has been found to decrease when using SGLT-2 inhibitors to treat patients aged 75 and older. This decrease did not occur with other diabetes medication

35
Q

Complications of diabetes: what are the microvascular and macrovascular complications and what are their complications?

A

Microvascular disease:
* Retinopathy - eyes
* Neuropathy - NS
* Nephropathy - kidney

Macrovascular disease:
* Myocardial infarction
* Stroke
* Peripheral vascular disease

Neuropathic pain, foot ulcers, amputation
* Heart failure, stroke
* Renal dialysis, renal failure
* Blindness / impaired sight

36
Q

Future potential treatments (ER)

A
  • FGF21 gene therapy
  • Ginkgo biloba
  • Suppression of factors that damage beta cells: ChREBPβ and Dusp26
37
Q

FGF21 gene therapy (ER)

A

FGF21 is naturally produced by the body and is vital in energy metabolism.
FGF21 binds to its receptor the fibroblast growth factor receptor or FGFR, requiring a beta-klotho coreceptor due to low affinity binding, and the receptor undergoes autohphosphorylation on its tyrosine residues. This facilitates FGFR substrate 2 alpha binding which passes on the activation signal to various pathways such as the Ras/Raf MAPK, PKC, JAK/STAT, and PI3K/Akt pathways, causing downstream transcription of genes promoting energy metabolism
Research has found that its addition into various different organ systems such as the liver, adipose tissue, and skeletal muscle can be used to continuously produce it
In animal models, it was able to cause weight loss and decrease insulin resistance High potential - not used in human models yet

https://www.sciencedaily.com/releases/2018/07/180709104608.htm

38
Q

Ginkgo biloba (ER)

A

Ginkgo biloba has been noted for its effects in improving dementia and Alzheimer’s disease, though research has investigated its potential in treating T2DM:
Animals with T2DM models were treated with Ginkgo biloba and it was found to increase the mass of pancreatic beta cells and insulin produced
The mechanisms by which this was undergone was not fully illustrated, though those treated with Ginkgo biloba downregulated certain antioxidant enzymes, glutathione and superoxide dismutase 2 (SOD2), which can cause damage and destruction of beta cells and so their downregulation is theorised to be hoe Ginkgo biloba cause its positive effects

39
Q

ChREBPβ (ER)

A

Carbohydrate response element binding protein-beta (ChREBPβ) is a protein that is thought to have a role in the destruction of beta cells in T2DM
The mechanism behind this is that increased glucose metabolism promotes a cycle where ChREBPβ is overproduced and causes glucose toxicity and damage to beta cells through thioredoxin interacting protein (Txnip) which inhibits the antioxidant enzyme thioredoxin (Txn), thereby promoting oxidative damage
This was found to be able to be treated through the expression of its alternate form ChREBP⍺, which uses a different pathway (nuclear factor-erythroid factor 2 (Nrf2)) which doesn’t result in beta cell oxidative damage
The use of medication suppressing ChREBPβ and/or promoting ChREBP⍺ is promising, though there has not been sufficient trials and testing for its use
- https://www.sciencedaily.com/releases/2022/08/220804130534.htm

40
Q

Dusp26 (ER)

A

Adipsin, a protein produced in body fat, protects beta cells by activating the molecule C3a which protects and supports beta cells through suppression of Dusp26
Improper Dusp26 regulation results in decreased expression of core beta cell genes - sensitising the cell to death
Research into this found that suppression of Dusp26 activity in mice with T2DM resulted in increased health and insulin production
This promise in treatment is further supported through data support - a large multivariable comparison for T2DM found that those with highest levels of adipsin had up to a 50% reduction in diabetes incidence compared to those with the lowest levels

BIOL31571 (11 decks)

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