3 - T1DM Flashcards by Maxim Wallace

Define diabetes mellitus

Hypergycaemia

Caused by insufficient:

Insulin secretion
Insulin action

Associated with significant morbidity / mortality

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In Caucasian Northern Europe, what is the most common aetiology of T1DM?

T-cell mediated autoimmune destruction of the Beta-cells within the pancreas.

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How many people in the UK are diagnosed with DM?

4.7 million

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How many are estimated to have DM by 2035?

> 5 million

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How many people have been diagnosed with diabetes worldwide?

425 million

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How much does diabetes cost the UK?

£10 billion

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What % of this £10 billion is spent on preventable complications?

80%

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What % of TOTAL NHS budget is spent on diabetes and complications?

10%

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By 2035, what is the projected % spend of TOTAL NHS budget on diabetes and complications?

17%

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What are the symptoms of diabetes?

Polyuria
Polydipsia
Unexplained weight loss
Tiredness
Blurred vision
Diabetic ketoacidosis

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How do you diagnose diabetes?

Either:

Fasting plasma glucose > 7.0 mmol/L

Random plasma glucose > 11.1 mmol/L

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What is the gold standard for diabetes diagnosis?

Oral glucose tolerance test (OGTT) - 75g of glucose.

2h-post glucose-load plasma glucose > 11.1mmol/L

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What test is required if patient is asymptomatic but blood glucose levels are suggestive of diabetes?

Repeat glucose measurement on a different day to confirm.

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Why is misdiagnosing diabetes dangerous?

Affect life insurance
Ability to drive
Perform employment duties

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Who is HbA1c not possible to use as a clinical diagnostic test?

Young people
T1DM
Pregnant
Haemoglobinopathies

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What does HbA1c measure?

Measures glycated haemoglobin.

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What are the 3 advantages of HbA1c?

1) No need to fast
2) Lower variability
3) More stable for transporting samples

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What are the reference ranges for HbA1c?

<42mmol/L = normal

42-47 = pre-diabetes

> 47 = diabetes

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What are the 2 features of a pancreatic beta cell?

Nucleus

Insulin secretory granules (fried eggs)

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What are the 2 components of an insulin secretory granule?

Dense insulin core

Loose surrounding zone

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In the production of insulin, what is the role of the ER?

ER produces a pro-hormone.

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What is the role of the golgi apparatus in the production of insulin?

Cleaves the pro-hormone by pro-hormone-convertases

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What pro-hormone convertases are present in the golgi apparatus?

PC2 and PC1/3

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What are the two products of pro-hormone insulin cleavage?

1) Mature insulin

2) C-peptide

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Which cells produce insulin?

Beta cells in the pancreatic islets of langerhans

Which cells produce glucagon?

Alpha cells

What are the 3 main targets of insulin / glucagon?

Muscle Liver Adipose tissue

What glucose transporter is responsible for bringing glucose into the beta cell?

GLUT1

Describe the process of insulin secretion.

Glucose transport into cell Metabolism produces ATP ATP-sensitive K+ channels close, resulting in depolarisation. Voltage-gated calcium channels open, resulting in calcium influx. Insulin secretory granules exocytosed

What is the incretin effect?

The markedly higher insulin response when glucose is ingested compared to when given through IV

Give 2 examples of an incretin?

GLP-1 GIP

What cells produce GLP-1?

Intestinal L-cells

What type of GPCR is GLP-1 receptor?

GalphaS

What pattern of insulin secretion occurs? What is it described as?

Biphasic 1st phase: Triggering stimulus releases granules already close to membrane of beta-cell immediately. 2nd phase: Expansion and replenishment of readily-releasable pool before second wave of insulin secretion.

What is PDX1? What occurs in high glucose levels?

A transcription factor regulated by glucose PDX1 activated to increase transcription of insulin gene.

What are the two pathways that are activated in response to insulin-receptor activation?

PI3K pathway RAS/MAPK pathway

What subsequent processes is the PI3K pathway involved in?

Growth + differentiation + Metabolic actions

What subsequent processes is the RAS/MAPK pathway involved in?

Growth + differentiation Survival + Gene expression

What are the 2 differences between T1A-DM and T1B-DM?

No autoimmune markers detectable in T1B-DM. ``` T1A = insulin deficiency T1B = Absolute deficiency ```

What 3 features are associated with T2DM?

Beta-cell failure / insulin resistance. Later presentation Associated with obesity

What is gestational diabetes mellitus?

Glucose intolerance / diabetes during pregnancy.

When does gestational diabetes mellitus usually occur?

During 2nd / 3rd trimester

Following parturition after gestational diabetes mellitus, what is the outcome in the context of the mother's DM?

Can NOT have DM. Will be at a higher risk of getting it.

What is maturity onset diabetes of the young? (MODY)

Monogenic cause of diabetes that occurs in young-adult life, as a result of a mutation in a gene responsible for pancreatic beta cell function, differentiation or proliferation.

Give 3 examples of genes that, if mutated, result in Maturity onset diabetes of the young (MODY)

Glucokinase PDX1 HNF-1alpha

How is MODY diagnosed?

<25 years old | Familial inheritance

What % of DM patients have MODY?

1-2%

What is permanent neonatal DM ?(PNDM)

Monogenic cause of diabetes that occurs following birth.

What two important genes can cause permanent neonatal DM? What are they responsible in coding for?

KCNJ11 / ABCC8 The ATP-sensitive K+ ion channel

What is an emergency complication of T1DM?

DKA

What is the T2DM equivalent of DKA?

Hyperosmolar non-ketotic coma (HONK)

What are two important genes in the predisposition of T1DM?

HLA DR4 HLA DR3

What percentage of children with T1A-DM have either one of HLA-DR3/4?

90%

What is the original gene and its location in regard to HLA DR3/4?

HLA Class II Chromosome 6

What does HLA stand for?

Human Leukocyte Associated

What are the 3 classes of HLA genes?

Class 1 = all nucleated cells (necessary for viral infection response) Class 2 = APC cells Class 3 = Complement

What factors can trigger T1DM?

``` Viruses Bacteria Gluten Toxins Cow's milk ```

What viruses can trigger T1DM?

Coxsackie B4 virus Picornavirus

What is the usual natural history of the disease and its progression?

A progressive decline in insulin secretory capacity, as a result of continual auto-immune destruction of Beta-cells.

In the pathogenesis of T1DM, what is the honeymoon phase?

Occurs after first hyperglycaemia. Pancreatic beta-cells and pancreatic stem cells regenerate themselves to increase beta-cell mass and normalise glucose level. However, quickly gets overrun by autoimmune disease again.

What % of T1DM patients have the presence of autoantibodies circulating in their blood?

90%

What are autoantibodies a predictor of?

Risk of T1DM development.

Name the 4 auto-antibodies commonly found in

GAD65 Islet antigen-2 Insulin Zinc transporter

What is Insulitis?

Invasion of pancreatic islets by lymphocytes (CD4+ / CD8+). | Characteristic of T1DM

How do you treat T1DM?

Insulin

How is insulin administration given to match normal physiology?

Basal dose Short-acting insulin analogue following meal consumption.

Give 2 examples of long-acting insulin analogues

Glargine Detemir (1x daily)

Give 2 examples of short-acting insulin analogues

Lispro Aspart

What are 4 other methods of treating T1DM?

Kidney / pancreas transplant Insulin pumps (open / closed) Islet transplant Insulin inhalation

What is an issue with islet transplantation?

Requires 3 donors Remission lasts 5 years before it occurs again.

What are the 4 future treatments for T1DM?

· Advanced closed-loop insulin pumps · Cell-based therapies: islet transplantation (ongoing trials), stem cell therapies · β-cell regenerative medicine · Prevention / immune modulation

What is the bionic pancreas and how does it work?

Real time insulin / glucagon pump that alleviates the major clinical / personal issues that are bound to T1DM. Blood glucose monitor and doses insulin / glucagon in relative amounts every 5 minutes. Catheter requires changing weekly.

What is T1DM?

Absolute deficiency of insulin.

If diagnosis of T1DM occurs before 1 year of age, what two genetic conditions should be considered?

Maturity onset diabetes of the young | or other monogenic causes of diabetes, e.g. permanent neonatal diabetes mellitus

What is hypoglycaemia defined as in regards to blood glucose concentrations, in mmol/L?

<3.5mmol/L