Lecture 5 - Type 2 diabetes mellitus

Question 1

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

Answer 1

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

Question 2

Polymorphism

Answer 2

The presence of different variant forms of a gene

Question 3

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

Answer 3

> 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

Question 4

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

Answer 4

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

Question 5

Environmental factors in diabetes formation

Answer 5

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)

Question 6

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

Answer 6

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

Question 7

At what point is nutrient overload?

Answer 7

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

Question 8

os: what is it?

Answer 8

oxidative stress (damage)

Question 9

Gestational diabetes: what is one way it may occur?

Answer 9

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

Question 10

Types of type 2 diabetes drugs

Answer 10

• Insulin secretagogues
• Incretin therapies
• Reduce glucose supply
• Insulin sensitizers

Question 11

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

Answer 11

Act on kATP channels to release insulin despite glucose presence

• Sulphonylureas
• Meglitinides

Question 12

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

Answer 12

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

Question 13

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

Answer 13

Reduce/slows glucose absorption in the GI tract

• α-Glucosidases
• Amylin analogues
• SGLT2 inhibitors

Question 14

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

Answer 14

Reduce circulating FFA and their intrinsic insulin resistance inducing effects

• Thiazolidinediones (TZDs)
• Biguanides

Question 15

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

Answer 15

Insulin secretagogues

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

leccy

Question 16

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

Answer 16

Incretin therapies

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

Question 17

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

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

Incretin therapies

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

Incretin effect: what is it?

Answer 22

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)

Question 23

Metformin: what are the medications

Answer 23

Biguanides - insulin sensitisers

Question 24

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?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

Renal tubular glucose reabsorption: what is it controlled by?

Answer 26

Sodium-glucose transporter 2

Question 27

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

Answer 27

Sodium-glucose transporter 2 Low-affinity glucose binding - reabsorbs ~80% of glucose filtered by the kidneys SGLT2 is possibly overexpressed in T2DM

Question 28

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

Answer 28

Inhibit SGLT2, allowing more glucose to be excreted in the urine SGLT1 isn't inhibited - it has high-affinity glucose binding

Question 29

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

Answer 29

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

Question 30

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

Answer 30

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

Question 31

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

Answer 31

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

Question 32

Bariatric surgery: what does it result in?

Answer 32

* 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

Question 33

How is diabetes treatment changing?

Answer 33

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

Question 34

How is diabetes treatment changing? (ER)

Answer 34

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

Question 35

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

Answer 35

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

Question 36

Future potential treatments (ER)

Answer 36

* FGF21 gene therapy * Ginkgo biloba * Suppression of factors that damage beta cells: ChREBPβ and Dusp26

Question 37

FGF21 gene therapy (ER)

Answer 37

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

Question 38

Ginkgo biloba (ER)

Answer 38

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

Question 39

ChREBPβ (ER)

Answer 39

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

Question 40

Dusp26 (ER)

Answer 40

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