An introduction to diabetes mellitus Flashcards
What is the action of insulin on glucose (in fed state)
- decrease HGO
* increase muscle uptake
What is the action of insulin on protein (in fed state)?
• decrease proteolysis
What is the action of insulin on fat (in fed state)?
- decrease lipolysis
* decrease ketogenesis
Where are GLUT-4 found?
common in myocytes (muscle) and adipocytes (fat)
lies in vesicles hydrophobic chains in outside and hydrophilic chains on inside (for 7-fold)
What is the role of GLUT-4?
result in a 7-fold increase in glucose uptake recruited and enhanced by insulin
(see diagram 4/32)
Describe the effects of insulin on cell metabolism (on a myocyte)
In the fed state, no need for protein as fuel source.
Protein breakdown inhibited by insulin.
Amino acids converted into protein to use for storage later on - helped by other hormones (e.g. GH + IGF-1).
If you need the gluconeogenic amino acids (AAs) - e.g. alanine, these amino acids can leave the muscle cells and into the liver.
These processes are helped by cortisol.
What happens in the liver in both the fed and fasting states?
in fasting state (low insulin levels):
- AAs taken up by liver
- AAs converted into glucose via gluconeogenesis; increases hepatic glucose output (HGO)
in fed state:
- insulin encourages amino acids to be converted into protein to be stored within the liver
- insulin inhibits gluconeogenesis; reducing hepatic glucose output (HGO)
(see diagram 6/32)
What are the various fuel stores?
Carbohydrate (liver + muscle) - depletable within a one day fast
Mass: 0.5kg
Energy: 19KJ/kg)
Time: 16hrs
Protein (20% of fuel stores)
Mass: 8-9kg
Energy: 17KJ/kg)
Time: 15days
Fat
Mass: 9-10kg
Energy: 37KJ/kg
Time: 30-40days
What is the role of lipoprotein lipase (LPL)?
enzyme breaks down triglycerides that would otherwise be unable to leave the circulation
What happens to triglycerides?
In fed state, increase of triglycerides in bloodstream:
- triglycerides are too big to be taken up by adipocytes without being broken down first
- triglycerides broken down by LPL into non-esterified fatty acids and glycerols
- these can be taken up by adipocytes
- glucose taken up as well by GLUT-4 (encouraged by insulin); don’t necessarily need breakdown products of triglycerides, insulin will also promote glycerol and non-esterified to be converted into triglycerides for later use when needed
- insulin inhibits breakdown of triglycerides as you do not need an alternative energy source [Insulin mediates this pathway (to activate LPL)]
in fasting state:
- GH and cortisol promote the breakdown of triglycerides into glycogen and NEFAs
- these released by adipocytes and then taken up by liver
(see diagram 8/32)
What is the hepatic portal circulation for?
blood leaves from right side of heart, goes to lungs, goes to left side of heart, distributed to rest of body
there is a separate hepatic portal circulation - allows blood to go straight from the heart, through the gastrointestinal tract (pick up any nutrients) and take that straight to the liver for processing.
insulin is released straight into the separate hepatic portal circulation
(see diagram 9/32)
Describe what happens to triglycerides in the liver.
fed state:
- glycerol taken up by liver
- stored as triglycerides
fasting state:
- glycerol taken up by liver
- converted into glucose by gluconeogenesis
- increase hepatic glucose output
Hepatic gluconeogenesis 25% HGO after 10 hour fast
(see diagram 10/32)
What is the cerebral energy requirement for glucose, ketone bodies and NEFA?
Most bodily tissues can utilise all of these as fuel, brain can only use glucose and ketone bodies (glucose preferred).
The brain’s inability to utilise fatty acids as a fuel make it unique among body tissues
Describe the production of ketone bodies.
NEFA taken up by liver fed state:
- no need to break down glucose
- insulin inhibits breakdown of NEFA, which have been converted from fatty acetyl-CoA into ketone bodies
fasting state:
- glucagon encourages production of ketone bodies in liver
- have low circulating insulin levels
- ketone bodies released from liver
(see diagram 12/32)
What is hepatic glycogenolysis?
generation of glucose from stored glycogen in the liver
Describe the process of hepatic glycogenolysis.
fed state:
- glucose enters liver through GLUT-4
- Insulin encourages conversion into glycogen
fasting state:
- glucagon breaks down glycogen into glucose-6-P
- generates glucose to be released from liver
Describe what happens in the muscle cells in both the fed and fasting state.
fed state:
- glucose taken up by muscle cells (encouraged by insulin)
- can be stored as glycogen
fasting state:
- the take up of insulin is inhibited by glucagon and other hormones like GH
- glycogen can be released back into glucose when muscle cells need ATP (but glucose cannot actually be RELEASED by muscle cells)
- NEFA can also be taken up and used as an energy source
(see diagram 14/32)
What happens in the fasting state?
- Low insulin-to-glucagon ratio
- [Glucose] 3.0-5.5mmol/l
- increased [NEFA]
- decreased [amino acid] when prolonged
- increased Proteolysis into AAs
- increased Lipolysis into glycogen and NEFA
- increased HGO from glycogen and gluconeogenesis
- Muscle to use lipid
- Brain to use glucose, later ketones
- increased Ketogenesis when prolonged
What happens in the fed state?
- Stored insulin released then 2nd phase
- High [insulin] to [glucagon] ratio
- Stop HGO
- ↑ Glycogen
- ↓ gluconeogenesis
- ↑ protein synthesis
- ↓ proteolysis
- ↑ Lipogenesis
What is the fasting glucose for diabetes mellitus?
Fasting glucose >7.0 mmol/L
What is the random glucose for diabetes mellitus?
Random glucose >11.1 mmol/L
How do you diagnose diabetes mellitus?
Oral glucose tolerance test
• Fasting glucose
• 75g glucose load
• 2-hour glucose
HbA1c (>48mmol/mol) - average of glucose over last 3 months
A diagnosis requires 2 positive tests or 1 positive test + symptoms
What is the pathophysiology in type 1 diabetes?
- Autoimmune condition
- Absolute insulin deficiency type 1 diabetes can lead eventually into T cell mediated destruction of insulin producing beta cells in the pancreas
- leading to absolute insulin deficency
- increased proteinolysis
- increased HGO
- increase lipolysis (may converted into ketone bodies over time) high glucose in blood and urine water osmosed into urine
- osmotic diuresis
What is diabetic ketoacidosis?
- pH <7.3, ketones +3, HCO3- <15, gluc >11
* Serious acute complication
What are the clinical presentations of T1DM?
- Weight loss
- Hyperglycaemia
- Glycosuria with osmotic symptoms (polyuria, nocturia, polydipsia)
- Ketones in blood and urine
What diagnostic tests can be used to test for T1DM?
- Antibodies: GAD, IA2
- C-peptide
- Presence of ketones
What happens in insulin induced hypoglycaemia?
(people with T1DM are reliant on exogenous insulin) too much exogenous insulin can induce hypoglycaemia (very low blood sugar) stop HGO; fall of glucose levels
increased glucose uptake by muscle cells
What are the counter-regulatory responses to hypoglycaemia?
increased Glucagon increased Catecholamines increased Cortisol increased Growth hormone this results in: increased Hepatic glucose output with glycogenolysis and gluconeogenesis increased Lipolysis
What happens if you have recurrent hypoglycaemia?
body gets used to episodes
• Reduced ability to recognise symptoms of hypoglycaemia
• Due to loss of counterregulatory response
What are the autonomic symptoms and signs of hypoglycaemia?
- Sweating
- Pallor
- Palpitations
- Shaking
What are the neuroglycopenic symptoms and signs of hypoglycaemia?
• Slurred speech • Poor vision • Confusion • Seizures • Loss of consciousness
Define severe hypoglycaemia
an episode where a person needs third party assistance to treat
medical emergency
A 32 year old woman with T1DM feels sweaty and unwell at 11am whilst at work. Her CBG is 3.2mmol/L. Which of of the following is a potential cause of her low glucose?
- mismatch of insulin dose and carbohydrate content of breakfast
- exercise the previous evening
- cycling to work
- alcohol with dinner the previous evening
A 24 year old man with T1DM feels a bit shaky after running. His CBG is 3.0mmol/L. Which of the following would be the most appropriate hypoglycaemia treatment?
Jelly babies (quick acting carbohydrates) – should take something with low fat content (otherwise fat will delay absorption of glucose)
A 50 year old woman is found unconscious. A CBG is done and is 1.5mmol/L. Select the most appropriate treatment from the following available options.
1mg glucagon IM injection
What is the pathophysiology in type 2 diabetes - insulin resistance?
All metabolic sites and all arms of intermediary metabolism
• Glucose
• Fatty acids
Enough insulin to suppress
• Ketogenesis
• Proteolysis
Insulin resistance resides in liver, muscle and adipose tissue
Describe the simplified mechanism of insulin resistance.
- insulin binds to insulin receptor
- activates P13K-Akt pathway (responsible for metabolic actions - insulin resistance resides within this pathway)
- the body tries to produce more insulin to compensate
- increase peripheral insulin concentration
- activates the MAPK pathway, which is responsible of growth and proliferation of insulin
- growth of arterioles
- high blood pressure
What are the consequences of insulin resistance?
- High [TG]
- Low [HDL
- Insulin resistance
- Adipocytokines
- Inflammatory state
- Energy expenditure
Hypertension
• BP >135/80 mmHg
Waist circumference
• Men >102 cm
• Women >88 cm
Fasting glucose
• >6.0 mmol/L
What are the clinical presentations of T2DM?
- Hyperglycaemia
- Overweight
- Dyslipidaemia
- Less osmotic symptoms
- With complications
- Insulin resistance
- Later insulin deficiency
What are the risk factors for T2DM?
Age increase in BMI ethnicity PCOS Family Hx inactivity
What are the possible complications of T2DM?
- Eye disease (diabetic retinopathy, glaucoma, cataract)
- renal failure (diabetic, nephropathy)
- diabetic foot
- stroke
- heart damage
- nerve disease (peripheral neuropathy)
- arteriosclerosis
What are the dietary recommendations of healthy eating?
- total calories control
- reduce calories as fat
- reduce calories as refined carbohydrate
- increased calories as complex carbohydrate
- increase soluble fibre
- decrease sodium
How do you manage Type 1 diabetes?
- exogenous insulin (basal-bonus regime)
- self-monitoring of glucose
- structured education
- technology
- monitoring and prevention of long-term diabetes-related complications: retinopathy, neuropathy, nephropathy, cardiovascular
How do you manage Type 2 diabetes?
- diet
- oral medication
- structured education
- may need insulin later
- monitoring and prevention of long-term diabetes-related complications: retinopathy, neuropathy, nephropathy, cardiovascular
