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Endocrinology Year 2 > Pathophysiology and treatment of type 1 diabetes > Flashcards

Pathophysiology and treatment of type 1 diabetes Flashcards

1
Q

When autoimmune Type 1 diabetes presents later in life (>decades), what is it called?

A

Latent autoimmune diabetes in adults (LADA)

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2
Q

State two monogenic causes of diabetes (hereditary form of DM).
Present as T1DM/T2DM?

A

Mitochondrial Diabetes
Maturity Onset Diabetes of the Young (MODY)

  • Can present phenotypically as Type 1 or Type 2 diabetes
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3
Q

What conditions and triggers are required for the onset of type 1 diabetes mellitus?

A

Environmental trigger in the presence of a genetic predisposition => autoimmune attack of the beta cells

May present following pancreatic damage or other endocrine disease.

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4
Q

Name three endocrine diseases that are associated with diabetes.

A

Phaeochromocytoma
Cushing’s Syndrome
Acromegaly

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5
Q

Which type of diabetes has a bigger genetic component?

A

Type 2 Diabetes Mellitus

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6
Q

What can be measured in the blood to give an indication of beta cell mass/insulin production? Why?

A

C-peptide

Proinsulin is cleaved in Golgi to form insulin and C-peptide and the two components are stored together in secretory granules in cytoplasm

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7
Q

In the pathogenesis of T1DM, what is one of the first pathological signs?

A

Loss of first phase insulin release

When the β-cells are stimulated and the stimulus is maintained, there is a biphasic pattern of insulin release (initial sharp rise in insulin release over a period of 10 minutes; second release of insulin which reaches a plateau approximately 2–3 hours later)

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8
Q

Why is T1DM described as a ‘relapsing-remitting’ disease?

A

Over time the beta cell mass appears to reduce, then stabilise, then reduce again (until hypoglycaemic state)

There is a theory that this is due to the imbalance in effector T-cells and regulatory T-cells

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9
Q

State the reasons why knowledge of the immune basis of T1DM is important

A
  • Increased prevalence of other autoimmune disease (associated with diabetes)
  • Risk of autoimmunity in relatives
  • Measurement of auto antibodies can be useful clinically (in diagnosing)
  • Immune modulation offers the possibility of novel treatments
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10
Q

What are the histological features of T1DM?

A

Lymphocyte infiltration of beta cells

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11
Q

On which chromosome is the HLA found?

A

Chromosome 6

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12
Q

In terms of the antigen types encoded by different HLA gene regions, what are the major genetic determinants of T1DM?

A

The major genetic determinants of T1D are polymorphisms of class II HLA genes encoding DQ and DR.

Specifically, the DR3 and DR4 alleles of the HLA-DR region => most significant risk

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13
Q

What are the markers of diabetes (which are not used in clinical practice)?

A
  • Islet cell antibodies (ICA)
  • Glutamic acid decarboxylase (GADA)

Not used:

  • Insulin antibodies (IAA)
  • Insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family
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14
Q

State some symptoms of T1DM

A
  • Polyuria
  • Nocturia
  • Polydipsia
  • Blurring of vision
  • Thrush (due to increased risk of infection)
  • Weight loss
  • Fatigue
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15
Q

What are the signs of T1DM?

A
  • Dehydration
  • Cachexia
  • Hyperventilation (Kussmaul breathing)
  • Smell of ketones (‘like nail polish’)
  • Glycosuria
  • Ketonuria
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16
Q

What does insulin have a negative effect on (inhibitory effects)?

A
  • Decreases hepatic glucose output (glycogenolysis + gluconeogenesis)
  • Inhibits glucagon release (via paracrine stimulation of alpha cells)
  • Inhibits lipolysis and hence ketogenesis in liver (since the release of fatty acids and transport to liver is required for beta-oxidation to acetyl-CoA and then subsequent conversion to ketone bodies)
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17
Q

What does insulin have a positive effect on (stimulatory effects)?

A
  • Increases GLUT4* mediated glucose uptake (in muscle and adipose tissue)
  • Stimulates glycolysis
  • Stimulates glycogenesis
  • Stimulates amino acid uptake
  • Stimulates protein synthesis (via an indirect genomic effect)
  • Stimulates lipogenesis
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18
Q

State 4 other hormones that increase hepatic glucose output.

A

Catecholamines
Cortisol
Growth Hormone
Glucagon

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19
Q

Describe the factors that control insulin release. Outline the mechanism by which glucose (and certain amino acids) stimulate insulin release from beta cells

A

Note that there are two levels of insulin secretion - basal secretion (since some cells are dependent on the insulin- dependent GLUT4 transporters in order to receive sufficient intracellular glucose) and enhanced release when blood glucose levels rise (e.g. post-prandial)

  • As the blood glucose level rises insulin output increases*
  • Certain amino acids (glycine, alanine and arginine) directly stimulate insulin release
  • Free fatty acids (FFA) are generally potent enhancers of glucose-stimulated insulin granule secretion/exocytosis (acting via GPCRs)
  • Incretins (gastrointestinal hormones) stimulate insulin production and β-cell mass (e.g. by cell proliferation) e.g. gastrin, cholecystokinin, GLP1
  • Sympathetic stimulation is associated with an inhibition of insulin secretion while parasympathetic (vagal) activity stimulates its release (these effects are indirect and involve the islet vasculature, so no direct innervation of islet cells)
  • Glucagon appears to have a stimulatory effect on insulin release, while somatostatin from the δ-cells is inhibitory
  • Glucose enters beta via GLUT2 and are converted to glucose-6-phosphate by glucokinase; further metabolism of G6P (glycolysis + kreb’s) produces ATP; ATP closes ATP-sensitive potassium channels in the cell membrane;
    transient build-up of K+ in the cell => membrane depolarisation => activates voltage-dependent calcium channels which open; influx of calcium ions down its concentration gradient is associated with
    the movement of granules (containing insulin and C-peptide) towards the cell membrane, the fusion of the
    granule membrane with the plasma membrane and the release of granule contents into the bloodstream by exocytosis
20
Q

State the actions of glucagon and describe the control of its release

A
  • Stimulates glycogenolysis and gluconeogenesis, increasing blood glucose concentration
  • Stimulates the breakdown of triglycerides to fatty acids in adipose tissue. The accompanying increase in glycerol production then feeds into the gluconeogenic pathway in the liver

Control:
- Stimulus for glucagon release is a fall in the blood glucose level (e.g. during fasting).
- The same gastrointestinal hormones that enhance insulin release (e.g. cholecystokinin) also stimulate glucagon release
- Increased sympathetic activity is associated with
stimulated glucagon release
- Insulin itself has an inhibitory effect on glucagon release probably at least partly by a paracrine effect, and this probably explains why the glucagon levels in untreated diabetic patients tend to be higher than would be expected for the given raised blood glucose concentration
- Somatostatin from the δ-cells also has an inhibitory effect on glucagon release

21
Q

Describe how insulin deficiency leads to polyuria, dehydration, and polydipsia and diabetic ketoacidosis (DKA). Explain the associated symptoms/signs

A
  • The lack of insulin + corresponding elevation of glucagon => increased HGO; High glucose levels spill over into the urine (surpasses renal threshold for glucose absorption), taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis. This leads to polyuria, dehydration (when can’t drink enough or vomiting), and polydipsia.
  • The absence of insulin => release of free fatty acids from adipose tissue (lipolysis), which are converted via beta oxidation (in the mitochondria of liver cells) into acetyl CoA.
  • If the amounts of acetyl-CoA generated challenge the processing capacity of the TCA cycle; i.e. if activity in TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies.
  • The ketone bodies, however, have a low pKa and therefore turn the blood acidic (metabolic acidosis).
  • The body initially buffers the change with the bicarbonate buffering system of the blood, but this system is quickly overwhelmed and other mechanisms must work to compensate for the acidosis. One such mechanism is hyperventilation to lower the blood carbon dioxide levels (a form of compensatory respiratory alkalosis). This hyperventilation, in its extreme form, may be observed as Kussmaul breathing.

Other clinical signs: ketonuria, abdominal pain, vomiting => coma (look for precipitating factor)

22
Q

What is the defining/diagnostic biochemical feature of insulin deficiency? But under what circumstances may this be a normal observation, and when would you diagnose someone with DKA? Why is DKA uncommon in T2DM?

A

Elevated ketone bodies

Ketosis also occurs due to increased stress hormones and fasting e.g. in a non-diabetic subject say at 6.00am in the morning before breakfast. The diagnosis of ketoacidosis is made on the combination of hyperglycaemia, ketones in the urine and a metabolic acidosis on blood gas analysis (low pH, low bicarbonate, low PC02).

DKA is common in T1DM. In T2DM, insulin production is present but is insufficient to meet the body’s requirements as a result of end-organ insulin resistance. Usually, these amounts of insulin are sufficient to suppress ketogenesis. If DKA occurs in someone with type 2 diabetes, their condition is called “ketosis-prone type 2 diabetes” but is very rare.

23
Q

State some long-term complications of T1DM.

A

Neuropathy
Nephropathy
Retinopathy
Vascular Disease

24
Q

What is the main treatment for T1DM?

A

Exogenous insulin (SC injection)

25
Q

What is the treatment for DKA?

A

The main aims in the treatment of diabetic ketoacidosis are:

  • replacing the lost fluids and sodium with normal saline* (sliding scale regime); as soon as the patient is hydrated they will be able excrete hydrogen ions and produce bicarbonate.
  • suppressing the high blood sugars and ketone production with insulin (given as an intravenous sliding scale i.e. the capillary glucose is measured once an hour and the insulin administration rate is adjusted according to that capillary glucose)
  • replace potassium (sliding scale)

*Note: do not attempt to replace the whole deficit too quickly as possible => the patient (especially children) are then at risk of cerebral oedema

26
Q

Describe the dietary changes that are recommended in T1DM

A
  • reduce calories as fat
  • reduce calories as refined carbohydrate
  • increase calories as complex carbohydrate
  • increase soluble fibre
  • balanced distribution of food over course of day with regular meals and snacks
27
Q

Describe the features of the insulin that is GIVEN WITH MEALS

A

Short-acting
Human Insulin
Insulin analogues are genetically engineered to mimic normal physiology

28
Q

State three forms of insulin that are GIVEN WITH MEALS.

A

Lipsro
Aspart
Glulisine

29
Q

Describe the features of BACKGROUND insulin.

A

Long-acting

Bound to zinc or protamine

30
Q

State three forms of insulin that is given as BACKGROUND insulin.

A

Glargine
Detemir
Degludec

31
Q

What do insulin pumps do?

A

Continuous insulin delivery
There are pre-programmed basal rates and boluses for meals
But these DO NOT measure blood glucose so the feedback loop isn’t complete

32
Q

Describe the use of islet cell transplants.

A

Islet cells can be harvested from donors and injected into the liver of a patient with diabetes
They must be on immunosuppressants for life

33
Q

How is capillary monitoring done and what does it give a measure of?

A

Prick the finger and test the blood drawn
It is a measure of capillary blood glucose (which differs slightly from venous blood glucose)
NOTE: you can also get continuous glucose monitors, which aren’t as accurate but show you a trend in blood glucose over 24hrs (need to be calibrated with capillary glucose)

34
Q

What is HbA1c? What is HbA1c level used to guage?

A

Glucose (and other monosaccharides) will spontaneously bind to haemoglobin when in the bloodstream (=> glycated haemoglobin). The formation of the sugar-Hb linkage indicates the presence of excessive sugar in the bloodstream, often indicative of diabetes. As the average amount of plasma glucose increases, the fraction of glycated haemoglobin increases in a predictable way.

HbA1c levels indicate glycaemic control over the past 3 months (red cell life span = 120 days); and has been shown to be related to risk of complications

35
Q

What HbA1c level are T1DM patients aiming for?

A

< 7% (53 mmol/mol)

36
Q

When might the HbA1c level not be accurate?

A

In any case of increased haemoglobin turnover e.g. haemolytic anaemia and haemoglobinopathies (which affect red cell life span)
Rate of glycation, faster in some individuals

37
Q

What are the main acute complications of T1DM?

A

Hypoglycaemia

Metabolic acidosis

38
Q

DKA tends to be in patients with T1DM, however, some subsets of T2DM patients also get ketoacidosis. What are these subsets?

A

Black and Asian patients with T2DM

May be due to pancreatic insufficiency at a time of stress

39
Q

Define hypoglycaemia.

A

Plasma glucose < 3.6 mmol/L (but note that occasional hypos inevitable as a result of treating diabetes)

40
Q

Define severe hypoglycaemia

A

Any level of hypoglycaemia that requires another person to treat it

41
Q

Most mental processes are impaired at what blood glucose? Consciousness impaired at what blood glucose?

A

Most mental processes impaired at <3 mmol/l

Consciousness impaired at <2 mmol/l

42
Q

What can recurrent hypos result in?

A

Loss of warning (‘hypoglycaemia unawareness’)

This can lead to poor glycaemic control

43
Q

At what times during the day do hypos tend to happen?

A

Pre-lunch

Nocturna

44
Q

What can trigger a hypo?

A 
Unaccustomed exercise
Missed meals
Inadequate snacks
Alcohol (may make you unaware of hypo symptoms)
Inappropriate insulin regime
45
Q

State some signs and symptoms of hypoglycaemia.

A

Signs and symptoms are due to increased sympathetic activity and due to impaired CNS function:

Palpitations
Tremor
Sweating
Pallor/cold extremities
Anxiety
Drowsiness
Confusion
Altered behaviour
Focal neurological deficits
Coma
46
Q

How is hypoglycaemia treated?

A

Oral glucose + complex carbohydrate (to maintain blood glucose after initial treatment)

Parenteral glucose (if consciousness impaired)

  • IV dextrose (e.g. 10% glucose infusion)
  • 1 mg glucagon IM
47
Q

What effect does insulin have on intracellular potassium? Why can insulin replacement alone be dangerous? What should be done to prevent this?

A
  • Insulin maintains the intracellular K+ concentration; (normal range is 4-5mmol/l mainly intracellular)
  • In the absence of insulin, K+ moves out of cells into the extracellular fluid.
  • Glucose-induced osmotic diuresis => increased K+ loss in the urine => plasma K+ concentration appearing normal if measured.
  • However, a potentially dangerous hypokalaemia can develop when insulin replacement is given, since there is a rapid increased movement of K+ back into the cells when the body’s total K+ content is reduced.

Hypokalaemia increases the risk of dangerous irregularities in the heart rate. Therefore ensure :

  • continuous ECG observation of the heart rate
  • repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l.
  • If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalaemia.

Endocrinology Year 2 (18 decks)

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