Type 1 Diabetes (1)

Question 1

Describe “normal metabolism” after a meal

Answer 1

>meal
>digestion
>blood glucose level increases
>insulin released by beta cells in pancreas
>glucose taken by by cells
>metabolic pathways
>co2 + biochemical energy (e.g. ATP)

Question 2

Where is Insulin produced?

Answer 2

In the islets of langerhans in the pancreas (beta cells)

after a meal, BGL is high, glucose is released into islets and into the beta cells
- triggers release of insulin that is stored in granules in the beta cells

Question 3

3 main destinations of glucose and insulin?

Answer 3

Liver, muscle, adipose tissue

Insulin helps these tissues pick up the glucose molecules in the blood and store as an energy source

Insulin causes cells to upregulate GLUT and allow glucose to enter the cells
>decreases BGL
>glucose now stored as energy for future use
>storage molecule is glycogen

Question 4

What is going on in T1D?

Answer 4

> after meal, BGL increases
no insulin released
impaired glucose uptake by body’s cells
increased blood and urinary glucose (because glucose isnt getting into cells, so sticks around in blood then eventually filters and overflows into the kidneys where it leaves through urine)

> high ratio of glucagon:insulin
(glucagon helps regulate glucose storage (catabolism))
(too much glucagon so body thinks its starving, produces more sugar so you end up with higher BGL and urinary glucose)

> increased glycogen, fat, and protein catabolism
(body thinks its starving even though BGL is high)

> increased ketone body synthesis
decreased blood pH (ketone bodies are acidic)/dehydration
Unconsciousness if not treated with exogenous insulin
(typically show up in ER with diabetic ketoacidosis)

Question 5

What are the symptoms of T1D?

Answer 5

Polyuria (increased urination)

Glycosuria (increase in glucose in urine)

Polydipsia (excessive thirst which results in excessive drinking)

Polyphasia (increased hunger which is paradoxical because there is energy/sugar there but its not being used)

Question 6

What causes the loss of insulin in T1D?

Answer 6

T1D is an autoimmune disease where body’s own immune cells are destroying the insulin producing beta cells

Immune system kills beta cells over course of disease, but leaves other cells in the pancreatic islets intact
-the few remaining cells have reduced capacity to produce insulin so therefore increased levels of BGL

Question 7

Once the beta cell mass has been reduced below a certain threshold, ____

Answer 7

the body can no longer regulate blood glucose levels

> without insulin, the body’s cells are not stimulated to take up glucose

Question 8

Increased blood glucose levels result in:

Answer 8

Polyuria, polydipsia, ketoacidosis

Question 9

Immunopathogenesis of T1D

Answer 9

> APCs activate auto-reactive lymphocytes

> activated T cells mediate specific destruction of insulin producing beta cells

> beta cell destruction exacerbated by the release of proinflammatory cytokines and reactive oxygen species form adaptive and innate immune cells

> activated B cells produce autoantibodies against beta cell antigens that serve as biomarkers for diagnosing T1D

Question 10

Pancreatic and islet abnormalities in type 1 diabetes

Answer 10

Endocrine compartment (secrete hormones)
>overexpression HLA class I molecules (that present antigen to T cells)
>variable distribution and severity of infiltrating immune cells
>loss of beta cells and insulin expression

Exocrine compartment (secreting digestive enzymes)
>loss of pancreatic volume
>exocrine tissue atrophy
>healthy adult pancreas >80g, T1D pancreas <40g
>note: islet mass is only 2% of pancreatic mass

Non-endocrine islet cells
>possible changes in islet vasculature and extracellular structure, but still under investigation

Question 11

Why does the immune response target pancreatic beta cells?

Answer 11

> principle target is insulin
abundantly expressed in beta cells
insulin-specific autoantibodies detected in T1D patients and at-risk individuals can be used as a predictive biomarker

> T cells isolated form the pancreatic islet of T1D patients respond to insulin-derived peptides presented by HLA molecules on the surface of APCs and beta cells
(i.e. autoreactive t cells)

Question 12

T1D vs T2D

Answer 12

T1D: autoimmune mediated destruction of insulin-producing beta cells
>5-10% oif cases

T2D: body cells become resistant to insulin, body has to produce more and more insulin to keep up
>insulin resistance, insulin deficiency
>90-95% of cases

Question 13

Diagnostic criteria of T1D

Answer 13

2016 America Diabetes Association (followed in Aus)

One or more of the following plus #5

1. A random venous plasma glucose level of >11.1 mmol/L in PT with classic HYPERglycaemic symptoms or HYPERglycaemic crisis (polydipsia and weight loss)
2. Fasting plasma glucose level of >7mmol/L
   (usually a test for T2D, not T1D)
3. Plasma glucose level of >11.1mmol/L measured 2 hours after a glucose load of 1.75g/kg
4. A glycated haemoglobin (HbA1c) level of >6.5%
   (excess glucose in blood tends to bind non-covalently to other proteins, one of them being haemoglobin. Gives you an idea of how well a person is controlling their BGL and reflects a period of 2-3 months)
5. Autoantibodies against beta cell antigens (e.g. insulin)

Question 14

Who gets Diabetes Mellitus? Prevalence and Incidence

Answer 14

Worldwide DM (all cases) ~422 mil individuals, T1D accounts for 5-10%

Most individuals diagnosed with T1d are between ages of 5-19, but still can get diagnosed after 19 (if autoimmune response started later in life)

~95% of diabetes diagnosed in children is T1D

Cost of >$570 million annually in Australia

Question 15

T1D: Genetic Presidposition

Answer 15

> 90% individuals with T1D do not have first degree family history

> 3-5% chance if you have a parent with T1D

> 8% chance if you have a sibling with T1D

> 50% chance if you have an identical twin with T1D

Question 16

Explain odds ratio

Answer 16

> measure of association between an exposure and an outcome

OR=1: exposure does not affect odds of outcome
(not contributory to T1D)

OR>1: Exposure associated with higher odds of outcome
(pathogenic/risk factor for T1D)

OR<1: Exposure associated with lower odds of outcome
(protective)

Question 17

Alleles encoding MHC molecules and Insulin confer the highest risk of T1D

Answer 17

Genes that encode for MHC Class II and Insulin

HLA-DQ2 = OR >3.6
HLA-DQ8 = OR > 11.4
HLA-DQ2/DQ8 = OR >16.6

Heterozygote has higher odds ratio

Question 18

Epidemiological conundrum of T1D

Answer 18

Doesnt seem like there is any pattern to which countries have high or low incidence of T1D

Question 19

Rising incidence of T1D

Answer 19

Greatest observed increases in incidence are among children <15 years of age

If incidence rates continue to increase at the same rate, then global incidence would double in the next decade

Some recent data:
>incidence in adults is declining
>leveling off across all age ranges

Question 20

Wide variation in disease incidences

Answer 20

Comparing Estonia and Finland

> only 120km apart
Estonia less than 1/3 of T1D incidence as in Finland

> environmental factors and genetics

Question 21

T1D: Genetic Predisposition + Environmental Factors

Answer 21

> Infectious microbes/gut microbiome
(emerging idea of hygiene hypothesis that early childhood infection might temper the immune system for genetically at risk individuals)

> Virus infection
(viral infections that can be detected in the pancreatic islets trigger local inflammation and then goes on to attract autoreactive lymphocytes that happen to be in the periphery)

> Sunlight and Vitamin D (countries with higher incidence of T1D are far from equator)

> Diet (accelerator hypothesis that obesity and high sugar diet places additional stress on beta cells that are already under assault by immune system)

*Hard to study these effects in individuals that have already developed T1D
>largely retrospective studies looking at T1D patients, need large perspective studies to investigate these particular hypotheses

Question 22

Current treatment for T1D?

Answer 22

Exogenous Insulin for Glycaemic control

> multiple BGL measurements 4x a day
Daily multiple-dose insulin regimen (~4 injections per day) to mimic physiological insulin release
Detecting hypoglycaemia events (i.e. sudden decrease in BGL)
»>ingestion of a quick-acting glucose source (e.g. lollies)

Question 23

Metabolic complications of T1D even with Insulin Treatment

Answer 23

Lack of insulin causes:

1) Release of FFA from adipose tissue (lipolysis)
>converted by liver into ketone bodies (beta oxidation)
>ketone bodies have low pKa
»>decreased blood pH
»>acetone (fruity breath)

2) Increased glucagon (body thinks there is no glucose source)
>increased glucose by liver (gluconeogenesis)
>increased glucose removed by kidney along with water and solutes (osmotic diuresis)
»>polyuria (increased urination)
»>dehydration
»>polydipsia (increased hunger)

Question 24

Diabetic Ketoacidosis

Answer 24

> treatment in hospital occurs 1-5x per 50 patient years in children with established disease
associated with 13-19% of T1D related deaths
Treatment: fluids, insulin, electrolytes (K+)

Question 25

Hypoglycaemia

Answer 25

> Decreased BGL due to suboptimal insulin treatment
loss of consciousness or seizure occur 1-4x per 50 patient years
recurrent hypoglycaemia results in an increased likelihood of hypoglycaemia unawareness
(it is dangerous because it means people are passing out or having seizures while doing normal daily activities. is a factor for individuals who are eligible for islet transplantation)

> associated with 4-10% of T1D related deaths
Treatment: sugar source (e.g. glucose tablets, lollies)

Question 26

Long-term complications of chronic diabetes even with insulin treatment

Answer 26

Microvascular complications

• hyperglycemia is the primary risk factor
• intensive management of BGL within a “normal range” is associated with slower progression and reduced incidence of microvascular disease

Diabetic retinopathy

• New BV form at the back of the eye and burst, causing vitreous hemorrhages
• > 80% individuals with T1D develop retinopathy
• can lead to blindness if not managed properly
• usually happens 15-25 years after diagnosis of T1D and can lead to blindness
• symptoms such as blurry vision, seeing dark spots or floaters, given anti-vegf to prevent new vessel formation and try and increase their management of glucose control

Question 27

Diabetic nephropathy

Answer 27

Long term complications of T1D

> looking at glomerulus within kidney, interested in GFR

> increased protein (albumin) excretion in urine in absence of other renal conditions
33% of pts with T1D develop persistent microalbuminuria (30-299mg/24h) within first 2 decades of diabetes onset
40% PTs with microalbuminuria progresses to macroalbuminuria (>300mg per 24h)
Progressive decline in GFR
put on dialysis once GFR is below 10ml/min

Question 28

Microvascular complications

Answer 28

Neuropathy (decreased sensation in toes and fingers)

Autonomic NS malfunction
>hypoglycaemia unawareness
>sweating
>postural hypotension

> > > poor blood supply + nerve damage = ulcers
amputation
lower-extremity amputation by 65 years of age: 11% for women and 21% for men with T1D

Question 29

Macrovascular complications

Answer 29

> coronary heart disease
cerebrovascular disease
peripheral artery disease

These conditions are not specific to diabetes, but T1D increases risk of developing those conditions
>up to 10 fold increased risk of cardiovascular events (e.g. myocardial infarction, stroke, angina) and death

Question 30

Long-term complications summary:

Answer 30

Overall, up to 80 of people with T1D do not control their BGL well enough to avoid the increased risk of developing these chronic conditions

It’s not a matter of IF these PTs will develop these complications, but WHEN they do, and how we go about treating them

Question 31

Conceptual model for the natural history and pathogenesis of T1D

Answer 31

1) Genetic predisposition probably the key driver or linkage to immune abnormalities
2) Beyond precipitating, environment might influence entire natural history
3) Presence of 2 or more islet autoantibodies might represent asymptomatic T1D (can be detected even without clinical symptoms, normal blood glucose homeostasis still going on)
4) Overall loss of beta cells is potentially linear, but could show a relapsing or remitting pattern (beta cells not responding, mass has gone down, a lot of factors)

5) Increasing glucose level deviation as individual approaches symptomatic onset
(wouldnt notice because you come back to normal levels very quickly, only outside of normal range does diabetes and hypoglycaemia occur -> show progressive loss of insulin release, still asymptomatic)

6) Beta cell mass and function not always zero in patients
(clinical diabetes with residual insulin secretion, honeymoon period where individual might be put on insulin, but dont need as much as an individual who has full on clinical diabetes with zero residual insulin secretion)