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PBL SEM 4 > glucose and insulin physiology > Flashcards

glucose and insulin physiology Flashcards

1
Q

what are normal glucose levels?

A

4-6mmol/L

8mmol/L post-prandial (2 horus after eating)

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2
Q

what cannot substitute glucose, hence making delivery critical?

A

CNS

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3
Q

how much glucose is lost from the kidneys a day?

A

<0.3g/day

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4
Q

what secretes glucagon?

A

alpha cells of Islets of Langerhans

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5
Q

what is insulin secreted from?

A

beta cells in the Islets of langerhans in the endocrine pancreas

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6
Q

what does insulin do to blood glucose levels and what is it secreted in response to?

A
  • lowers glucose levels
  • secreted in response to a glucose load
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7
Q

what are the insulin/glucagon sensitive tissues?

A

liver, muscle, fat (adipocytes)

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8
Q

what does glucagon serve to do?

A

increase glucose levels — it is secreted in response to low glucose levels

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9
Q

when is insulin production switched off and by what?

A

at low levels of glucose by glucagon

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10
Q

the fasted state triggers the release of what?

A

glucagon from alpha cells

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11
Q

what does glucagon do?

A

acts on the liver to stimulate endogenous glucose production from its glycogen stores

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12
Q

what does relatively raised blood glucose levels stimulate?

A

beta cells to secrete insulin — switches off glucagon secretion

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13
Q

what else does insulin do apart from decreasing glucagon secretion?

A
  • acts on insulin sensitive tissues to increase their uptake of glucose (thus lowering it from the bloodstream)
  • acts on liver to switch off endogenous glucose production from glycogen
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14
Q

when we eat, enteroendocrine cells in SI and LI are stimulated to produce hormes, mainly what?

A

GLP-1

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15
Q

what is GLP-1 secreted in response to?

A

glucose and other nutrient load such as amino acids

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16
Q

what does GLP-1 do?

A

serves to stimulate insulin secretion — there are GLP-1 receptors throughout the cells in the body, but in particular on beta cells

GLP-1 is a good treatment for diabetes - there are GLP-1 receptor agonists.

GLP-1 also promotes satiety (feeling full). also used for obesity treatment.

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17
Q

T1DM vs T2DM

A

T1DM = autoimmune destruction of B cells
T2DM = defects in insulin release, sensing and/or signalling

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18
Q

what can cause hyperglycaemia?

A
  • impaired insulin secretion — due to loss of beta cells (eg. autoimmune (T1D), chronic pancreatitis etc)
  • impaired insulin action — due to decreased insulin sensitivity (can occur i T2D)
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19
Q

what does impaired section and action of insulin result in?

A

increase in endogenous glucose production
- mainly because of lack of insulin switching it off
- also because glucagon is inappropriately secreted

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20
Q

what is neonatal diabetes?

A

when babies are born with few or no beta cells due to a genetic mutation

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21
Q

hypoglycaemia in diabetics?

A

average of 2 episodes of symptomatic hypoglycaemia per week. on average of one episode of severe, at least temporarily disabling, hypoglycaemia, often with seizure or coma, per year

hypoglycaemia unawareness

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22
Q

what is what are the main transporters in glucose homeostasis?

A

passive glucose transporters (GLUTs) and sodium coupled/linked transporters (SGLTs)

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23
Q

describe GLUTs

A

passive — glucose binds to protein, changes its shape, allowing glucose to enter

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24
Q

describe SGLTs

A

Na+ used to drive glucose across membrane down a Na+ gradient

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25
Q

whcih glcusoe transporters are used on the apical and basolateral membranes, rather than just apical?

A

GLUTs

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26
Q

where are SGLT1 and 2 mainly found?

A
  • SGLT1 — mainly located on cells in GIT, with some expression in kidney
  • SGLT2 — mainly in PCT of kidney
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27
Q

what SGLT is a uniporter?

A

SGLT2 = 2 Na+ for every glucose molecule

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28
Q

what is Km?

A

Km = conc of glucose that causes saturation of transporter

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29
Q

SGLT2 vs SGLT1 Km

A

SGLT2 = Km 5mM — higher affinity
SGLT1 = Km 2mM — lower affinity

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30
Q

are SGLTs insulin sensitive or insensitive?

A

insensitive — don’t require insulin — use a high Na+ conc grad outside to facilitate glucose movement

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31
Q

what solute carrier genes encode SGLT1 + 2

A

SGLT1 = SLC5A1
SGLT2 = SLC5A2

32
Q

describe SGLT2 inhibitors

A
  • approved for mono and combination therapy of T2DM
  • prevent reabsorption of glucose within the kidneys — pass out excess glucose in urine
  • lowers blood glucose levels
33
Q

what do mutations in SLC5A1 cause?

A

glucose-galactose malabsorption

34
Q

what do mutations in SLC5A2 cause?

A

familial glucosuria

35
Q

which GLUT transporters are insulin sensitive/insensitive?

A

GLUT1 and GLUT2 are insulin insensitive
GLUT4 is insulin sensitive

36
Q

how many GLUT transporters are there?

A

13

37
Q

what are GLUT1 + 2 critical for?

A

glucose absorption (GIT, renal, hepatic) and glucose signalling (islet cells, CNS)

38
Q

what is GLUT4 used for?

A

drives insulin-induced glucose uptake — lowers blood glucose levels

39
Q

where are GLUT1/2/4 located?

A

1 = brain
2 = kidney, liver, pancreas
4 = adipose tissues, striated muscle, heart

40
Q

Km of GLUT1/2/4

A

GLUT4 and 1 have similar Km for glucose approx 5) which is lower than GLUT2 (17mM)

41
Q

how much glucose is excreted through kidneys?

A

<0.5g/day

42
Q

what GLUTs are located in pancreas?

A

GLUT1 + 2

43
Q

what GLUTs are located in kidney?

A

2 and 9

44
Q

what GLUTs are located in fat?

A

4

45
Q

what GLUTs are located in gut?

A

2 and 5

46
Q

what GLUTs are located in brain?

A

1,2,3,4

47
Q

what GLUTs are located in liver?

A

2

48
Q

what is vectorial transport?

A

transport of molecules in only one direction

49
Q

what is used to bring glucose across membrane form apical side into enterocyte?

A

SGLT1

50
Q

via what does glucose leave the enterocyte on the basolateral side?

A

GLUT2

51
Q

glucose is taken up into RBCs via what?

A

GLUT1

52
Q

proximal convoluted tubule — desire glucose absorption

A

PCT divided into early and late

  • over 90% of glucose in early is absorbed by SGLT2
  • late — almost all remaining glucose by SGLT1
53
Q

in the PCT, glucose is transported across the basolateral membrane by what?

A

GLUT2 and GLUT1

54
Q

under healthy conditions, what % of filtered glucose is absorbed?

A

> 99%

55
Q

how is renal absorption in diabetes affected?

A
  • the absorptive capacity of glucose transporters is overwhelmed
  • lots passed out in urine = glycosuria
  • presence of glucose in urine results in large volumes of urine being produced (due to osmosis) — therefore one of the 1st symptoms is increased urinary frequency and polyuria
56
Q

what are SGLT2 inhibitors?

A
  • treatment for diabetes
  • promote glucose loss by preventing the reabsorption of glucose in the early PCT — glucose levels drop
  • SE of these drugs is increased frequency and polyuria
57
Q

what is the main glucose transproter in beta cell?

A

GLUT1 (GLUT2 also present)

58
Q

describe glucose-induced insulin release

A
  • glucose metabolism leads to the generation of signalling molecules like ATP
  • ATP stimulates closure of K+ channel in the cell
  • depolarisation of beta cell
  • Na+ influx and Ca++ influx
  • Ca++ influx leads to signalling cascades
  • exocytosis of insulin
  • insulin released
59
Q

describe K+ channel inhibitors

A
  • used in diabetes
  • stimulate endogenous insulin release
  • cause K+ channel closure —> persistent depolarisation
  • persistent Ca++ channel opening
  • insulin release
60
Q

how does GLP-1 work?

A
  1. activate GLP-1 receptor
  2. G protein stimulation
  3. stimulation of adenylate cyclase
  4. elevation of cAMP
  5. activation of PKA (protein kinase A) and Epac2 = involved in exocytosis —> insulin release
61
Q

where is GLP-1 produced and what is it secreted in response to?

A

produced in endocrine cells in SI and LI. secreted in response to nutrient load in GIT

62
Q

what do GLP-1 receptor agonists do?

A

stimulate endogenous insulin release

63
Q

what does insulin stimulate?

A
  • glycolysis
  • glycogen synthesis
  • glucose uptake
  • lipogenesis
  • protein synthesis
  • gene expression
  • DNA synthesis
  • amino acid uptake
  • NaK ATPase
64
Q

what does insulin inhibit?

A
  • gluconeogenesis
  • lipolysis
  • apoptosis
  • autophagy
65
Q

what are highly sensitive insulin tissues?

A

liver, skeletal muscle, adipocytes

66
Q

what happens to GLUT4 in the absence of insulin?

A

sequestered in intracellular vesicles

67
Q

what happens to GLUT4 when insulin binds to its receptor?

A

when insulin binds to its receptor, the components of the GLUT4 transporter can be assembled and are transported to the cell membrane to increase the number of transporters on the CM that are available for glucose uptake, therefore increasing the efficiency of glucose uptake in the presence of insulin

68
Q

how does insulin increase glucose uptake?

A

by facilitating GLUT4 expression in the cell membrane — ultimately lowers blood glucose levels

  1. insulin binds to its receptor
  2. tyrosine kinase activation
  3. signalling molecules
  4. translocated GLUT4 transproters from intracellular vesicles — inserted into plasma membrane — increases efficacy of glucose uptake in insulin-sensitive tissues eg. liver, skeletal msucle, fat
  5. glucose uptake
69
Q

why does the insulin receptor itself become activated when insulin binds?

A

because it contains an intrinsic tyrosine kinase component

70
Q

what is the most widely used drug in T2D and how does it work?

A

= metformin
- enhances sensitivity to insulin by targeting intracellular signalling pathways
- so cells more sensitive to insulin

71
Q

insulin is also a _____ hormone

A

growth — one of the reasons for weight gain

72
Q

what are the effects of defects in insulin-sensing on gluconeogenesis and lipolysis?

A

brake removed — no longer inhibited

73
Q

in which diabetes are there defects in insulin release, sensing and/or signalling?

A

2

74
Q

what are the effects of decreased insulin on glucose production and peripheral glucose uptake? what does this lead to?

A
  • increased glucose production
  • decreased peripheral glucose uptake

leads to HYPERGLYCAEMIA

75
Q

short term effects of hyperglycaemia

A

saturated SGLT system in kidney —> glucosuria leading to dehydration, polypdipsia, osmotic diuresis —> ketoacidosis

76
Q

what cells are more sensitive to toxicity of excess glucose that others?

A

capillary endothelial cells, mesangial cells, neurons and Schwann cells in peripheral nerve

77
Q

what are the effects of hyperglycaemia on glucose production in the liver, lipolysis in adipocytes and glucose uptake in muscle?

A
  • increased glucose production (gluconeogenesis)
  • increased lipolysis
  • decreased glucose uptake

PBL SEM 4 (50 decks)

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