Biochemistry Diabetes and Hypoglycaemia Flashcards Preview

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Flashcards in Biochemistry Diabetes and Hypoglycaemia Deck (60):
1

Definition

A group of disorders characterised by a relative or absolute deficiency of insulin secretion and/or action leading to hyperglycaemia, disturbed metabolism of carbohydrate, fat and protein and the development of chronic complications.

2

Natural History of Type 2 Diabetes

Altered Glucose Metabolism
IGT
Diagnosis of T2D
Progression of T2D

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Pattern of Disease

Rising Insulin resistance
B-cell function decrease
Insulin Resistance increasing
Post-meal glucose increasing
Fasting glucose increasing

4

Before diagnosis unnoticed

Micro and macro vascular disease
50% beta cell dysfunction

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Beta cell dysfunction

A range of functional abnormalities is present:
➢ Abnormal oscillatory insulin release
➢ Increased pro-insulin levels
➢ Abnormal 2nd-phase insulin response
➢ Progressive loss of beta-cell functional mass

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Insulin Physiology

Peptide hormone, MW 6000

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Insulin secreted by

Beta-cells
Produced as pro-insulin

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Insulin structure

Two chains (alpha and beta) joined by two disulphide bridges

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Insulin production process

Proteolysis of C-peptide → equimolar amounts

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Insulin action

Acts by binding to specific receptors in the plasma membranes of target cells thus enhancing glucose entry into cells.

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Insulin actions on muscle

Increased uptake and utilisation of glucose and amino acids
Increased cell uptake of potassium, phosphate, amino acids

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Insulin actions on liver

• Increased glycogen synthesis
• Decreased liver glycogen breakdown
• Decreased gluconeogenesis from fats and AAs
• Increased protein synthesis

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Insulin action on adipocytes (fat cells)

• Inhibits fat breakdown (reduced lipolysis)
• Increased fat synthesis

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Glucagon action

Increases hepatic glycogenolysis

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Adrenalin action

Increased glycogenolysis, increased lipolysis

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Growth hormone action

Increased protein synthesis
Increased lipolysis
Decreased utilisation of glucose

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Cortisol action

Increased gluconeogenesis + protein breakdown
Decreased glucose uptake

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Catabolic Hormones:

Glucagon action
Adrenalin action
Growth hormone action
Cortisol action

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Diabetes can be diagnosed in one of 4 ways:

1. Random plasma glucose >11.1 mmol/L
2. Fasting plasma glucose >7.0 mmol/L
3. 2h plasma glucose >11.1 mmol/L during oGTT
4. HbA1c

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Diagnostic criteria

• Confirmation on a second day by any of the above methods is required unless hyperglycaemic: symptoms are present (thirst, polyuria, weight loss, infections etc.)
• Diagnosis should not be based on samples taken during stress

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Blood glucose process

Whole blood 10-15% lower than plasma
Preservations not 100% effective
• Heparin/serum – loss of 0.33 mmol/L per hour
• Fluoride oxalate – loss of about 10% overnight

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OGGTT (glucose tolerance tests)

Used to be the ‘gold standard’ for diagnosing diabetes in UK
Dynamic function test
Baseline sample for glucose after overnight fast
75g of glucose given (Polycal)
Second sample at 120 minutes

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Haemoglobin A1c (HbA1c): Looking for

Insulin/glycated Hb/fructosamine
Non-enzymatic glycation of N-terminal valine of haemoglobin beta chains

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Haemoglobin A1c (HbA1c): Process

Non-diabetic HbA1c values vary markedly between subjects, while values in the same individual change little over time:
There may be high or low ‘glycators’
Kidney threshold for glucose

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Haemoglobin A1c (HbA1c): Expressed as

The percent of total haemoglobin (normal 4-6%) (20 mmol/mol – 42 mmol/mol)

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Advantages of using HbA1 c

• Gives an idea of chronic glucose exposure
• Does not reflect recent food intake or exercise
• Reflects both fasting and post-prandial hyperglycaemia
• Knowledge of HbA1c seems to alter behaviours

Patient Preference:
• No need to fast
• No need to consume glucose which can b unpalatable
• No need to wait around for 2 hrs
Test more experience
• Probably offset by cost of oGTT

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Circumstances in which HbA1c to diagnose diabetes

Young adults children (false negative) – reflects mean blood glucose over the past 2-3 months
Recent onset of symptoms of diabetes
Pregnancy
Abnormal Hb variants
Abnormal red cell survival – haemolysis
Anaemia
Polycythaemia (falsely high)
Renal impairment
Iron deficiency

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HbA1c is proportional to

Mean plasma glucose

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Other glycosylated proteins

Fructosamine
Glycosylated albumin

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Fructosamine

• Mirrors glycosylation if plasma proteins
• Indicates previous 3 weeks glycaemic exposure
• Used pregnancy/children, patients with haemolytic anaemia

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Glycosylated Albumin

• Indicates previous several days glycaemic exposure
• Not commonly used

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Self Monitoring –Pitfalls

Sample collection
• Hand washing
• Sample size
Meter use
• Calibration
• Cleaning
• Follow protocol

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Monitoring for Ketosis

➢ Urine test strips used by patients to self monitor for ketones
➢ Recommended for Type 1 DM patients when blood glucose is >14 mmol/L
➢ Especially during “sick” days

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Looking for complications

Need to monitor for long-term consequences:
Renal
➢ Plasma creatinine, eGFR
➢ Urinary microalbumin
Lips
➢ Fasting lipid profile
Thyroid function test
➢ Autoimmune association IDDM
➢ May be justified especially in elderly females

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Microalbuminuria – Risk for factor

Nephropathy
Cardiovascular disease
Total mortality

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Microalbuminuria – Reversibility

Microalbuminaemia is reversible

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Adult Hypoglycaemia → Pathophysiology

Imbalance between factors raising and lowering blood glucose levels

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Adult Hypoglycaemia → Increase glucose via

Food
Counter-regulatory hormones

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Adult Hypoglycaemia →Decrease blood glucose

Insulin/Oral Meds
Physical Activity

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Adult Hypoglycaemia → Definition

Threshold for symptoms varies between individuals
Venous plasma glucose <2.5 mmol/L without symptoms during fasting

41

Spectrum of hypoglycaemia

Paediatrics – inborn errors of metabolism
Diabetes mellitus – treatment with insulin and sulphony;ureas
Adult hypoglycaemia – in absence of diabetes

42

Symptoms of hypoglycaemia

Are frequently non-specific, depend on the degree of hypoglycaemia, the age of the patient and how rapidly the blood glucose falls
Onset may be sudden without warning
Early recognition and intervention can prevent an emergency
1. Adrenergic
2. Neuroglycopenic

43

Adrenergic symptoms

Sympathetic NS activation
➢ Tremor
➢ Palpitations
➢ Sweating
➢ Hunger
➢ Anxiety
➢ Nausea

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Neuroglycopenic symptoms

Confusion
Behavioural change
Seizures/Neurological
Tiredness, Headache
Coma

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Neuroglycopenic symptoms due to

Result from more gradual decline in blood glucose
Unusual to appear in patients with fasting hypoglycaemia, unless blood glucose falls below 2.2 mmol/L

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Somogyi effect and nocturnal hypo’s

Hypoglycaemia at night is often slept through

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Symptoms include

Morning headaches
Hangover feeling on wakening
Nocturnal sweating
High levels of blood glucose noted before breakfast

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Hypoglycaemia treatment

Glucose, monitor closely after event
Ensure sufficient CHO to restore liver glycogen stores

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Severe hypo

Glucagon
- Unconscious/Unresponsive
- Seizure
- Uncooperative

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Classification of adult hypoglycaemia

Fasting
Postprandial

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Fasting

Under-production of glucose
Increased insulin action

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Post-prandial

Following gastric surgery
‘idiopathic reactive’

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Other Causes of Hypoglycaemia:

Underproduction of glucose
Increased insulin action
Drug induced hypoglycaemia

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Underproduction of glucose

Endocrine (adrenal, pituitary insufficiency
Severe liver disease
Renal Failure

55

Drug induced hypoglycaemia

ETOH
Salicylates
Quinine
Quinidine
Pentamidine
Haloperidol
Trimethoprim and Sulfamethoxade
NSAIDS
Colchicine
Fibrates
Chloramphenicol
Ketaconazole
PAS
MAO-Is
Thalidomide
Selegeline

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Increased Insulin Action

Insulinoma
Non-islet cell tumours
Factitious insulin administration
Factitious sulphonylurea

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Biochemical diagnosis of Insulinomas

➢ Measure glucose (insulin and C-peptide) at time of symptoms. Reagent strop glucose may be unreliable
➢ Measure glucose (insulin and C=peptide) after overnight fast or more prolonged fast (48 or 72h if index of suspicion high)
➢ Sulphoulurea screen if insulin and C-peptide are elevated

58

Non-Islet cell Tumours

➢ Rare mesenchymal tumours such as sarcoma or hepatoma
➢ Paraneoplastic release of insulin-like substances such as IGF-1 or 2
➢ Extremely poor prognosis at time of presentation
➢ Maintaining euglycaemia may be difficult outside the hospital

59

Factitious insulin administration

➢ Hypoglycaemic symptoms
➢ Low blood glucose
➢ Elevated insulin
➢ Suppressed C-peptide (due to Exogenous insulin)
➢ Psychiatric history
➢ Often health professionals (access to insulin)

60

Post-prandial hypoglycaemia

➢ Post-gastrectomy, there is rapid transit of glucose into the small intestine and release of hormones that stimulate (excessive) insulin secretion leading to hypoglycaemia

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