4.8 - An Introduction to Diabetes Mellitus

Question 1

What are the features of GLUT-4 transporters?

Answer 1

• common in myocytes and adipocytes
• highly insulin-responsive
• lies in vesicles
• recruited and enhanced by insulin
• 7-fold increase glucose uptake

Question 2

What are the effects of insulin on protein in myocytes in the fed state?

Answer 2

• protein breakdown inhibited
• along with IGF-1 and GH, converts amino acids to protein for storage
• gluconeogenic amino acids (e.g. alanine) can leave myocyte if needed elsewhere like in the liver - cortisol helps with this by inhibiting protein synthesis (facilitate protein –> AA)

Question 3

What is the effect of glucagon on the liver in the fasting state?

Answer 3

• gluconeogenic amino acids released from myocytes enter the liver, which glucagon helps
• glucagon encourages breakdown of protein into AA in liver to enter gluconeogenesis
• glucagon increases gluconeogenesis to form glucose to increase hepatic glucose output (HGO) –> cortisol also does this

Question 4

What is the effect of insulin on the liver in the fed state?

Answer 4

• the same amino acids that enter the liver are encouraged to be made into proteins by insulin
• insulin also inhibits gluconeogenesis in the liver to reduce HGO

Question 5

How long do carbohydrate, protein and fat stores in the body last before they are depleted as fuel?

Answer 5

• carbohydrate (liver and muscle) - 16 hours –> depletable within a one day fast
• protein - 15 days
• fat - 30-40 days

Question 6

What happens to triglycerides in the blood when they reach adipocytes?

Answer 6

1. lipoprotein lipase in capillary wall/adipocyte is activated by insulin and breaks down triglycerides into glycerol and non-esterified fatty acids (NEFA)
2. NEFA and glycerol are taken up by adipocytes

Question 7

How does insulin interact with adipocytes in the fed state?

Answer 7

• glucose can be taken up by adipocytes through GLUT-4 - encouraged by insulin
• insulin promotes reformation of triglycerides for later use when needed by combining glycerol and NEFA in adipocytes
• insulin also inhibits breakdown of triglycerides in adipocytes as you do not need an alternative energy source

Question 8

What happens to adipocytes in fasting state?

Answer 8

• BGC and insulin is low so growth hormone (GH) and cortisol is secreted
• these encourage triglyceride breakdown in adipocytes into NEFA and glycerol, which leave adipocytes and are taken to the liver

Question 9

How is the circulation adapted for quick reactions to changes in blood glucose?

Answer 9

• there is a separate hepatic portal circulation - allows blood to go straight from heart through GI tract, picking up nutrients, to liver for processing
• insulin is released straight into hepatic portal circulation, so an increase in BGC can quickly be responded to

Question 10

What happens when glycerol reaches the liver in a fed vs fasting state?

Answer 10

• glycerol enters the liver and is converted into glycerol-3-phosphate
• in a fed state (glucose is not needed), G3P is converted into triglycerides for storage
• in a fasting state (glucose needed), G3P undergoes gluconeogenesis to make glucose and increase HGO

Question 11

What fuel can the brain use?

Answer 11

• glucose - preferred energy source
• ketone bodies
• cannot use NEFA - inability to use fatty acids as a fuel makes the brain unique

Question 12

How are ketone bodies produced?

Answer 12

• NEFA released from adipocytes are taken up by the liver
• in a fed state, insulin is released which inhibits conversion of fatty-acyl-CoA into ketone bodies
• in fasting state, glucagon is released which promotes conversion of NEFA into ketone bodies to be used as an alternative energy source

Question 13

What is hepatic glycogenolysis?

Answer 13

• when glucose levels are low, glucagon acts on liver and promotes breakdown of glycogen into glucose-6-phosphate
• G6P converted into glucose and outputted from liver to increase BGC
• alternatively, when glucose levels are high, glucose enters the liver through GLUT-4 which is encouraged by insulin
• insulin then promotes G6P to be converted into glycogen to be stored

Question 14

What happens in myocytes when glucose is high vs low? (How does the glucose itself interact with the cell)?

Answer 14

• in fed state, insulin encourages glucose to enter myocyte where it is converted into glycogen and stored in the muscle to use, for the muscle to use only (cannot release glucose into system)
• NEFA can also be used as energy source by myocyte
• in fasting state, GH and glucagon inhibit glucose from entering myocyte so it can stay in circulation and be used in more important parts e.g. brain

Question 15

What overall happens in the body in fasted state?

Answer 15

• low insulin : glucagon ratio
• [glucose] maintained at 3.0 - 5.5 mmol/L
• increased [NEFA] from increased lipolysis
• increased proteolysis = increased amino acids (but they decrease when prolonged fast)
• increase in HGO from glycogen and gluconeogenesis
• muscles use lipids and brain uses glucose + later ketones
• increased ketogenesis when prolonged

Question 16

What overall happens in the body in fed state?

Answer 16

• stored insulin released in 1st phase, then slow release in 2nd phase
• high insulin : glucagon ratio
• stop HGO
• increased glycogen storage, lipogenesis and protein synthesis
• decrease gluconeogenesis and proteolysis

Question 17

How is diabetes mellitus diagnosed?

Answer 17

• fasting glucose levels >7.0 mmol/L
• random glucose >11.1 mmol/L
• oral glucose tolerance test (fasting glucose, 75g glucose load, 2-hour glucose)
• HbA1c (>48 mmol/mol) –> gives average glucose over last three months
• a diagnosis requires two positive tests, or one positive test + symptoms

Question 18

What is the pathophysiology in type 1 diabetes mellitus (T1DM)?

Answer 18

• autoimmune disease of T-cell-mediated destruction of insulin-producing beta cells in pancreas –> absolute insulin deficiency
• leads to proteolysis into AAs, and increased HGO
• also high glucose in urine = water osmoses into urine = high urine production - osmotic diuresis
• fat starts to be broken down into glycerol + NEFA –> if this happens for prolonged period you get ketone bodies forming –> high glucose and high ketone bodies in blood –> diabetic ketoacidosis (serious acute complication)

Question 19

How do T1DM patients present?

Answer 19

• weight loss
• hyperglycaemia
• glycosuria (glucose in urine) with osmotic symptoms:
• polyuria - lots of urine made
• nocturia - passing of urine in night
• polydipsia - feeling very thirsty due to losing so much fluid
• ketones in blood and urine

Question 20

What diagnostic tests distinguish between T1DM and T2DM?

Answer 20

• markers like antibodies - GAD, IA2
• low C-peptide
• presence of ketones

Question 21

What happens if T1DM patients take too much exogenous insulin?

Answer 21

• they get hypoglycaemic
• you eventually stop HGO so glucose levels fall even further
• normally insulin in body switches off production of more, but taking exogenous insulin means the mechanism is not there = stays in circulation
• glucose continues to be taken up by muscle and BGC continues to drop

Question 22

What is the counterregulatory response to hypoglycaemia?

Answer 22

• increased glucagon, catecholamines, cortisol and GH
• this leads to increased HGO with glycogenolysis and gluconeogenesis, and increased lipolysis

Question 23

Why is it important to avoid hypoglycaemia?

Answer 23

• makes people feel awful and lethargic
• recurrent episodes of hypoglycaemia can lead to impaired awareness of hypoglycaemia where our body gets used to being hypoglycaemic = reduced ability to recognise symptoms until glucose much lower (loss of counterregulatory response)

Question 24

What are symptoms and signs of hypoglycaemia?

Answer 24

Autonomic:

• sweating
• pallor
• palpitations
• shaking

Neuroglycopenic:

• slurred speech
• poor vision
• confusion
• seizures
• loss of consciousness

Question 25

How is severe hypoglycaemia defined?

Answer 25

An episode where a person needs third party assistance to treat

Question 26

What is the management for T1DM like?

Answer 26

• exogenous insulin (basal-bolus regime) –> multiple daily injections (long-acting injection once a day, short-acting ones before you eat)
• self-monitoring of glucose e.g. finger-prick test
• structured education
• technology like insulin pumps and continuous glucose monitoring tech
• monitoring and prevention of long-term diabetes complications like retinopathy, neuropathy etc

Question 27

What is T2DM?

Answer 27

• insulin resistance residing in liver, muscle and adipose tissue - at all metabolic sites and all arms of intermediary metabolism of glucose and fatty acids
• however, there is enough insulin to suppress ketogenesis and proteolysis

Question 28

How does insulin resistance work at a cellular level? PI3K-Akt pathway

Answer 28

• when insulin binds to receptor, this activates the PI3K-Akt pathway which results in metabolic actions of glucose and fat metabolism –> insulin resistance is in this pathway
• in early stages of insulin resistance, the body compensates by producing more insulin so for a while you can get away with this which can maintain your blood pressure = you can have insulin resistance without T2DM early on

Question 29

How does insulin resistance work at a cellular level? MAPK pathway

Answer 29

• the MAPK pathway leads to growth and proliferation
• there is no insulin resistance in this pathway
• so when insulin increases due to resistance of other pathway (to compensate), this leads to side effects with this pathway e.g. growth of arterioles –> high BP and other effects

Question 30

What are the consequences of insulin resistance?

Answer 30

• dyslipidaemia - derangement of lipids
• hypertension
• increased weight
• high glucose
• inflammatory state in body
• increases energy expenditure
• adipocytokines
• high triglycerides and low HDL

Question 31

How do T2DM patients present?

Answer 31

• hyperglycaemia
• overweight
• dyslipidaemia
• less osmotic symptoms than T1DM
• with complications - most patients present later in life where they have been insulin resistant for a while
• later insulin deficiency
• major cause of renal failure and end stage renal impairment requiring dialysis
• can cause nerve problems
• can lead to amputations
• can lead to macrovascular complications like stroke and MI

Question 32

What are risk factors for developing T2DM?

Answer 32

• age
• higher BMI
• ethnicity - Asians are high risk
• PCOS
• family history
• inactivity

Question 33

What is treatment for T2DM?

Answer 33

• healthy eating / diet - total calories control, reduce calories as fat and refined carbohydrates, increase calories as complex carbohydrates and soluble fibre, decrease sodium
• oral medication
• structured education
• may need insulin later if beta cells stop working
• monitoring and prevention of long-term conditions (retinopathy, neuropathy, nephropathy, cardiovascular)