Clinical Biochemistry: Diabetes and Hypoglycaemia Flashcards
1
Q
How are blood glucose levels maintained?
A
- Dietary carbohydrate
- Glycogenolysis - breakdown of glucose to glucose-1-phosphate and glycogen
- Gluconeogenesis - Generation of glucose from non-carbohydare substances, e.g. amino acids
2
Q
What is the liver’s role in maintaining glucose levels?
A
- After meals liver stores glucose as glycogen
- During fasting liver makes glucose available through glycogenolysis and gluconeogenesis
3
Q
Why is it important to regulate glucose levels?
A
- Brain and the eryhtrocytes require continuous supply of gucose so we need to avoid blood glucose deficiency
- Also, high glucose levels causes pathological changes to tissues such as:
- Micro/macro vascular diseases
- Neuropathy
4
Q
Explain some of the functions of insulin in different organs
A
- Adipose tissue: Increased glucose uptake and lipogenesis; decreases lipolysis
- Striated muscle: Increases glucose uptake; glycogen synthesis and protein synthesis
- Liver: Increases Glycogenelysis (Glycogen synthesis) and Liopgenesis; decreases gluconeogenesis
5
Q
What are some of the other functions insulin?
A
- Decreases ketogenesis - production of ketone bodies vai breakdown of fatty acids
- Decreases proteolysis in striated muscle
- Increases uptake of ions (especially K+ and PO43-)
6
Q
What is diabetes mellitus?
A
- A metabolic disorder characterised by chronic hyperglycaemia, glycosuria, excess gluocose in urine, and associated abnormalities of lipid and protein metabolism
7
Q
How does hyperglycaemia develop as a result of diabetes mellitus?
A
- Results from increased hepatic glucose production and decreased cellular glucose uptake
8
Q
What are the different types of diabetes mellitus?
A
- Type 1: Insulin secretion is deficient due to autoimmune destruction of b-cells in pancreas by T-cells
- Type 2: Insulin secretion is retained but there is target organ resistance to its actions
- Secondary: Caused by chronic pancreatitis, pancreatic surgery, secretion of insulin antagonists
- Gestational: Occurs during pregnancy
9
Q
Describe some of the characteristics of type 1 diabetes
A
- Predominantly occurs in children and young adults; but other ages as well.
- Sudden onset (days/weeks)
- Appearance of symptoms may be preceded by ‘prediabetic’ period of several months
10
Q
What is the most common cause of type 1 diabetes?
A
- Most common cause is autoimmune destruction of B-cells
- Involves interaction between genetic and environment factors
- Strong link with Human leukocyte antigen (HLA) genes within the Major histocompatibility complex (MHC) region on chromosome 6
11
Q
Explain the pathogenesis of type 1 diabetes
A
- HLA class II cell surface presents foreign and self antigens to T-lymphocytes which causes them to initiate an autoimmune response
- As a result circulating autoantibodies are produced against cell antigens such as:
- Glutamic acid decarboxylase - found in pancreas
- Tyrosine-phosphatase-like molecule
- Islet auto-antigen
12
Q
What is the most commonly detected associated with type 1 diabetes?
A
- Islet cell antibody
13
Q
Describe the pathophysiology of type 1 diabetes
A
- Both genetic predispoistion and environmental factors result in the production of autoantigens on insulin-producing β cells
- This is different to type 2 diabetes as that is much more dependent on genetic predisposition
- These autoantigen-presenting β cells circulate within blood stream and lymphatics
- Autoantigen is then processed and presented by antigen presenting cells (APC)
- This results in the activation of T helper 1 lymphocytes and T helper 2 lymphocytes
- Activated T helper 1 lymphocytes secrete Interferon gamma (IFN γ) and Interleukin 2 (IL-2)
- IFN γ leads to activation of macrophages which release Interleukin 1 (IL-1) and Tumour Necrosis Factor α (TNF α)
- IL-2 leads to activation of autoantigen-specific T cytotoxic (CD8) cells
- BOTH OF THESE LEAD TO DESTRUCTION OF β CELLS
- Activated T helper 2 lymphocytes secrete Interleukin-4 (IL-4)
- IL-4 leads to activation of B lymphocytes which produce islet cell antibodies and anti glutamic acid decarboxylase (antiGAD) antibodies
- THIS ALSO LEADS TO DESTRUCTION OF β CELLS
14
Q
Why does destruction of the pancreatic β cells cause hyperglycaemia?
A
- Because it causes absolute deficiency of both insulin & amylin
15
Q
What is Amylin?
A
- Glucoregulatory peptide hormone co-secreted with insulin
16
Q
What is the function of Amylin?
A
- It lowers blood glucose by slowing gastric emptying
- Takes a longer time for food to enter intestine so takes longer for food to be broken down
- This means glucose enters blood circulation from food break down in a more controlled manner
- Also suppresses glucagon output from pancreatic cells
17
Q
What is the function of glucagon?
A
- Breaks down glycogen to form glucose
18
Q
How does insulin deficiency as a result of type 1 diabetes result in a diabetic coma?
A
- Insulin deficiency due to type 1 diabetes leads to hyperglycemia as tissues unable to take up blood glucose
- Hyperglycaemia leads to polyphagia (excessive appetite)
- Excess glucose in blood plasma goes to kidney where it is unable to reabsorb all the excess glucose
- This results in glycosuria (excess glucose in urine)
- This results in more water entering urine resulting in polyuria (excessive urination)
- Polyuria leads to volume depletion which causes polydipsia (excessive thirst)
- Volume depletion results in dehydration which affcets the brain causing diabetic coma
19
Q
Apart from the resulting hyperglycaemia, how else does insulin deficiency lead to a diabetic coma?
A
- Insulin deficiency causes increased lipolysis (breakdown of lipids)
- This causes an increase in free fatty acid levels
- Free fatty acids undergo β oxidation in the liver which produces ketone bodies
- Ketone bodies produced are hightly acidic and so result in a decrease in blood pH (diabetic ketoacidosis)
- This diabetic ketoacidosis leads to a diabetic coma
20
Q
Describe some characteristics of type 2 diabetes
A
- Slow onset (months/years)
- Patients middle aged/elderly – prevalence increases with age
- Strong familiar incidence (genetic predisposition)
21
Q
Describe the pathogenesis of type 2 diabetes
A
- Pathogenesis uncertain – possibly due to insulin resistance; β-cell dysfunction:
- May be due to lifestyle factors - obesity, lack of exercise
22
Q
What are some of the metabolic complications of type 2 diabetes?
A
- Hyper-osmolar non-ketotic coma (HONK) or Hyperosmolar Hyperglycaemic State (HHS)
- Symptoms include:
- Development of severe hyperglycaemia
- Extreme dehydration - due to polyuria
- Increased plasma osmolality
- Impaired consciousness
- No ketoacidosis - insulin still present in type 2 diabetes so it inhibits lipolysis
- Death if untreated
23
Q
How is diabetes diagnosed?
A
- Diagnosis in the presence of symptoms is as follows:
- Random plasma glucose level ≥ 11.1mmol/l (200 mg/dl)
- Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl) - Fasting defined as no caloric intake for at least 8 h
- Oral glucose tolerance test (OGTT) - plasma glucose level ≥ 11.1 mmol/l
- Diagnosis in the absence of symptoms is as follows:
- Test blood samples on 2 separate days
24
Q
Why can type 1 diabetes lead to weight loss?
A
- Lipolysis and proteolysis due to absence of insulin results in weight loss
- Large amounts of water loss due to polyuria can also result in weight loss
25
Q
What is the Impaired Glucose Tolerance (IGT) test?
A
- A test used to diagnose pre-diabetes
- Involves checking fasting plasma glucose level which should be < 7mmol/L
- OGTT also done in people with fasting plasma glucose of < 7.0 mmol/
- Value of OGTT should have a value of 7.8 – 11.1 mmol
26
Q
What is the Impaired Fasting Glycaemia (IGF) test?
A
- Test to see if someone has impaired fasting glycaemia (type of pre-diabetes)
- Involves testing Fasting plasma glucose which should be 6.1 to 6.9 mmol/L
- Also involves OGTT which should have a value of < 7.8mmol/L
27
Q
When should the oral glucose tolerance test (OGTT) be used?
A
- In patients with IFG
- In unexplained glycosuria (high glucose levels in urine)
- In clinical features of diabetes with normal plasma glucose values
- Normally used to diagnose acromegaly - excessive production of growth hormone by pituitary gland
- During OGTT growth hormone level will remain high but glucose will decrease - indicating acromegaly but not diabetes
28
Q
How does the oral glucose tolerance test (OGTT) work?
A
- Blood glucose level taken beforre test
- Patient given 75g oral glucose and blood glucose level taken after 2 hours
- Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate
29
Q
Explain the step by step treatment of type 2 diabetes
A
-
Step 1: Diet and exercise
- Some people may not need other steps but others may need other treatments
-
Step 2: Oral monotherapy - Metformin
- Metfromin helps control blood glucose by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose
- Both of these effects help person respond better to their own insulin
- Only given to people with type 2 diabetes as it acts only in the presence of endogenous insulin
-
Step 3: Oral combination therapy
- Sulphonylureas - they work mainly by stimulating pancreatic cells to make more insulin.
- They also help insulin to work more effectively in the body.
- Gliptins (Dipeptidyl peptidase inhibitor (DPP-4): Inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
- Incretin helps the body produce more insulin, when needed, and reduce the amount of glucose being produced by liver
- More incretin = lower blood glucose level
- Step 4: Insulin + oral agents
30
Q
Why would you monitor glycaemic control?
A
- To prevent complications or avoid hypoglycaemia
31
Q
How are you able to self-monitor glycaemic control?
A
- Capillary blood measurement
- Urine analysis: glucose in urine gives indication of blood glucose concentration above renal threshold
32
Q
What are some non-self monitoring techniques used to monitor glycaemic control?
A
- Checking Blood HbA1c (glycated Hb) every 3-4 months
- Glycated Hb is covalent linkage of glucose to residue in Hb.
- Checking of urinary albumin (index of risk of progression to nephropathy
33
Q
What are some long term complications of both type 1 and type 2 diabetes?
A
- Micro-vascular disease: leads to retinopathy, nephropathy, neuropathy
- Macro-vascular disease: related to atherosclerosis heart attack/stroke
34
Q
What is hypoglycaemia?
A
- Defined as a plasma glucose level < 2.5 mmol/L
35
Q
What are some caues of hypoglycaemia?
A
- Drugs are the most common cause
- Common in type 1 diabetes
- Less common in type 2 diabetes taking insulin and insulin secretagogues
- Uncommon in patients who DO NOT have drug treated diabetes mellitus
- In these patients hypoglycaemia may be caused by:
- Alcohol
- Critical illnesses such as hepatic, renal or cardiac failure
- Sepsis
- Hormone deficiency
36
Q
How can hypoglycaemia be caused in patients with diabetes?
A
- Exogeneous insulin & insulin secretagogues such as glyburide, glipizide and glimepiride are examples of some of the sulfonylureas that may cause hypoglaycaemia in diabetic patients
- Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation so less glucose in plasma
37
Q
How can hypoglycaemia be caused in patients without diabetes?
A
- Drugs such as alcohol may cause hypoglycaemia
- Other drugs most commonly found to cause hypoglycaemia are:
- Quinolone
- Quinine
- Beta blockers
- ACE inhibitors
- IGF-1
- Endocrines disease; e.g. cortisol disorder
- Inherited metabolic disorders, e.g. hereditary fructose intolerance
- Insulinoma
38
Q
How can ethanol cause hypoglycaemia?
A
- Inhibits gluconeogenesis, but not glycogenolysis.
- The hypoglycaemia will typically follow several days after alcohol binge with limited food intake; resulting in hepatic depletion of glycogen.
39
Q
How can sepsis caus hypoglycaemia?
A
- Sepsis produces cytokines
- These cytokines accelerate glucose utilization and induce inhibition of gluconeogenesis in the setting of glycogen depletion
40
Q
How can chronic kidney disease (CKD) cause hypoglycaemia?
A
- Mechanism not clear, but likely to involve:
- Impaired gluconeogenesis
- Reduced renal clearance of insulin
- Reduced renal glucose production
41
Q
What is Reactive hypoglycaemia (postprandial hypoglycaemia)?
A
- Recurrent drop in blood glucose level a few hours after eating
- Can occur in both people with and without diabetes - common in overweight individuals or those who have had gastric bypass surgery
42
Q
What can cause reactive hypoglycaemia?
A
- Cause is unclear:
- A benign tumour in the pancreas may cause an overproduction of insulin
- Too much glucose may be used up by the tumour itself.
- May also be caused by deficiencies in counter-regulatory hormones: e.g. glucagon
43
Q
Describe the response to hypoglycaemia in normal patients
A
- When plasma glucose level declines in fasted state the pancreatic beta-cells secretion of insulin is decreased (1st defence)
- This leads to increase in Hepatic glycogenolysis and gluconeogenesis
- Also leads to reduced glucose utilisation of peripheral tissue
- Counter-regulatory hormones are released: Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis (2nd defence)
- Noradreanline is released from adrenal medulla to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis (3rd defence)
- If hypoglycaemia is prolonged beyond 4 hours, cortisol and growth hormone will support glucose production and limit utilisation (4th defence)
44
Q
What are some signs and symptoms of hypoglaycaemia?
A
-
Neurogenic (autonomic) symptoms:
- Triggered by falling glucose levels
- Activated by ANS & mediated by sympathoadrenal release of catecholamines and Acetylcholine
-
Neuroglycopaenia:
- Due to neuronal glucose deprivation.
45
Q
What are some symptoms of Neuroglycopaenia?
A
- Confusion
- Difficulty speaking
- Ataxia - Lack of voluntary coordination of muscle movements
- Paresthesia - Tickling/prickling sensation of the fingers
- Seizures
