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Phase 2- Endocrine > Week 2 > Flashcards

Week 2 Flashcards

1
Q

What is diabetic ketoacidosis?

A

Defined as metabolic acidosis (pH <7.3) (bicarbonate <15 mmol/l) with hyperglycaemia (>13.9 mol/l) and ketosis (++)

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2
Q

What happens in DKA at the kidney?

A

Glucose (and ketones) are freely filtered at glomerulus.
Maximal reabsorption threshold of glucose exceeded.
Increased solute concentration in tubular lumen causes osmotic gradient.
Increased water loss in urine

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3
Q

How does [K+] change in DKA?

A

Hypoaldosteronism exacerbates renal K+ loss. Lack of insulin prevents K+ from moving into cells. Plasma K+ levels may be elevated but total body K+ depleted

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4
Q

How does insulin deficiency lead to DKA?

A

Insulin deficiency promotes lipolysis, which leads ketone production, and proteolysis which results in increased gluconeogenesis, increasing serum glucose concentration. Furthermore, insulin deficiency blocks glucose uptake in peripheral tissues, also leading to increased serum glucose

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5
Q

What counter-regulatory hormones are activated in DKA?

A

Adrenaline, cortisol and growth hormone

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6
Q

What do the counter-regulatory hormones stimulate?

A

Adrenaline: glycogenolysis, gluconeogenesis and lipolysis
Cortisol: gluconeogenesis, lipolysis and inhibition of peripheral glucose uptake.
Growth hormone: same as cortisol

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7
Q

What is required for treatment of DKA?

A

IV fluid (treats hypovolaemia), IV insulin (treats insulin deficiency) and IV potassium (hypokalaemia)

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8
Q

What is there risk of in hyperosmolar hyperglycaemic state?

A

Risk of central pontine mylinolysis and cerebral oedema due to large fluid shifts

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9
Q

What is hyperosmolar hyperglycaemic state?

A

A state of high blood sugar without significant ketoacidosis

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10
Q

What is hyperosmolar hyperglycaemic state?

A

A state of high blood sugar without significant ketoacidosis, caused by a relative (rather than absolute) insulin deficiency

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11
Q

How do ketones cause metabolic acidosis?

A

Increased production of acidic ketone bodies reduced plasma pH. Increased renal excretion of H+ initially, loss of bicarbonate ions. Increased respiratory rate (later kussmal breathing) and impaired renal compensation with persistent/worsening acidosis and renal hypoperufsion

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12
Q

Why is IV insulin essential in DKA?

A

It switches off ketogenesis and uncontrolled catabolism; blood sugar may return to normal quickly with IV insulin

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13
Q

Describe potassium in DKA?

A

Admission potassium may be high, normal or low. Total body potassium, will require supplementation. Insulin therapy causes intracellular shift of potassium. Potassium requires regular and close monitoring. Cardiac monitoring required.

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14
Q

How does osmotic diuresis differ in HHS than DKA?

A

Chronic renal impairment is common, and there is a reduced capacity to excrete glucose. In HHS it has a longer, more insidious onset and a more profound hypovolaemia. Impaired thirst leads to lack of water replacement

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15
Q

How is HHS treated?

A

IV fluid, insulin and potassium. Plasma glucose will fall with fluid alone, and insulin is started when plasma glucose is stable. Target blood glucose 10-15 mmol/l is acceptable. Less aggressive potassium replacement required, due to less pronounced potassium shift than in DKA

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16
Q

What is the supportive treatment for HHS?

A

Patients can often be hypercoagulable and venous thrombosis is common.

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17
Q

What is the supportive treatment for HHS?

A

Patients can often be hypercoagulable and venous thrombosis is common. HHS is often precipitated or complicated by other pathologies

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18
Q

What are the major clinical differences between DKA and HHS?

A

DKA patients are usually T1DM and <65y, whereas HHS patients are usually >65y and T2DM. There is no residual insulin in DKA, but there is some in HHS. Dehydration in DKA but significant dehydration and hypernatraemia in HHS. No acidosis in HHS.

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19
Q

What is the normal response to hypoglycaemia?

A

Insulin secretion decreases, and counter regulatory mechanisms are activated: increased glucagon, adrenaline, noradrenaline, acetylcholine, cortisol and growth hormone

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20
Q

What are the initial symptoms of hypoglycaemia?

A

Initial symptoms are autonomic: sweating, tremor, palpitations, hunger and anxiety

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21
Q

What re the late symptoms of hypoglycaemia?

A

Late symptoms are neuroglycopaenic (not enough glucose in the brain): confusion and impaired conscious level

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22
Q

What is hypoglycaemia unawareness associated with?

A

Frequent episodes of hypoglycaemia (mechanisms unclear, altered sensing of hypoglycaemia in CNS)

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23
Q

How is mild hypoglycaemia (BM <4 mmol/l) treated?

A

15-20g of fast acting carbohydrate. Retests after 15-20 mins- longer acting carbohydrate may prevent further drop in blood sugar

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24
Q

How is severe hypoglycaemia treated?

A

15-20g of fast acting carbohydrate, and, if reduced conscious level, intramuscular glucagon and IV dextrose if IV access possible

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25
Q

What may be the best predictor of type 2 diabetes?

A

Insulin resistance

26
Q

Is there a genetic component of T2DM?

A

Yes- 39% of people with T2DM have one parent with the disease, lifetime risk of someone with a first degree relative with T2DM is 5-10 times higher than age/sex/weight matched. Some ethnic groups have greater susceptibility

27
Q

What does leptin do?

A

Tells hypothalamus about amount of stored fat

28
Q

What does adiponectin do?

A

Redeces levels of free fatty acids

29
Q

What does resistin do?

A

Enhances hypothalamic stimulation of glucose production

30
Q

What genetic conditions predispose individuals to T2DM?

A

Insulin receptor gene mutations: severe hyperinsulinaemia, associated with acanthuses nigircans and hyperandrogenism

31
Q

How is insulin secretion impaired?

A

Glucotoxicity can lead to impaired beta cell function, glucokinase defects impair insulin secretion, and pancreatic beta cell transcription factor mutation: reduced insulin production in response to glucose

32
Q

What are the effects of GLP-1 in humans?

A
  1. Beta cell: enhances glucose-dependent insulin secretion in the pancreas
  2. Alpha cell: suppresses postprandial glucagon secretion
  3. Liver: reduces hepatic glucose output
  4. Stomach: slows the rate of gastric emptying
  5. Brain: promotes satiety and reduces appetite
33
Q

What are the primary sources of dietary lipids?

A

Triglycerides, cholesterol and phospholipids

34
Q

Where does lipid digestion occur?

A

Small intestine

35
Q

What enzymes digest lipids?

A

Pancreatic lipase and colipase. Enzymes also require bile salts (synthesised from cholesterol, secreted by liver through bile duct and emulsify fats to micelles)

36
Q

How are lipids absorbed?

A

Triglycerides (TAG) are re-formed in the intestinal cell- packaged with cholesterol, lipoproteins a other lipids to form chylomicrons. Chylomicrons are released into the lymphatic system by exocytosis

37
Q

What happens to the chylomicron during transport?

A

Lipoprotein lipase takes up fatty acids into adipose tissue from the chylomicron, leaving a chylomicron remnant travelling to the liver

38
Q

How are fats stored in the plasma?

A

Plasma TAG (lipoproteins (VLDL) and FFA (albumin-bound)

39
Q

What can fats be metabolised in cells?

A

Ketone bodies, beta-oxidation and phospholipid synthesis

40
Q

What is beta oxidation?

A

Generation of energy from fatty acids. Fatty acids first added to acetyl CoA to form fatty acyl-CoA

41
Q

What is beta oxidation?

A

Generation of energy from fatty acids. Fatty acids first added to CoA to form fatty acyl-CoA, within the mitochondrion. Fatty acyl CoA are degraded by oxidation at the beta-carbon. This occurs in rounds reducing size of fatty acyl chain by 2 carbons each time- producing 1 FADH2, NADH and acetyl CoA (2 carbons per turn), ends up with final acetyl CoA

42
Q

What must fatty acyl-CoA cross?

A

Inner mitochondrial membrane; requires carrier molecule, carnitine (derived form lysine and methionine, high in muscle)

43
Q

How is ATP produced by beta oxidation?

A

Acetyl CoA can be further oxidised to yield ATP (TCA cycle/oxidative phosphorylation). For instance, the ATP yield of palmitate (C16) is 106 ATP- fatty acids are an excellent source of ATP

44
Q

How are TAG synthesised?

A

Esterification of 3 fatty acids and glycerol:
- lipoprotein lipase (LPL) hydrolyses TAG in chylomicrons/VLDL
- diacylglycerol acyl transferase (DGAT) re-esterifies to TAG
Glycerol is obtained from glycolysis

45
Q

How does lipolysis occur?

A

Breakdown of the TAG into glycerol + 3 FAs. Hormone sensitive lipase in adipose tissue. Hormone-sensitive lipase is activated by cAMP-dependent phosphorylation in response to adrenaline in fasted state, inhibited by insulin. Glycerol is transported to the liver for gluconeogenesis

46
Q

How are fatty acids synthesised?

A

Fatty acids are built 2 carbons at a time (limit is 16 carbons). Key regulatory enzymes are acetyl CoA carboxylase (forms maolnyl CoA) and fatty acid synthase (see lecture slides for diagram) Requires NADPH and occurs in cytoplasm

47
Q

What does biotin deficiency cause?

A

Dysfunction of lipid metabolism (biotin required by acetyl CoA carboxylase)

48
Q

What does maolnyl CoA inhibit?

A

Fatty acid transport into the cell via carnitine PT

49
Q

How are ketone bodies formed?

A

Acetyl CoA + acetyl CoA = acetoacetyl CoA
Acetoacetyl CoA - CoA = acetoaceate.

Acetoaceate can be converted to acetone and beta-hydroxybutyrate

50
Q

What are the functions of essential fatty acids?

A

Cell membrane formation, required for proper growth and development, as well as for brain and nerve function. Precursors for eicosanoids, prostanoids and leukotrienes - inflammatory response

51
Q

What does insulin stimulate in lipid metabolism?

A

GLUT4-mediated transport of glucose. ACC activity, increases expression of FAS and increases activity of LPL (in adipose)

52
Q

How does insulin inhibit lipolysis?

A

Insulin stimulated breakdown of cAMP, therefore (nor)adrenaline no longer able to stimulate lipolysis

53
Q

How does insulin inhibit lipolysis?

A

Insulin stimulated breakdown of cAMP, therefore (nor)adrenaline no longer able to stimulate lipolysis

54
Q

How does chronic hyperglycaemia lead to capillary damage?

A

Increased blood flow, causing increased capillary pressure. Thickened and damaged vessel walls, and endothelial damage (leakage of albumin and other proteins)

55
Q

What happens if [glucose] rises intracellularly?

A

Excessive glucose enters polio pathway:

  • sorbitol accumulates
  • less NADPH available for cell metabolism
  • build up of ROS and oxidative stress
  • cell damage
56
Q

What are the early stages of retinopathy?

A

Hyperglycaemia leads to damage to small vessel wall, and micro-aneurysms. When vessel wall is breached, dot haemorrhages appear. Protein and fluid is left behind forming hard exudates. Micro-infarcts- cotton wool spots

57
Q

What happens in the later stages of retinopathy?

A

Damage to veins; venous budding, blockage of blood supply. Ischaemia caused by VEGF and other growth factors: neovascularisation, proliferative retinopathy and vitreous haemorrhage. Fluid is not cleared from macular area- macular oedema

58
Q

What are the stages if diabetic nephropathy?

A

Renal enlargement and hyperfiltration, leading to microalbuminuria, leading to macroalbuminuria, leading to end stage kidney disease

59
Q

What is the early pathophysiology of nephropathy?

A

Renal hypertrophy, increase in GFR. Afferent arteriole vasodilates; glomerular pressure, thickened GMB, capillary damage, shear stress on endothelial cells. End result- leakage of protein into urine

60
Q

How does diabetic neuropathy occur?

A

Capillary damage leads to reduced blood supply to neural tissue, resulting in impairments in nerve signalling that affects both sensory and motor function. Glucose leads to inability to transmit signals through nerves; metabolic changes: sorbitol accumulation, vascular changes: capillary damage, structural changes

61
Q

What is charcot foot?

A

Numb foot, repetitive micro-trauma and stress fractures. Dysregulated blood flow: increased bone turnover, fragile bone

62
Q

What are the autonomic neuropathy complications?

A

Cardiovascular- postural hypotension
GU- erectile dysfunction
GI- gustatory sweating, gastroparesis

Phase 2- Endocrine (4 decks)

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