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Physiology > Week 3 lecture - T2DM > Flashcards

Week 3 lecture - T2DM Flashcards

Exam

1
Q

Diabetes definition

A

‘A variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors and usually characterised by inadequate secretion or utilisation of insulin, by excessive urine production, by excessive amounts of sugar in the blood and urine, and by thirst, hunger and loss of weight’ (Merriam-Webster Medical dictionary).

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2
Q

What is the UK prevalence for T2DM?

A

~6%
~2.5 million people have prediabetes

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3
Q

Key characteristics of T2DM

A
  • Poorly controlled blood glucose (hyper and hypoglycaemia)
  • Defective insulin production and/ or utilisation
  • Defective lipid metabolism (T2DM is impaired substrate metabolism not just glucose)
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4
Q

Difference between T1DM and T2DM:

A
  • T1DM: pancreas cant produce insulin (usually starts early in life)
  • T2DM: primary cause in first instance is insulin resistance (usually later in life e.g., around 40-50yrs) – it can lead to beta cell exhaustion and lack of insulin production with progression
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5
Q

normal blood sugar levels

A

~5mmol

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6
Q

Fasting blood glucose levels for T2DM

A

~17mmol
- produce too much glucose due to gluconeogenesis. Using non carbohydrate precursors like glycerol from your adipose tissue, lactate and certain amino acids to create more glucose and is throwing it out into the circulation

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7
Q

How much glucose that enters the circulation after a meal is taken up by skeletal muscle?

A

90%

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8
Q

What does diabetes look like?

A
  • Higher fasting glucose and postprandial hyperglycaemia
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9
Q

HbA1c

A

A marker that tells you average glucose concentrations over the course of 3-4months (glycated haemoglobin is essentially CHOs attached to haemoglobin molecules. RBCs last for ~3months before they’re broken down, so it measures CHOs attached to RBCs).
Shows glucose control over a long period of time.

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10
Q

Excess mortality in people with T2DM (Tancredi et al 2015)

A
  • Overall, 15% higher risk of death in T2DM pts
    -Each 1% increase in glycated haemoglobin was associated with a 12% increase in mortality
    -Dose response: as glycaemic response gets worse, the risk of death increases (particularly stark in individuals who develop diabetes at a younger age).
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11
Q

Major complications of diabetes:

A
  • Diabetic retinopathy (leading cause of blindness)
  • Stroke (2-4 x inc risk)
    Diabetic nephropathy (leading cause of end-stage kidney disease)
    Diabetic Neuropathy (50% of T2DM pts get some form of somatic and autonomic)
  • 8/10 pts with diabetes die of CV events
  • Vascular disease is responsible for 60-65% of premature mortality associated with diabetes
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12
Q

Microvascular disease

A

small vessels in the eye (diabetic retinopathy), diabetic neuropathy (blood supply to the nervous system), diabetic nephropathy (explains the link to chronic kidney disease)
Maintaining very tight blood glucose levels can prevent these microvascular problems

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13
Q

Macrovascular disease

A

Strokes, coronary heart disease.
High levels of glucose damage your large blood vessels, which lead to things like atherosclerosis

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14
Q

How does hyperglycaemia cause vascular dysfunction?

A
  • Hyperglycemia → glucose / energy in endothelial cells (passive uptake)
  • ROS production → AGE products / PKC activation
    1) NfKb (inflammatory signalling)
    2) Growth factor signalling
    3) Endothelin (platelet aggregation) Vascular permeability → monocytes → foam cells → atherosclerosis Endothelial dysfunction → hypertension
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15
Q

Initiation of atherosclerosis

A

High levels of glucose passively get into the blood vessels, they go through the endothelium (the 1st single cell layer of blood vessel), they get into the middle layers of the blood vessels and cause metabolic toxicity – they kick of inflammatory signalling, trigger growth factor signalling, cause platelets to aggregate, and cause permeability in the endothelial layer. This results in monocytes escaping into the blood vessels, LDL cholesterol going in and the monocytes engulf the LDL resulting in foamy cells. This is the initiation of atherosclerosis.

There is also damage to the smooth muscle later with the vasculature – if the smooth muscle isn’t contracting and relaxing appropriately it can lead to problems e.g., poor blood pressure control

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16
Q

Pathophysiology of diabetes - gene X environment interaction

A

Increased (genetic) risk associated with developing diabetes: e.g., your propensity to develop insulin resistance, the ability of the pancreatic beta cells to produce more insulin to try and overcome that insulin resistance

17
Q

What are the 3 key organs associated with metabolism regulation?

A

skeletal muscle, adipose tissue, liver

18
Q

Gluconeogenesis defintion

A

The new formation of glucose from non-carbohydrate sources, amino acids, lactate, glycerol

19
Q

Tissue specific regulation of metabolism in the fasted state (Healthy)

A

The liver provides glucose, muscles can take up glucose, the adipose tissue is donating glycerol and this helps to maintain normal glucose levels

20
Q

Tissue specific regulation of metabolism in the fed/ insulin stimulated state (healthy)

A

In an insulin sensitive liver – insulin will stop the liver from producing glucose (shut down glycogenolysis and gluconeogenesis), in adipose tissue it should stimulate the uptake of glucose and the formation of triglyceride.
- Insulin has a storage effect (it is an anabolic hormone)
- In skeletal muscle it should foster the uptake of glucose either for use or for storage as muscle glycogen

21
Q

Tissue specific regulation of metabolism In insulin resistant pts

A
  • In the face of high insulin levels the liver is continuing to produce too much glucose
  • The adipose tissue is throwing out fatty acids and glycerol
  • Skeletal muscle cant take the glucose out the circulation
  • Explains exaggerated glucose excursions to a meal because the muscle cant respond to it
  • If adipose tissue is insulin resistant, you’ll have high levels of fatty acids circulating all the time- these FAs will get take up into the liver and contribute to excess fatty build-up in the liver, further increasing insulin resistance in the liver
22
Q

High risk – hyperinsulinemia – key characteristics:

A
  • First degree relatives of individuals with T2D
  • Initially with insulin resistance, the pancreas contributes more to release more insulin, and initially its successful – as the condition deteriorates, despite even more insulin release it becomes not enough and blood glucose begins to rise. Eventually the pancreas will give up and the insulin release will decrease/ flat line
  • Glucose homeostasis normal
  • Mild fasting hyperinsulinemia
  • Sometimes lean
23
Q

Pre-diabetic key characteristics

A
  • impaired glucose tolerance / glucose intolerant
  • hyperinsulinemia
  • often obese
  • impaired B-cell function
24
Q

How many years is suggested as the figure for which obesity can be reduced to regain beta cell function?

A

~6 years

25
Q

Primary care-led weight management for remission of type 2 diabetes (DiRECT); an open-label, cluster randomised trial (Lean et al 2018):

A

12 – 20-week total diet replacement (~850 kcal)
The more weight that was lost – the more diabetes went into remission
- 85% of ppts who lost 15kg put their diabetes into remission
- Mechanism: weight loss clears fat in the pancreas and liver which is important for glucose control. Fatty pancreas stops the beta cells producing insulin, because lipid is toxic to beta cells.

26
Q

Sedentary time and T2DM incidence (Patterson et al 2018)

A

1% and 9% increase in RR with every additional hour of total sedentary time and TV viewing (adjusted for physical activity)
Weak but positive association – as sedentary time goes up the risk of developing T2DM goes up. The risk for TV viewing is steeper (additional poor health behaviours e.g., snacking)

27
Q

Physical activity and T2DM incidence (Smith et al 2018)

A
  • Non-linear association (stronger for VPA & LTPA than total PA)
  • The risk of developing T2DM reduces as LTPA increases (dose response)
  • Meeting PA guidelines (11.25 h MET/h/wk) → 26% risk reduction in developing diabetes
  • Doubling PA guidelines (22.5 MET/h/wk) → 36% risk reduction
  • BMI partially attenuated effects – if you control for BMI the association is weaker but still persists
28
Q

Tissue specific mechanism by which exercise impacts T2DM (Kirwin et al 2017):

A

Adipose tissue: decrease inflammation and fat mass, increase insulin sensitivity.
Muscle: increase glucose uptake, glucose and FA oxidation and insulin sensitivity.
Liver: increase insulin sensitivity, decrease hepatic glucose production and triglyceride accumulation.
Circulatory system: decrease BP, blood glucose, HbA1c, serum triglycerides ad FFAs.
Pancreas: increase beta-cell mass, increase insulin and decrease glucagon

29
Q

Exercise and adipose tissue

A

Exercise improves adipose tissue insulin sensitivity – reduces the higher rate of flux of fatty acids and glycerol in the circulation and improves the inflammatory profile in adipose tissue.

30
Q

Exercise effects:

A
  • Rodents in an exercise intervention have been shown to improve their hepatic insulin sensitivity
  • You can improve the livers ability to oxidise fat which will reduce the ectopic fat liver build up in the liver.
  • People who are more active improve the health of their pancreatic beta cells
31
Q

Acute exercise:

A

contraction increases glucose uptake independent of insulin (insulin is supressed during exercise). When doing exercise you create vasculature within the muscle, promote the translocation of glucose transporters to enable glucose to come in through the cell membrane in the skeletal muscle, you improve oxidative phosphorylation. The net effect = muscle glucose uptake and glucose metabolism in muscle
- During exercise you have a beneficial impact on glucose metabolism
- For up to 48hr after exercise, insulin sensitivity is enhanced
Interaction between exercise training status and insulin sensitivity – when you do exercise/ are exercise trained, skeletal muscle becomes more insulin sensitive
- Glucose can get into the muscle, in response to exercise independent of the insulin pathway

32
Q

Insulin at rest:

A

insulin triggers glucose uptake but the effect is attenuated when insulin resistance is present
- For any given concentration of insulin, you get more glucose uptake in an insulin sensitive person (due to recruitment of the vasculature, GLUT4 metabolism within skeletal muscle and the expression of enzymes within muscle)

33
Q

Mechanisms by which exercise impacts glucose uptake:

A
  • Insulin binds to receptor on muscle cells. triggers a cascade of evets which lead to glucose transporters moving from the intracellular location to the plasma membrane to let glucose in.
  • exercise causes skeletal muscle contraction. Resulting in: mechanical stretch of muscle fibre, the generation of reactive oxygen species (due to increase in anaerobic metabolism), a decrease in energy charge in response to contracting skeletal muscle and the changes in ATP to ADP ratio, changes in calcium metabolism.
  • These pathways lead to GLUT4 transporters moving to plasma membrane to allow glucose uptake.
34
Q

The 5S’ identified in the 24hour physical behaviour’s for T2DM:

A

Sweating, Strengthening, Sleep, Stepping, Sitting

35
Q

Lecture summary:

A
  • T2DM is characterised by deranged glucose and lipid metabolism which leads to micro and macrovascular disease
  • Excess sedentary behaviour, physical inactivity and poor cardiorespiratory fitness increase the risk of T2DM incidence
  • ‘lifestyle interventions’ can prevent the transition to T2DM in those most at risk
  • RCTs and meta-analyses demonstrate that regular exercise can produce clinically relevant reduction sin HbA1c in people with T2DM
  • Equivocal evidence regarding whether exercise or lifestyle intervention can reduce mortality in patients with T2DM

Physiology (7 decks)

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