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Applied Biochemistry > Cell Signaling, Insulin > Flashcards

Cell Signaling, Insulin Flashcards

1
Q

what is the major metabolic fuel?

A

glucose

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2
Q

how are circulating levels of glucose tightly regulated>

A

opposing actions of insulin and glucagon

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3
Q

insulin

glucagon

A

lowers blood glucose levels

raises blood glucose levels

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4
Q

glycogenesis

A

converts smaller carbon molecules such as pyruvate into G6P to glucose to glycogen

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5
Q

where is glucose derived from?

A

material ingested in the diet

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6
Q

carbohydrates exist in nature as (3)

A

polysaccharides (starch, glycogen)
disaccharides (sucrose, maltose, lactose)
monosaccharides (galactose, glucose, fructose)

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7
Q

starch represents about –% of carbohydrate intake for westerners (–% sucrose, –% lactose)

A

60%

20%, 10%

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8
Q

carbohydrates are broken down into — in the gut

A

hexoses

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9
Q

hexoses cannot pass freely though the cell membrane, so they are absorbed via

A

glucose transporters like GLUT4

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10
Q

the mammalian brain depends upon glucose as it is the primary/major source of energy. the brain uses –% of all glucose derived energy

A

20%

when glucose levels drop, the brain still uses up all the glucose at the expense of other cells

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11
Q

regulation of high blood glucose levels

A

the pancreas secretes insulin from the beta islet cells
glucose is converted to glycogen in the liver, glucose is converted to glycogen in the muscle, and glucose + 3 FA are converted to triglycerides in the adipose tissue
achieve normal blood glucose levels

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12
Q

regulation of low blood glucose levels

A

the pancreas releases glucagon from alpha islet cells
glycogen is converted to glucose in the liver, glycogen is converted to glucose in the muscle, and triglycerides are converted to glucose + 3 FA in adipose tissue
achieve normal blood glucose levels

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13
Q

what does phosphorylation do to an enzyme or receptor?

A

can either reversibly turn an enzyme or receptor on or off

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14
Q

reversible phosphorylation results in a conformational change in the structure of enzymes and receptors, causing them to become (2)

A

activated or deactivated

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15
Q

what type of bond is a protein-phosphate bond?

A

high energy

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16
Q

which specific side chains of enzymes or receptors does phosphorylation occur? (4)

A

serine
threonine
tyrosine
histidine

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17
Q

phosphorylation of glycogen synthase kinase-3 by AKT in the insulin pathway

A

inactivates

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18
Q

some proteins require phosphorylation in order to be recognized by ubiquitin ligases which designate or mark proteins for

A

proteosomal degradation

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19
Q

kinase

A

enzyme catalyzing a phosphorylation reaction

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20
Q

kinases utilize a…

A

high energy source of phosphate, most commonly ATP

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21
Q

phosphatase

A

enzyme that removes phosphate residues (dephosphorylation)

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22
Q

a conformational change results in

A

activation or inhibition

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23
Q

how insulin and glucagon regulate glucose/glycogen metabolism

A

release of insulin in the blood stream activates protein phosphatase which dephosphorylates glycogen synthase, activating it to produce glycogen. insulin also activates protein phosphatase to dephosphorylate glycogen phosphorylase, inhibiting it from producing G1P

release of glucagon/epinephrine in the blood activates cAMP which activates phorphorylase kinase to phosphorylate glycogen phosphorylase which activates it to produce G1P. glucagon/epinephrine activate cAMP which activates protein kinase A to phosphorylate glycogen synthase, inhibiting it from producing glycogen

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24
Q

initial form of insulin

A

proinsulin

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25
Q

insulin biosynthesis

A

initially made as proinsulin from beta cells of the pancreas. proinsulin is bigger than the active form of insulin. 2 different prohormone convertases (1 &2) cleave insulin at two different sites to form active insulin and C peptide

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26
Q

where else have we seen prohormone covertase 2?

A

prohormone convertase 2 actives SCREB 1 and 2 proteins by cleaving them into their active form

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27
Q

insulin synthesis release by the pancreas

A

insulin is stored inside granules in the beta cells for immediate release of insulin when it is needed. when glucose levels are high, insulin is released. glucose is transported via GLUT2 transporter into the cell, glucose is then converted into ATP through glycolysis. as ATP:ADP ratio increases, that causes the closing of a K+ ATP channel. when that channel closes, that causes the membrane to depolarize. depolarization of the membrane opens up a voltage gated channel. Ca+ acts to stimulate exocytosis of the stored insulin granules, insulin granules move to the membrane, fuse and dump their insulin. a the same time, Ca+ activates insulin gene expression via CREB

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28
Q

CREB

A

calcium responsive element binding protein

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29
Q

exocytosis is —

CREB to stimulate insulin gene expression is —

A

rapid

slow

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30
Q

exocytosis of stored insulin is rapid because

A

the insulin is already stored in vesicles in the cell

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31
Q

normal fasting blood glucose

A

70-130 mg/dL

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32
Q

kinetics of insulin release

A

initial fast response phase is followed by a more prolonged phase requiring new synthesis of insulin for the duration of the glucose spike

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33
Q

what is the insulin receptor?

A

a transmembrane receptor composed of an alpha and beta chain that is activated by insulin, IGF1 (insulin growth factor 1), and IGF2 (insulin growth factor 2)

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34
Q

the insulin receptor belongs to a class of

A

tyrosine kinase receptors

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35
Q

binding of ligand (IGF2 or insulin) to the alpha chains of the ectosomain induces a structural change (conformational change) in the receptor, leading to

A

autophosphorylation of tyrosine residues within the intracellular TK domains of the beta chain

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36
Q

these changes recruit (cause the binding of) specific adapter. proteins (IRS, SHC, etc) to the receptor. this facilitates specific changes in

A

glucose homeostasis

ex. glycogen synthesis

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37
Q

peptide receptors are always

A

transmembrane

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38
Q

where can IGF2 bind?

A

IGFR or insulin receptor if there is a high concentration of insulin

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39
Q

activation of the receptor results in

A

downstream signaling with intracellular 2nd messenger cascades

40
Q

how many glucose transporters are there?

A

13

41
Q

what are the main glucose transporters?

A

GLUT1-5

42
Q

glucose can either be transported through (2)

A

facilitated (passive) diffusion or active transport

43
Q

GLUT1 tissue distribution (4)

A

brain, erythrocytes, placenta, fetal tissue

44
Q

GLU2 tissue distribution (4)

A

liver
kidney
intestine
pancreatic beta-cells

45
Q

GLUT3 tissue distribution

A

brain

46
Q

GLUT4 tissue distribution (2)

A

muscle

adipose tissue

47
Q

GLUT5 tissue distribution

A

jejunum

48
Q

Km is the concentration of glucose at which there is

A

a half maximal rate of transport

49
Q

Km is inversely proportional to the affinity of glucose for the

A

transport proteins

50
Q

mechanical model for Na+ coupled sugar transport

A

Na+ binds to the channel protein, resulting in a conformational change which allows the binding of glucose which results in another conformational change. close and Na+ are then both transported into the cell

51
Q

insulin increases the translocation of — to the cell membrane

A

GLUT4

52
Q

how does insulin increase the translocation of GLUT4 to the cell membrane?

A

insulin binds to the receptor which results in a signal transduction cascade so that vesicles containing GLUT4 (GLUT4 secretory vesicles - GSV) are exocytosed to fuse with the membrane so GLUT4 transporters integrate into the membrane, allowing glucose to enter the cell

53
Q

what does SGLT1 mediate?

A

intestinal absorption of glucose from the diet on the luminal side of the intestinal enterocyte

54
Q

SGLT1

A

sodium-glucose co-transporter 1

55
Q

GLUT2 is important in the basolateral efflux of glucose into the

A

blood stream

56
Q

SGLT1 is also important in the glucose-mediated secretion of — hormones

A

incretin

57
Q

incretin hormones (2)

A

GIP

GLP1

58
Q

gut transport of glucose

A

glucose and transported into the enterocyte via SGLT1. this results in a high conc of glucose and Na+ inside the enterocyte. GLUT2 on the basolateral membrane can move glucose down its conc gradient into the blood stream. Na+ is moved out of the cell via a Na+/K+ ATPase on the basolateral membrane

59
Q

transport of glucose is coupled to the energetically favorable inward transport of …

A

Na+ from the lumen into the blood

60
Q

what are incretin hormones?

A

gut hormones which are released after that stimulate the secretion of insulin by beta cells of the pancreas

61
Q

major incretins (2)

A

GIP (gastric inhibitory peptide)

GLP1 (glucagon like peptide 1)

62
Q

how are GLP1 and GIP inactivated?

A

the enzyme dipeptidyl peptidase 4 (DPP-4), which is released from endothelial cells of blood vessels

63
Q

what is a DPP4 inhibitor?

A

serine protease

64
Q

inhibition of DPP4 leads to

A

increased insulin secretion and decreased glucagon levels and consequently improvement in hyperglycemia

65
Q

the first DPP4 inhibitor approved by the FDA in 2006 was

A

sitagliptin

66
Q

mechanism of action of GLP-1RAs and DPP-4 inhibitors

A

glucose is taken up by the gut, as it increases in the blood supply, incretin hormones are secreted. they bind to a receptor on the beta and alpha cell of the pancreas and stimulate insulin/inhibit glucagon. GLP1 and GIP want to reduce these levels. DPP4 inhibitors allow for the stimulation of insulin

67
Q

insulin

A

hormone lower blood glucose by stimulating cellular uptake and glycogen synthesis
ex. humalin R

68
Q

metaformin

A

works on the liver to reduce release of glucose in type 2 diabetes. not applicable to type 1 diabetics
ex. metformin HCl, glucaphage

69
Q

acarbose

A

by inhibition of intestinal alpha glucosidases, it delays carbohydrate digestion, prolongs overall carbohydrate digestion, reducing the rate of glucose absorption
ex. precose

70
Q

sulphonylureas

A

increase insulin release by pancreas

ex. amaryl

71
Q

GLP1 receptor agonists

A

incretin receptor agonists

ex. trulicity

72
Q

DPP4 inhibitors

A

increase incretin levels

73
Q

thiazolidinediones

A

reduces fatty acid oxidation and thereby increases use of glucose as a fuel
ex. rosiglitazone

74
Q

SGLT2 inhibitors

A

sodium glucose cotransporter inhibitor. blocks reabsorption of glucose by the kidney
ex. farxiga

75
Q

in addition to glucose metabolism, insulin regulates key steps affecting

A

lipolysis (lipid metabolism)

76
Q

how does insulin regulate lipolysis?

A

beta cell binds to an insulin receptor on the adipocyte which stimulates a protein kinase cascade which leads to the stimulation/activation of phosphodiesterase 3B which converts cAMP to AMP. AMP stimulates lipase which is important in converting triglycerides into free FA. when you have high circulating levels of glucose, you dont want FA dumped into the blood. so you inhibit adipocyte release of free FA through this signaling cascade

77
Q

as the concentration of insulin increases, lipolysis – and glucose uptake –

A

decreases

increases

78
Q

acetyl coA carboxylase (ACC) regulating FA metabolism

A

acetyl coA is converted to malonyl coA (via ACC). malonyl coA shuts down beta-oxidation of FA by blocking a transporter which moves free FA from the cytoplasm into the mitochondria

79
Q

1st committed step of FA metabolism

A

acetyl coA to malonyl coA via ACC

80
Q

high levels of malonyl coA blocks

A

mitochondrial beta-oxidation because you no longer have substrate for beta-oxidation to take place

81
Q

ACC is regulated by

A

insulin and glucagon

82
Q

when blood glucose levels are high,

A

insulin increases, which actives a phosphates which activates ACC to convert acetyl coA to malonyl coA

insulin stimulates production of acetyl coA and malonyl coA which are the two building blocks needed for FA synthesis

83
Q

when blood glucose levels are low,

A

glucagon increases, which phosphorylates ACC to inhibit it, therefore you dont inhibit FA transport into the mitochondria, so they can move through the mitochondria to form energy

84
Q

insulin increases the rate of which two storage pathways?

A

lipogenesis

glycogenesis

85
Q

insulin stimulates lipogenesis by acting on which two targets?

A

pyruvate dehydrogenase which forms acetyl coA and acetyl coA carboxylase (ACC) which forms malonyl coA from acetyl coA (two major control points)

86
Q

insulin stimulates the activity of

A

pyruvate dehydrogenase phosphatase

87
Q

pyruvate dehydrogenase phosphatase mechanism

A

removes phosphate from pyruvate dehydrogenase allowing for the conversion of pyruvate to acetyl coA

this mechanism leads to the increased rate of catalysis of this enzyme and increases the levels of acetyl coA. increase acetyl coA will increase the flux through not only the fat synthesis pathway but also the CAC

88
Q

malonyl coA is an inhibitor of

A

FA transport and oxidation by mitochondria

89
Q

insulin leads to dephosphorylation of ACC which

A

activates the enzyme

90
Q

glucagon increases phosphorylation of ACC which

A

inhibits ACC and slows FA synthesis

91
Q

ATP generation linked to beta-oxidation of FA demands more oxygen than glucose, thereby enhancing the risk for neurons to become

A

hypoxic

92
Q

beta-oxidation of FA generates

A

superoxide

93
Q

superoxide taken together with poor antioxidative defense in neurons causes

A

severe oxidative stress

94
Q

the rate of ATP generation based on adipose tissue derived DA is — than that using blood glucose as fuel

A

slower

95
Q

in periods of extended continuous and rapid neuronal firing, FA oxidation cannot guarantee

A

rapid ATP generation in neurons

Applied Biochemistry (52 decks)

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