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BIOL31571 > Lecture 4 - Diabetes introduction and T1DM > Flashcards

Lecture 4 - Diabetes introduction and T1DM Flashcards

1
Q

Diabetes: What are its pathological components, what are the types, and what are they categorised by?

A

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

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2
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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3
Q

Diabetes stats: how many people are affected in the UK and globally and how many are caused by T1DM?

A

> 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

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4
Q

Diabetes diagnosis: noticeable symptoms and actual diagnosis.

A

Symptoms:
* Polyuria
* Polydipsia
* Unexplained weight loss
* Tiredness
* Blurred vision
* Diabetic ketoacidosis

  • Plasma glucose levels
  • Glycated haemoglobin measurements (HbA1c)
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5
Q

Plasma glucose levels: what levels suggest diabetes?

A
  • 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)
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6
Q

HbA1c measurements: what is it, when is it used, what levels suggest diabetes, and what are the advantages of using this diagnostic method?

A

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
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7
Q

Insulin biosynthesis

A
  • Pre-proinsulin - rER
  • Proinsulin - transport vesicles
  • Proinsulin - through GA to immature beta granule
  • Insulin + c peptide - mature beta granule
  • Insulin + c peptide - secretion
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8
Q

Insulin maturation: what is the process and in what form is it secreted?

A

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

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9
Q

c peptide: what is it, how is it produced, where is it produced, and what does it do?

A

Connecting peptide

Produced as a byproduct of insulin maturation

Pancreas beta cells

Secreted along with insulin

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10
Q

Insulin target tissues

A
  • Adipose - glucose recruits fatty acids
  • Liver - glucose gets converted to glycogen
  • Muscle - glucose recruits amino acids
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11
Q

Glucagon target tissues

A
  • Adipose - glycogen gets converted to glucose
  • Liver - glucose recruits fatty acids
  • Muscle - glucose recruits amino acids
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12
Q

Incretin effect

A

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

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13
Q

Insulin secretion: what is the main molecular mechanism behind it and what is another mechanism?

A

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

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14
Q

PDX1: what is it and what does it do?

A

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

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15
Q

Processes involved in insulin secretion

A

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

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16
Q

Processes involved in insulin action

A

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

17
Q

Type 1A diabetes mellitus: what is the main dysfunctional gene and what factors trigger the diabetes onset?

A

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

18
Q

Autoantibodies in type 1 diabetes: why are they significant, what are some examples, and why can they be useful?

A

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

19
Q

T1DM treatment: what are the types?

A
  • 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
20
Q

Insulin injection: what is it and where may it be obtained from?

A

Soluble insulin (porcine, bovine, human)

21
Q

Insulin pumps: what are they and how may they act?

A

Implantable pumps

Open or closed-loop systems

22
Q

Inhaled insulin: what is it affected by?

A

Affected by smoking (increased absorption), lung disease (decreased absorption)

23
Q

Cell-based therapies: what are the types?

A
  • Islet transplantation (ongoing trials)
  • Stem cell therapies
24
Q

Omnipod 5: what is it, how does it work, and how expensive is it?

A

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

25
Q

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?

A

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

26
Q

Pathway from insulin resistance/low insulin to hyperglycemia

A

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
27
Q

Pathway from hyperglycemia to osmotic diuresis

A

Hyperglycemia - blood glucose > renal threshold - glycosuria

Glycosia:
* Osmotic diuresis
* Polyuria
* Polydypsia
* Lower plasma Na⁺ and K⁺

28
Q

Pathway from hyperglycemia to hyperglycaemic coma

A

Hyperglycemia - hyperosmotic plasma - cell dehydration - hyperglycaemic coma

29
Q

Pathway from gluconeogenesis to diabetic ketoacidosis

A

Gluconeogenesis - increase in ketones - diabetic ketoacidosis

30
Q

HLA molecules: what are they, what are the types, where are they found, and what do they do?

A

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

BIOL31571 (17 decks)

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