Lecture 4 - Diabetes introduction and T1DM Flashcards
Diabetes: What are its pathological components, what are the types, and what are they categorised by?
Insulin resistance and beta cell dysfunction
Type 1A diabetes mellitus:
* Autoimmune
* Insulin deficiency
Type 1B diabetes mellitus:
* Absolute insulin deficiency
* No autoimmune markers
Type 2 Diabetes mellitus:
* Associated with obesity
* Insulin resistance / β-cell failure
* Usually present in adulthood
Gestational diabetes mellitus (GDM)
* Glucose intolerance or diabetes occurring during pregnancy – usually occurs during 2ⁿᵈ or 3ʳᵈ trimester
Insulin resistance: what is the molecular mechanism behind it and what is an example?
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
Diabetes stats: how many people are affected in the UK and globally and how many are caused by T1DM?
> 830 million people globally (WHO (2022))
5.6 million in the UK (Diabetes UK (2024))
Likely much higher - undiagnosed
T1DM accounts for 10% of cases
Diabetes diagnosis: noticeable symptoms and actual diagnosis.
Symptoms:
* Polyuria
* Polydipsia
* Unexplained weight loss
* Tiredness
* Blurred vision
* Diabetic ketoacidosis
- Plasma glucose levels
- Glycated haemoglobin measurements (HbA1c)
Plasma glucose levels: what levels suggest diabetes?
- Fasting plasma glucose ≥ 7.0 mmol/L
- Random plasma glucose ≥ 11.1 mmol/L
- 2 hour plasma glucose ≥ 11.1 mmol/L after consumption of 75g glucose – oral glucose tolerance test (OGTT)
HbA1c measurements: what is it, when is it used, what levels suggest diabetes, and what are the advantages of using this diagnostic method?
Glycated haemoglobin measurements in the blood
Used for screening and long-term follow up
UbA1c > 48mmol/mol
Normal: 30-35mmol/mol
- No need for fasting
- Lower variability (120 days)
- More stable for transporting samples
Insulin biosynthesis
- Pre-proinsulin - rER
- Proinsulin - transport vesicles
- Proinsulin - through GA to immature beta granule
- Insulin + c peptide - mature beta granule
- Insulin + c peptide - secretion
Insulin maturation: what is the process and in what form is it secreted?
Proinsulin, processed by proinsulin convertases to form mature insulin - most processing occurs in the Golgi apparatus
Secreted along with connecting (c) peptide produced as a byproduct
c peptide: what is it, how is it produced, where is it produced, and what does it do?
Connecting peptide
Produced as a byproduct of insulin maturation
Pancreas beta cells
Secreted along with insulin
Insulin target tissues
- Adipose - glucose recruits fatty acids
- Liver - glucose gets converted to glycogen
- Muscle - glucose recruits amino acids
Glucagon target tissues
- Adipose - glycogen gets converted to glucose
- Liver - glucose recruits fatty acids
- Muscle - glucose recruits amino acids
Incretin effect
Insulin levels have a lower rise if glucose is put into the body intravenously than when orally ingested
Due to hormones secreted by the gut
Insulin secretion: what is the main molecular mechanism behind it and what is another mechanism?
leccy
- Glucose enters the beta cell through the GLUT1 receptor and is metabolised, producing ATP as well as insulin transcription factors (such as PDX1), promoting insulin biosynthesis
- KATP channels influence the membrane potential - ATP gathered from glucose metabolism closes the channel, resulting in depolarization of the cell membrane
- The depolarised membrane (-30mV) activates voltage-gated calcium channels, causing an influx of Ca²⁺ ions
- Ca²⁺ ions promote the secretion of insulin granules
Glucagon-like peptide 1 (GLP-1) binds to the GLP-1 receptor which is released in the intestines after eating, this process is dependent on glucose presence - amplifies the effect of the main pathway
Once activated, the receptor activates adenylyl cyclase which then causes cAMP production which then promotes insulin synthesis and also activates PKA, resulting in the promotion of insulin secretion
PDX1: what is it and what does it do?
Pancreatic and duodenal homeobox 1
Necessary for the development of the pancreas, including the maturation of pancreatic beta cells and the differentiation of the duodenum
Processes involved in insulin secretion
Ion channels and transporters:
* kATP channels, voltage-gated Ca²⁺ channels, SERCA
* Regulation by nucleotides such as ATP
* Control of expression levels
Metabolism of glucose and other nutrients:
* Glucokinase, other enzymes in glycolysis and citric acid cycle
Insulin gene transcription
* PDX1, a transcription factor regulated by glucose
Packaging of insulin in secretory vesicles
* Zinc transporters, Zn packaged with insulin protein
Incretin effects:
* GLP1, GIP
Processes involved in insulin action
Insulin/IRS proteins:
* Result in PI3K activation, then AKT/PKB activation, causing metabolic functions, growth, differentiation, etc
* RAS/MAPK pathway activation, results in gene expression, growth, survival, differentiation, etc
Type 1A diabetes mellitus: what is the main dysfunctional gene and what factors trigger the diabetes onset?
HLA Class II locus on Ch.6.p (same location as the major histocompatibility complex):
* HLA DR4
* HLA DR3
* Present in >90% of children with Type 1A
(also present in background population at about 40-50% - predisposition only)
* Predisposition only – supported by monozygotic twins
Potential trigger factors:
* Viruses (eg Coxsackie B4, B5, picornaviruses),
* Bacteria, impaired mucosal immunity
* gluten, toxins, cow’s milk
Definite trigger factors
* Progressive decline in insulin secretory capacity due to autoimmune
destruction of β-cells
Autoantibodies in type 1 diabetes: why are they significant, what are some examples, and why can they be useful?
Autoantibodies present in serum in 90% of newly diagnosed T1D
- GAD65
- IA-2
- Insulin
- Zinc transporter 8
The number of autoantibodies present relates to the risk of progression to overt diabetes – predictive
T1DM treatment: what are the types?
- Insulin injection
- Newer insulin analogues
- Insulin pumps
- Pancreas/kidney transplantation
- Islet transplantation
- Inhaled insulin
- Advanced closed-loop insulin pumps
- Cell-based therapies
- β-cell regenerative medicine
- Prevention / immune modulation
- Omnipod 5
- Stem Cells and Regenerative medicine
Insulin injection: what is it and where may it be obtained from?
Soluble insulin (porcine, bovine, human)
Insulin pumps: what are they and how may they act?
Implantable pumps
Open or closed-loop systems
Inhaled insulin: what is it affected by?
Affected by smoking (increased absorption), lung disease (decreased absorption)
Cell-based therapies: what are the types?
- Islet transplantation (ongoing trials)
- Stem cell therapies
Omnipod 5: what is it, how does it work, and how expensive is it?
Artificial Pancreas – Closed Loop Pump
- App to monitor blood glucose levels
£2-3000 (£1-2000 per year running costs) for pump – lifespan 8 years. Expensive, but cost-benefit has now been proven
T1DM prevention and immune modulation: why is it ideal, why is it difficult, why must it be carefully controlled, and is there any medicine for this?
Preventing the autoimmunity of T1DM may prevent the condition’s onset
A way to selectively inhibit T-Cell activation involving autoantigens against β-cells is difficult
Specific Targeted approach - only want to affect harmful autoreactive T cells
Teplizumab – may delay the onset of T1DM in those with high-risk
Pathway from insulin resistance/low insulin to hyperglycemia
Insulin resistance/low insulin:
* Adipose tissue - breakdown of fats - gluconeogenesis
* Decreased tissue glucose uptake - muscle - breakdown of proteins - glycogenolysis
* Decreased tissue glucose uptake - liver - glycogenolysis
- Gluconeogenesis/glycogenolysis - Hyperglycemia
Pathway from hyperglycemia to osmotic diuresis
Hyperglycemia - blood glucose > renal threshold - glycosuria
Glycosia:
* Osmotic diuresis
* Polyuria
* Polydypsia
* Lower plasma Na⁺ and K⁺
Pathway from hyperglycemia to hyperglycaemic coma
Hyperglycemia - hyperosmotic plasma - cell dehydration - hyperglycaemic coma
Pathway from gluconeogenesis to diabetic ketoacidosis
Gluconeogenesis - increase in ketones - diabetic ketoacidosis
HLA molecules: what are they, what are the types, where are they found, and what do they do?
Human leucocyte antigens
- Class I molecules:
– Found on ALL nucleated cells
– Necessary for responses to viral infection - Class II molecules:
– Found on antigen-presenting cells
– Bind foreign antigen peptides and present
them to T helper lymphocytes
– 3 types of class II molecules – DP, DQ and
DR, each of these is subclassified by
numbers - Class III molecules
– Associated with complement activity
Cell surface glycoproteins, roles in the immune process
