Week 2 Endocrine Lectures Flashcards
1
Q
What are the dietary lipids?
A
- Triglycerides
- Cholesterol - capable of making it yourself not required in the diet
- Phospholipids
2
Q
Where does lipid digestion take place?
A
In the small intestine
3
Q
What are the main enzymes involved in lipid digestion?
A
Pancreatic lipase and colipase
4
Q
What do pancreatic lipase and colipase do?
A
Bread down TAG into 2 fatty acids and MAG
5
Q
What are bile salts synthesized from?
A
Cholesterol
6
Q
Where are bile salts secreted from?
A
The liver through the bile duct
7
Q
What do bile salts do?
A
Emulsify fats to micelles
8
Q
What happens to TAG in intestinal cells?
A
Packaged with cholesterol, lipoproteins and other lipids to form chylomicrons
9
Q
What happens once TAG has been packaged into chylomicrons?
A
Released into the lymphatic system by exocytosis
10
Q
what are used to transport fatty acids in the blood?
A
Lipoproteins
11
Q
What is beta-oxidation of fatty acids?
A
Generation of energy from fatty acids
12
Q
What is required for fatty acids to cross the inner mitochondrial membrane?
A
Requires a carrier molecule - carnitine - derived from lysine and methionine
13
Q
What are the steps of beta oxidation?
A
- Fatty acids + acetyl CoA = Fatty acyl-CoA
- fatty acyl CoA are degraded by oxidation at the β carbon
- produces 1 FADH2 NADH and acetyl CoA (2 carbons) per turn
14
Q
How is ATP produced from beta oxidation?
A
Acetyl CoA can be further oxidised to yield ATP (TCA cycle/oxidative phosphorylation)
15
Q
How are triglycerides formed?
A
Esterification of 3 fatty acids and glycerol
16
Q
What is responsible for the breakdown of triglycerides?
A
Hormone sensitive lipase in adipose tissue
17
Q
What activates hormone sensitive lipase?
A
cAMP
18
Q
How are fatty acids synthesised?
A
2 carbons at a time
19
Q
What are the key regulatory enzymes in fatty acid synthesis?
A
- Acetyl CoA carboxylase
- Fatty acid synthase
20
Q
What does Acetyl CoA carboxylase do?
A
Forms malonyl CoA
21
Q
What is biotin?
A
A B vitamin involved in the formation of malonyl CoA in fatty acid synthesis
22
Q
What inhibits FA oxidation?
A
Malonyl CoA
23
Q
Why are ketone bodies formed?
A
It is an “overflow” pathway for acetyl CoA
24
Q
What are essential fatty acids?
A
Fatty acids that cannot be synthesised and are obtained from the diet
25
What are the functions of essential fatty acids?
- Cell membrane formation
- required for proper growth and development
- required for brain and nerve function
- precursors for eicosanoids - prostanoids & leukotrienes - inflammatory response
26
What are the key hormonal regulators of lipid metabolism?
Insulin and (nor) adrenaline
27
What does insulin do in regards to lipid metabolism?
- Stimulates FA synthesis and TAG synthesis
| - Suppresses lipolysis
28
What does (nor)adrenaline do in regards to lipid metabolism?
Stimulates lipolysis
29
What does noradrenaline stimulate?
- cAMP synthesis
- cAMP-dependent protein kinase (PKA) activation
- PKA-mediated phosphorylation and activation of HSL
30
What is diabetic ketoacidosis?
Metabolic acidosis (pH<7.3) with bicarbonate <15mmol/l
- Hyperglycaemia
- ketosis
Characterised by uncontrolled catabolism
31
What is the normal response to hyperglycaemia?
Increase in insulin
| Decrease in glucagon
32
What happens in the kidney in diabetic ketoacidosis?
- Osmotic diuresis
• Glucose (and ketones) freely filtered at glomerulus
• Maximal reabsorption threshold of glucose exceeded
• Increased solute concentration in tubular lumen causes osmotic gradient
• Increased water loss in urine
- Potassium
• Hyperaldosteronism exacerbates renal K+ loss
• Lack of insulin prevents K+ from moving into cells
• Plasma K+ levels may be elevated but total body K+ depleted
33
Why is there metabolic acidosis in diabetic ketoacidosis?
Increased production of acidic ketone bodies reduces the plasma pH
34
What is the treatment for diabetic ketoacidosis?
IV fluid, IV insulin, IV potassium
35
Why is insulin essential in diabetic ketoacidosis?
Essential for switching off ketogenesis and uncontrolled catabolism
36
What happens to the ECG in hypokalaemia?
- Depressed ST segment
- Biphasic T wave
- Prominent U wave
37
What happens to the ECG in hyperkalaemia?
- Long PR interval
- Prolonged QRS
- Tall T wave
38
What is HHS?
A complication of diabetes when a person is in a hyperglycaemic state which results in high osmolarity with no significant ketoacidosis
39
what is the differences in the length of the presenting complaints in DKA and HHS?
DKA comes on quickly HHS takes longer
40
Is HHS more common in type 1 or type 2 diabetes?
Type 2
41
Is DKA more common in type 1 or type 2 diabetes?
Type 1
42
What are the signs of DKA?
- Hyperglycaemia
- Dehydration
- Acidosis
- Patient usually alert
43
What are the signs of HHS?
- Profound hyperglycaemia
- Significant dehydration and hypernatremia
- no acidosis
- Patient often drowsy
44
What is the normal response to hypoglycaemia?
Decreased insulin
| Increased Glucagon
45
What are the counter regulatory hormones for hypoglycaemia?
increases in:
- Glucagon
- Adrenaline
- Noradrenaline
- Ach
- cortisol
- Growth hormone
46
What are the early symptoms of hypoglycaemia?
- Sweating
- Tremor
- Palpitations
- Hunger
- Anxiety
47
What are the later symptoms of hypoglycaemia?
These are neurological as the brain doesn't have sufficient energy
- Confusion
- Impaired conscious level
48
What is hypoglycaemia unawareness?
Associated with frequent episodes of hypoglycaemia the mechanism is not clear.
Can result in significant mortality rates and driving restrictions
49
How is mild hypoglycaemia treated?
15-20g of fast acting carbohydrate
50
How is severe hypoglycaemia treated?
- 15-20g of fast acting carbohydrate
| - If there is reduced conscious level then IM glucagon and/or IV dextrose
51
What are the acute complications of diabetes?
- Ketoacidosis
| - Hypoglycaemia
52
What are the two categories of chronic diabetes complication?
Microvascular and macrovascular
53
What are the microvascular complications of diabetes?
Retinopathy
Neuropathy
Nephropathy
54
What are the macrovascular complications of diabetes?
Ischaemic heart disease
Peripheral vascular disease
Cerebrovascular disease
55
What is the basal bolus regime for treating diabetes?
Take long acting insulin in the morning then a bit of insulin with every meal
56
What causes microvascular disease?
- capillary damage
| - Metabolic damage
57
How does capillary damage happen in microvascular disease? (in diabetes)
- Hyperglycaemia
- Increased blood flow
- Increased capillary pressure
- Thickened and damaged vessel walls
- Endothelial damage - leakage of albumin and other proteins
58
How does metabolic damage happen in microvascular disease? (in diabetes)
- Most tissues need insulin to take up glucose
• Retina/ kidney/ nerves don’t
- Glucose metabolised to sorbitol by aldose reductase
59
What happens when glucose concentration rises?
- Excessive glucose enters polyol pathway
- sorbitol accumulates
- Less NADPH is available
- Build up of ROS and oxidative stress
Cell damage
60
Why is microvascular disease less of an issue in T2DM?
Patients usually die of CV complications/disease first
61
What is the leading cause of impaired vision in 20-74?
Diabetic retinopathy
62
When will nearly all diabetic patients acquire some degree of retinopathy?
>20years of diabetes
63
What happens in the early stages (non-proliferative) of retinopathy?
```
- Hyperglycaemia
• Damage to small vessel wall
• Microaneurysms
- When vessel wall is breached
• Dot haemorrhages
- Protein and fluid left behind
• Hard exudates
- Micro-infarcts
• Cotton wool spots
```
64
What happens in the later stages of retinopathy?
```
- Damage to veins:
• Venous budding
• Blockage of blood supply
- Ischaemia VEGF and other growth factors
• Neovascularisation
• Proliferative retinopathy
• Vitreous haemorrhage
- Fluid not cleared from macular area
• Macular oedema
```
65
What happens in proliferative retinopathy?
New vessels form to try and bypass the haemorrhages
66
How can retinopathy be prevented?
- Good glycaemic control
- stop smoking
- Good blood pressure control
67
How can retinopathy be treated?
- Address risk factors
- Ophthalmic review
o laser
o VEGF inhibitors (bevacizumab)
o Vitrectomy
68
What are the stages of nephropathy?
- renal enlargement and hyperfiltration
- Microalbuminuria
- Macroalbuminuria
- End stage renal failure
69
What is Microalbuminuria?
Tiny traces of albumin that are too small to be detected on dipstick
70
What are the first steps in Nephropathy?
- Renal hypertrophy
- Increase in GFR
- Afferent arteriole vasodilates
71
What is the result of the afferent arteriole of the kidney vasodilating in nephropathy?
* glomerular pressure
* thickened GBM
* capillary damage
* shear stress on endothelial cells
- End result – leakage of protein into urine
72
What are the later stages of nephropathy?
- Progressive glomerulosclerosis
- Glomeruli destroyed
- Progressive proteinuria
- Renal failure
73
What can be done for nephropathy?
- Screen for microalbuminuria - every year from diagnosis
- ACE inhibitors / Angiotensin receptor blockers
- Improve glycaemic control
74
What do SGLT2 inhibitors do?
Inhibit the reabsorption of glucose in the PCT meaning the glucose can be peed out
75
What is diabetic neuropathy?
Reduced blood supply to the neural tissue results in impairments in nerve signalling that affect both sensory and motor function
76
How does glucose lead to inability to transmit signals through nerves?
- Metabolic changes - sorbitol accumulation
- Vascular changes - capillary damage
- Structural changes
77
What are the symptoms of diabetic neuropathy?
- Numbness or loss of feeling (asleep or bunched up sock under toes)
- Prickling or tingling
- Burning pain
- Lancinating pain
- Unusual sensitivity or tenderness when feet are touched
78
What are the signs of diabetic neuropathy?
- Diminished vibratory perception
- Decreased knee and ankle reflexes
- Reduced protective sensation such as pressure, hot and cold, pain
- Diminished ability to sense position of toes and feet
79
What is the diabetic foot?
A combinations of neuropathy and peripheral vascular disease
80
What are the NICE classifications for diabetic foot?
- low risk - Normal sensation and pulses - annual review
- Medium risk - Neuropathy or absent pulses - review by podiatrist every 3-6/12 months
- High risk - Deformities or ulceration - review by podiatrist every 1-3 months
81
What is Charcot foot?
- Numb foot - Repetitive microtrauma - stress fractures
| - Dysregulated blood flow - Increased bone turnover - fragile bone
82
What are the effects of autonomic neuropathy?
- CV - Postural hypotension
- GU - Erectile dysfunction
- GI - Gustatory sweating and gastroparesis
83
What is diabetic amyotrophy?
Painful proximal neuropathy usually in the thigh/ buttock
84
What reduces the risk of all complications diabetes?
Good glycaemic control
85
What is the definition of diabetes mellitus?
a metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism, resulting from defects in insulin secretion, insulin action, or both.
86
What percentage of women with gestational diabetes will develop T2DM?
50%
87
What are the greatest triggers for T2DM?
Weight gain and genetic predisposition?
88
What is the significance of insulin resistance in T2DM?
- May be the best predictor of T2DM
- Gets worse as patients get older and heavier
- Can be present for years before the onset of T2DM
- Hyperinsulinemia can be found often in prediabetes and early stages
89
What does leptin do?
| T2DM
Tells the hypothalamus about the amount of stored fat
90
What does adiponectin do?
| T2DM
reduces levels of free fatty acids
91
What does TNFa(alpha) do?
Insulin receptor signalling interference
92
What does resistin do?
Enhances hypothalamic stimulation of glucose production
93
What happens when there is mutations to the insulin receptor gene?
Severe hyperinsulinemia, associated with acanthosis nigricans and hyperandrogenism
94
What is acanthosis nigricans?
a skin condition characterized by areas of dark, velvety discoloration in body folds and creases. The affected skin can become thickened.
95
What drug affects glucose absorption?
Acarbose
96
What drugs decrease glucose uptake?
Metformin
Pioglitazone
Conc. Insulin
Insulin/GLP 1 combinations
97
What drug decreases glucose reabsorption?
SGLT2 inhibitors
98
What drugs are used to treat impaired insulin secretion?
```
Insulin
Sulphonylureas
Meglitinides
GLP-1 receptor agonists
DPP-4 inhibitors
```
99
What drugs are used to treat increased glucose production?
Metformin
GLP-1 receptor agonists
DPP-4 inhibitors
Insulin
100
What are the effects of GLP-1 on the body?
1. Beta cells -Enhances glucose dependent secretion in the pancreas
2. Alpha cells - supresses postprandial glucagon secretion
3. Liver- Reduces hepatic glucose output
4. Stomach - Slows the rate of gastric emptying
5. Brain - Promotes satiety and reduces appetite
101
In normal renal glucose handling, how much glucose is reabsorbed by SGLT2?
90%
