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
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
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)
