Biochemistry of Insulin Flashcards

1
Q

how you insulin kill you

A

go into hypoglycemic coma

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2
Q

what makes insulin

A

beta cells in the pancreas, islets of langerhans

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3
Q

what do alpha cells make

A

glucagon

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4
Q

what do gamma cells make

A

somatostatin

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5
Q

what do PP cells in the pancreatic islets make

A

pancreatic polypeptide

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6
Q

what is the counter hormone (starvation hormone) to insulin

A

glucagon

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7
Q

where in beta cells is insulin synthesised

A

rough endoplasmic reticulum

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8
Q

describe the process of insulin synthesis

A

starts as larger single chain preprophormone (preproinsulin)
cleaved to form insulin

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9
Q

what is the structure of insulin

A

two polypeptide chains linked by disulfide bonds

connecting C peptide (a byproduct of cleavage)

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10
Q

what preparation of insulin is ultrafast/ultra short acting

A

insulin lispro

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11
Q

what affected how long insulin lasts

A

position of amino acids- affects how stable it is

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12
Q

what is the most rapidly acting insulin

A

insulin lispro

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13
Q

how is insulin lispro used clinically

A

Injected within 15 minutes of beginning a meal

short duration of action- must be used in combination with longer-acting preparation for Type 1 diabetes unless used for continuous infusion

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14
Q

describe the structure of insulin lispro

A

monomeric, not antigenic

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15
Q

what prep of insulin is ultra long lasting

A

glargine

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16
Q

when is glargine administered

A

single bedtime dose

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17
Q

describe the action of glargine

A

Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue

Peakless- prolonged action

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18
Q

how does glucose enter beta cells

A

GLUT2 glucose transporter (goes down concentration gradient)

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19
Q

what happens to glucose once it enters beta cells

A

phosphorylated by glucokinase

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20
Q

what senses the amount of glucose that enters a beta cell

A

glucokinase

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21
Q

what does increased metabolism of glucose lead to

A

an increase in intracellular ATP concentration

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22
Q

lists the steps of carb metabolism

A

glucose-6-P

glycolysis (also makes e- and CO2)

acetyl- CoA

TCA cycle

(e- go to oxidative phosphorylation)

=
36 ATP per glucose

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23
Q

what does ATP do in beta cells

A

inhibits the ATP sensitive K+ channel KATP- causes depolarisation of the cell membrane

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24
Q

what happens when the cell membrane of beta cells depolarises

A

voltage gates Ca2+ channels open - increase in Ca2+ conc leads to fusion of secretory vesicles within the cell membrane that release insulin

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25
Q

what blood glucose level should cause insulin to be released

A

> 5 mM

26
Q

how does the secretion of insulin related to the tyeps of diabetes

A

type 1 loss of beta cells

other types beta cells lose the ability to sense changes in glucose (due to hyperglycaemia takin glucose conc outwith the Km of glucokinase)

27
Q

describe the flow of the release of insulin

A

is biphasic-
as only 5% ready for immediate release (first phase)
reserve pool must become mobilised to be released in the second phase

28
Q

what happens to the biphasic release of insulin in poorly controlled T2DM- why

A

becomes flattened

- down regulation of the sensing process

29
Q

what drug can mimic the action of ATP to depolarise beta cells (and cause release of insulin) by inhibiting KATP

A

sulphonylurea (SURs)

30
Q

what two proteins make up the KATP channels

A

Kir6- inward rectifier subunit (pore)

SUR1- sulphonylurea receptor (regulatory subunit)

31
Q

what stimulates KATP (inhibits the secretion of insulin)

A

diazoxide

32
Q

when are SURs used

A

for patients who cant inject insulin (second line therapy as makes beta cells work very hard) or patients who have improved their glucose control

33
Q

what can mutations in Kir6.2 and SUR1 cause

A

Kir6.2- neonatal diabetes (constantly active KATP channels)

Kir6.2 or SUR1 mutations- congenital hyperinsulinism

34
Q

what is MODY

A

maturity onset diabetes of the young (familial form of type 2 diabetes)

monogenic diabetes with genetic defect in beta cell function

35
Q

what happens to glucokinase in MODY2

A

glucokinase activity impaired

glucose sensing defect- threshold for insulin release increased

36
Q

what are the roles of HNF transcription factors

A

play key roles in pancreas foetal development and neogenesis

regulate beta cell differentiation and function

37
Q

what is the important of genetic screening to differentiate MODY from type 1 diabetes

A

allows treatment of MODY with sulphonylurea rather than insulin as MODY patients have some beta function available

38
Q

name the diabetes:

loss of insulin secreting beta cells

A

type 1

39
Q

name the diabetes:

defective glucose sensing in the pancreas and/ or loss of insulin secretion

A

MODY

40
Q

name the diabetes:

intially hyperglycemia with hyperinsulinemia so primary problem is reduced insulin sensitivity in tissues

A

type 2 diabetes

41
Q

what does insulin ‘turn on’

A
amino acid uptake in muscle 
DNA synthesis 
protein synthesis 
growth responses 
glucose uptake in muscle and adipose tissue 
lipogenesis in adipose and liver cells 
glycogen synthesis in liver and muscle
42
Q

what does insulin ‘turn off’

A

lipolysis

gluconeogenesis in liver

43
Q

what receptor does insulin bind to

A

receptor tyrosine kinases

44
Q

what happens when insulin binds to the alpha subunits of tyrosine kinases

A

beta subunits dimerise and phosphorylate themselves (autophosphorylation)

e.g. activate the catalytic activity of the receptor

45
Q

what does insulin prevent

A

hyperglycemia

46
Q

what causes insulin resistance

A

reduced insulin sensing and/ or signalling
associated with obesity and complete lack of adipose tissue
can occure in monogenic diabetes due to mutation

47
Q

why is type 2 diabetes polygenic

A

as has input from environmental causes

48
Q

what is leprechaunism - donohue syndrome

A

autosomal recessive mutation in the gene for the insulin receptor

  • severe insulin resistance
  • developmental abnormalities (elfin facial appearance, short stature, absence of fat and muscle mass)
49
Q

what causes leprechaunism

A

defects in insulin binding or insulin receptor signalling

50
Q

what rabson mendenhall syndrome

A

autosomal recessive trait
severe insulin resistance, hyperglycemia and compensatory hyperinsulinemia
-developmental abnormalities
-acanthosis nigricans (hyperpigmentation)
-fasting hypoglycaemia
-diabetic ketoacidosis

51
Q

what are the symptoms of diabetic ketoacidosis

A

vomiting, dehydration, increased heart rate, acetone smell on breath

52
Q

where and how are ketone bodies formed

A

in liver mitochondrian
derived from acetyl-CoA
beta oxidation of fatty acids yields acetyl-CoA which enters TCA cycle (when fat and carb degeneration balanced)
if no oxaloacetate (e.g. due to no glycolysis) then acetyl CoA diverted to ketones

53
Q

what is the role of ketone bodies

A

diffuse into the blood stream and to peripheral tissues
important molecule of energy metabolism for heart muscle and renal cortex
emergency energy supply for brain during fasting

54
Q

what prevents ketone body overload

A

low levels of insulin inhibit lipolysis

55
Q

when is DKA at risk in T1DM

A

if insulin supplementation is missed

56
Q

when is DKA at risk in T2DM

A

rarer- can happen as insulin resistance and deficiency increases- alongside increase in glucagon

57
Q

how does DKA happen

A

Oxaloacetate is consumed for gluconeogenesis

When glucose is not available-fatty acids are oxidised to provide energy

Excess acetyl-CoA is converted to ketone bodies

Accumulation of ketone bodies can lead to acidosis

High glucose excretion causes dehydration, exacerbates acidosis
Coma, death

58
Q

what do ketone bodies do to the pH of the blood

A

decrease it

59
Q

when is ketosis seen

A

in glucose limiting conditions

60
Q

how do you treat DKA

A

insulin and rehydration

61
Q

what is the only hormone that can maintain euglycema following food ingestion

A

insulin