Biochemistry Diabetes and Hypoglycaemia Flashcards
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.
Natural History of Type 2 Diabetes
Altered Glucose Metabolism
IGT
Diagnosis of T2D
Progression of T2D
Pattern of Disease
Rising Insulin resistance B-cell function decrease Insulin Resistance increasing Post-meal glucose increasing Fasting glucose increasing
Before diagnosis unnoticed
Micro and macro vascular disease
50% beta cell dysfunction
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
Insulin Physiology
Peptide hormone, MW 6000
Insulin secreted by
Beta-cells
Produced as pro-insulin
Insulin structure
Two chains (alpha and beta) joined by two disulphide bridges
Insulin production process
Proteolysis of C-peptide → equimolar amounts
Insulin action
Acts by binding to specific receptors in the plasma membranes of target cells thus enhancing glucose entry into cells.
Insulin actions on muscle
Increased uptake and utilisation of glucose and amino acids
Increased cell uptake of potassium, phosphate, amino acids
Insulin actions on liver
- Increased glycogen synthesis
- Decreased liver glycogen breakdown
- Decreased gluconeogenesis from fats and AAs
- Increased protein synthesis
Insulin action on adipocytes (fat cells)
- Inhibits fat breakdown (reduced lipolysis)
* Increased fat synthesis
Glucagon action
Increases hepatic glycogenolysis
Adrenalin action
Increased glycogenolysis, increased lipolysis
Growth hormone action
Increased protein synthesis
Increased lipolysis
Decreased utilisation of glucose
Cortisol action
Increased gluconeogenesis + protein breakdown
Decreased glucose uptake
Catabolic Hormones:
Glucagon action
Adrenalin action
Growth hormone action
Cortisol action
Diabetes can be diagnosed in one of 4 ways:
- Random plasma glucose >11.1 mmol/L
- Fasting plasma glucose >7.0 mmol/L
- 2h plasma glucose >11.1 mmol/L during oGTT
- HbA1c
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
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
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
Haemoglobin A1c (HbA1c): Looking for
Insulin/glycated Hb/fructosamine
Non-enzymatic glycation of N-terminal valine of haemoglobin beta chains
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
Haemoglobin A1c (HbA1c): Expressed as
The percent of total haemoglobin (normal 4-6%) (20 mmol/mol – 42 mmol/mol)
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
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
HbA1c is proportional to
Mean plasma glucose
Other glycosylated proteins
Fructosamine
Glycosylated albumin
Fructosamine
- Mirrors glycosylation if plasma proteins
- Indicates previous 3 weeks glycaemic exposure
- Used pregnancy/children, patients with haemolytic anaemia
Glycosylated Albumin
- Indicates previous several days glycaemic exposure
* Not commonly used
Self Monitoring –Pitfalls
Sample collection • Hand washing • Sample size Meter use • Calibration • Cleaning • Follow protocol
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
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
Microalbuminuria – Risk for factor
Nephropathy
Cardiovascular disease
Total mortality
Microalbuminuria – Reversibility
Microalbuminaemia is reversible
Adult Hypoglycaemia → Pathophysiology
Imbalance between factors raising and lowering blood glucose levels
Adult Hypoglycaemia → Increase glucose via
Food
Counter-regulatory hormones
Adult Hypoglycaemia →Decrease blood glucose
Insulin/Oral Meds
Physical Activity
Adult Hypoglycaemia → Definition
Threshold for symptoms varies between individuals
Venous plasma glucose <2.5 mmol/L without symptoms during fasting
Spectrum of hypoglycaemia
Paediatrics – inborn errors of metabolism
Diabetes mellitus – treatment with insulin and sulphony;ureas
Adult hypoglycaemia – in absence of diabetes
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
Adrenergic symptoms
Sympathetic NS activation ➢ Tremor ➢ Palpitations ➢ Sweating ➢ Hunger ➢ Anxiety ➢ Nausea
Neuroglycopenic symptoms
Confusion Behavioural change Seizures/Neurological Tiredness, Headache Coma
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
Somogyi effect and nocturnal hypo’s
Hypoglycaemia at night is often slept through
Symptoms include
Morning headaches
Hangover feeling on wakening
Nocturnal sweating
High levels of blood glucose noted before breakfast
Hypoglycaemia treatment
Glucose, monitor closely after event
Ensure sufficient CHO to restore liver glycogen stores
Severe hypo
Glucagon
- Unconscious/Unresponsive
- Seizure
- Uncooperative
Classification of adult hypoglycaemia
Fasting
Postprandial
Fasting
Under-production of glucose
Increased insulin action
Post-prandial
Following gastric surgery
‘idiopathic reactive’
Other Causes of Hypoglycaemia:
Underproduction of glucose
Increased insulin action
Drug induced hypoglycaemia
Underproduction of glucose
Endocrine (adrenal, pituitary insufficiency
Severe liver disease
Renal Failure
Drug induced hypoglycaemia
ETOH Salicylates Quinine Quinidine Pentamidine Haloperidol Trimethoprim and Sulfamethoxade NSAIDS Colchicine Fibrates Chloramphenicol Ketaconazole PAS MAO-Is Thalidomide Selegeline
Increased Insulin Action
Insulinoma
Non-islet cell tumours
Factitious insulin administration
Factitious sulphonylurea
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
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
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)
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
