Diabetes and Hypoglycaemia Flashcards
How are blood glucose levels maintained?
- Dietary carbohydrate
- Glycogenolysis- breakdown of glycogen store to glucose
- Gluconeogenesis- making glucose from non-glucose sources e.g. lactate, alanine, fatty acids
What happens to glucose production in the fasting state?
In the fasting state there will be a decrease in insulin production by the pancreas
There will be an increase of gluconeogenesis
The peripheral uptake of glucose (that goes into muscle and adipose tissue) will decrease
There will be an increase in catabolism- lipolysis and proteolysis to release glucose into the blood stream
What is the role of insulin?
In the liver it inhibits gluconeogenesis
It upregulates glycogen synthesis and lipogenesis
In the muscle insulin is involved in peripheral uptake, glycogen and protein synthesis
In the adipose tissue it increases glucose uptake, lipogenesis and inhibits lipolysis
What are the hormones involved in glucose maintenance? Include their function and major metabolic paths.
Insulin
- Promotes storage
- Promotes growth
- Stimulates glucose storage in muscle, liver stimulates protein & fatty acids synthesis.
Glucagon - Mobilises fuel - Maintains blood glucose in fasting - Activates gluconeogenesis and glycogenolysis; activates fatty acid release
Epinephrine
- Mobilises fuels in acute stress
- Stimulates glycogenolysis;
stimulates fatty acid release
Cortisol
- Changing long term
- Amino acid mobilization
gluconeogenesis
Growth Hormone
- Inhibits insulin action
- Stimulates lipolysis
What is diabetes mellitus, and its different classifications?
A metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism
Type 1:
- Deficiency in insulin secretion
Type 2:
- Insulin secretion is retained but there is target organ resistance to its actions
Secondary:
- Due to chronic pancreatitis, pancreatic surgery, secretion of antagonists
Gestational:
- Occurs for the first time in pregnancy
What are the characteristics of Type 1 DM?
Predominantly 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
Commonest cause is autoimmune destruction of b-cells;
- interaction between genetic and environment factors.
- strong link with HLA genes within the MHC region on chromosome 6.
Environment: viruses (CMV, mumps, Rubella, EBV), drugs, stress.
Can all cause destruction of beta-cells
In susceptible individuals, environmental factors may trigger the immune-mediated destruction of pancreatic beta cells.
What is the pathogenesis of type 1 DM?
Destruction of B-cells starts with autoantigen formation
Autoantigens are presented to T-lymphocytes to initiate autoimmune response
There would be circulating autoantibodies to various -cell antigens against glutamic acid decarboxylase
- tyrosine-phosphatase-like molecule
- Islet auto-antigen
The most commonly detected antibody associated with type 1 DM is the islet cell antibody
How does type 1 DM develop as a result of autoimmune pancreatic beta-cell destruction in genetically susceptible individuals?
Up to 90% of patients will have autoantibodies to at least one of 3 antigens: glutamic acid decarboxylase (GAD); insulin; and a tyrosine-phosphatase-like molecule, islet auto-antigen-2 (IA-2).
Beta-cell destruction proceeds sub-clinically for months to years as insulitis (inflammation of the beta cell).
When 80% to 90% of beta cells have been destroyed, hyperglycaemia develops.
Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.
- Amylin is a glucoregulatory peptide hormone co-secreted with insulin.
· lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
What are the metabolic complications of Type 1 DM?*
Insulin deficiency leads to:
- increased hepatic output and impaired glucose uptake – hyperglycaemia - Increased glucose osmotic effect and causes diuresis, dehydration and circulatory collapse - Increased lipolysis blood level of ketone bodies formation (DKA) and metabolic acidosis.
How does type 2 DM present?
Presentation:
Slow onset (months/years)
Patients middle aged/elderly – prevalence increases with age
Strong familiar incidence
Pathogenesis uncertain – insulin resistance; β-cell dysfunction:
As the body tries to produce enough insulin beta cell hyperplasia happens to bring the glucose levels to normal so normoglycaemia
The beta cells continue to do that but eventually it leads to realy failure of beta cells leading to impaired glucose tolerance
Late beta cell failure leads to diabetes
What is the pathogenesis of the HONK state?
Hyperglycaemic, hyperosmolar non ketotic? state
Because of low insulin or resistance to insulin there is increased gluconeogenesis and increased glycogenolysis
This further leads to hyperglycaemia
This causes glycosuria where there is glucose in the urine which causes osmotic diuresis where there is water moving from the extracellular space to the blood vessels
This leads to loss of water and electrolytes further leading on to dehydration
IT also leads to increased blood viscosity which leads to thrombosis
The hyperglycaemia causes a large increase in plasma osmolarity which leads to cerebral dehydration which can cause impaired consciousness and a risk of cardiovascular collapse
How do you diagnose type 2 diabetes?
In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
- Random plasma glucose ≥ 11.1mmol/l (200 mg/dl ). OR
- Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8 h
OR
- Oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l
In the absence of symptoms:
- test blood samples on 2 separate days
When is the oral glucose tolerance test carried out?
OGTT should be carried out:
- in patients with IFG
- in unexplained glycosuria
- in clinical features of diabetes with normal plasma glucose values
75g oral glucose and test after 2 hour
Blood samples collected at 0 and 120 mins after glucose
What is the stepwise treatment of type 2 DM?
Initially the doctor will advise some lifestyle changes
If that doesn’t help you will be given oral monotherapy such as metformin
If that doesn’t help you are given oral combination
And lastly if nothing has worked you are given insulin sometimes with oral agents such as gliptins
DPP-4 inhibitors (gliptins) DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed.
GLP-1 agonist:- They work by copying, or mimicking, the functions of the natural incretin hormones in your body that help lower post-meal blood sugar levels.
What are the drug treatments for type 2 DM?
Metformin- decreases gluconeogenesis and increases peripheral use of glucose
Sulfonylureas- depolarizes the beta cells to release insulin
- E.g. glipizide, glimepiride, glyburide
Thiazolidinediones- activates the PPAR gamma receptor, it reduces insulin resistane
SGLT2 inhibitors- promotes glucose excretions, preventing glucose free absorption
- canagliflozin, empagliflozin
Incretin targeting drugs- helps body to produce insulin when needed and reduce the amount of glucose produced by the liver;
- DPP-4 inhibitors, prevent breakdown of natural incretins- sitagliptin, saxagliptin, linagliptin, alogliptin
- Synthetic GLP-1 analogues, helps to prevent breakdown of incretin- liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide
