Biochemistry Diabetes and Hypoglycaemia

Question 1

Definition

Answer 1

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.

Question 2

Natural History of Type 2 Diabetes

Answer 2

Altered Glucose Metabolism
IGT
Diagnosis of T2D
Progression of T2D

Question 3

Pattern of Disease

Answer 3

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

Question 4

Before diagnosis unnoticed

Answer 4

Micro and macro vascular disease

50% beta cell dysfunction

Question 5

Beta cell dysfunction

Answer 5

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

Question 6

Insulin Physiology

Answer 6

Peptide hormone, MW 6000

Question 7

Insulin secreted by

Answer 7

Beta-cells

Produced as pro-insulin

Question 8

Insulin structure

Answer 8

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

Question 9

Insulin production process

Answer 9

Proteolysis of C-peptide → equimolar amounts

Question 10

Insulin action

Answer 10

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

Question 11

Insulin actions on muscle

Answer 11

Increased uptake and utilisation of glucose and amino acids

Increased cell uptake of potassium, phosphate, amino acids

Question 12

Insulin actions on liver

Answer 12

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

Question 13

Insulin action on adipocytes (fat cells)

Answer 13

• Inhibits fat breakdown (reduced lipolysis)

* Increased fat synthesis

Question 14

Glucagon action

Answer 14

Increases hepatic glycogenolysis

Question 15

Adrenalin action

Answer 15

Increased glycogenolysis, increased lipolysis

Question 16

Growth hormone action

Answer 16

Increased protein synthesis
Increased lipolysis
Decreased utilisation of glucose

Question 17

Cortisol action

Answer 17

Increased gluconeogenesis + protein breakdown

Decreased glucose uptake

Question 18

Catabolic Hormones:

Answer 18

Glucagon action
Adrenalin action
Growth hormone action
Cortisol action

Question 19

Diabetes can be diagnosed in one of 4 ways:

Answer 19

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

Question 20

Diagnostic criteria

Answer 20

• 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

Question 21

Blood glucose process

Answer 21

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

Question 22

OGGTT (glucose tolerance tests)

Answer 22

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

Question 23

Haemoglobin A1c (HbA1c): Looking for

Answer 23

Insulin/glycated Hb/fructosamine

Non-enzymatic glycation of N-terminal valine of haemoglobin beta chains

Question 24

Haemoglobin A1c (HbA1c): Process

Answer 24

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

Question 25

Haemoglobin A1c (HbA1c): Expressed as

Answer 25

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

Question 26

Advantages of using HbA1 c

Answer 26

* 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 ```

Question 27

Circumstances in which HbA1c to diagnose diabetes

Answer 27

``` 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 ```

Question 28

HbA1c is proportional to

Answer 28

Mean plasma glucose

Question 29

Other glycosylated proteins

Answer 29

Fructosamine | Glycosylated albumin

Question 30

Fructosamine

Answer 30

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

Question 31

Glycosylated Albumin

Answer 31

* Indicates previous several days glycaemic exposure | * Not commonly used

Question 32

Self Monitoring –Pitfalls

Answer 32

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

Question 33

Monitoring for Ketosis

Answer 33

➢ 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

Question 34

Looking for complications

Answer 34

``` 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 ```

Question 35

Microalbuminuria – Risk for factor

Answer 35

Nephropathy Cardiovascular disease Total mortality

Question 36

Microalbuminuria – Reversibility

Answer 36

Microalbuminaemia is reversible

Question 37

Adult Hypoglycaemia → Pathophysiology

Answer 37

Imbalance between factors raising and lowering blood glucose levels

Question 38

Adult Hypoglycaemia → Increase glucose via

Answer 38

Food | Counter-regulatory hormones

Question 39

Adult Hypoglycaemia →Decrease blood glucose

Answer 39

Insulin/Oral Meds | Physical Activity

Question 40

Adult Hypoglycaemia → Definition

Answer 40

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

Question 41

Spectrum of hypoglycaemia

Answer 41

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

Question 42

Symptoms of hypoglycaemia

Answer 42

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

Question 43

Adrenergic symptoms

Answer 43

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

Question 44

Neuroglycopenic symptoms

Answer 44

``` Confusion Behavioural change Seizures/Neurological Tiredness, Headache Coma ```

Question 45

Neuroglycopenic symptoms due to

Answer 45

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

Question 46

Somogyi effect and nocturnal hypo’s

Answer 46

Hypoglycaemia at night is often slept through

Question 47

Symptoms include

Answer 47

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

Question 48

Hypoglycaemia treatment

Answer 48

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

Question 49

Severe hypo

Answer 49

Glucagon - Unconscious/Unresponsive - Seizure - Uncooperative

Question 50

Classification of adult hypoglycaemia

Answer 50

Fasting | Postprandial

Question 51

Fasting

Answer 51

Under-production of glucose | Increased insulin action

Question 52

Post-prandial

Answer 52

Following gastric surgery | ‘idiopathic reactive’

Question 53

Other Causes of Hypoglycaemia:

Answer 53

Underproduction of glucose Increased insulin action Drug induced hypoglycaemia

Question 54

Underproduction of glucose

Answer 54

Endocrine (adrenal, pituitary insufficiency Severe liver disease Renal Failure

Question 55

Drug induced hypoglycaemia

Answer 55

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

Question 56

Increased Insulin Action

Answer 56

Insulinoma Non-islet cell tumours Factitious insulin administration Factitious sulphonylurea

Question 57

Biochemical diagnosis of Insulinomas

Answer 57

➢ 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

Question 58

Non-Islet cell Tumours

Answer 58

➢ 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

Question 59

Factitious insulin administration

Answer 59

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

Question 60

Post-prandial hypoglycaemia

Answer 60

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