lecture 18

Question 1

where is insulin secreted from

Answer 1

beta cells of pancreatic islets

Question 2

what is produced by pancreatic alpha cells

Answer 2

glucagon

Question 3

how do beta cells know to secrete insulin

Answer 3

glucose enters the beta cells and is metabolised to ATP increasing the ATP: ADP ratio. This leads to cloure of ATP sensitive potassium channels and leads to membrane depolarisation. This causes voltage gated calcium chanels to open - increasing cycystolic calcium ion levels. This promotes insulin secretion

Question 4

how is insulin secreted since it is hydrophilic

Answer 4

via exocytosis - inside granules (vesicles)

Question 5

what are the metabolic effects of insulin

Answer 5

increases: glucose uptake, glycogen synthesis and fatty acid synthesis
decreases: glycogen breakdown, gluconeogenesis and lipolysis

Question 6

insulin is a type of ____ which explains its lipophobicity

Answer 6

hormone

Question 7

focus of insulin

Answer 7

to bring blood gucose levels back to a normal physiological level by switching off glucose production pathways

Question 8

what are the glucose production pathways switched off by insulin

Answer 8

gluconeogenesis and glycogen breakdown

Question 9

what organ supplies the insulin to the blood stream

Answer 9

liver

Question 10

how does insulin signalling pathways in target cells occur

Answer 10

insulin binds to the insulin receptor - which activates a cascade of signalling pathways to bring about its effects on metabolism and growth

Question 11

key output of signalling pathway is the activation of what

Answer 11

protein kinase B

Question 12

what are they key steps in insulin signalling and activation of PKB

Answer 12

insulin binds to receptor on the cell surface which leads to autophosphorylation of the receptor.
THe phosporylated residues on the iR act as binding sites fo IRS.
IR phosphorylates 4 tyrosine residues on IRS.
The lipid kinase: phosphoionitide 3 kinase binds to the phosphorylated residues on IRS proteins and converts PIP 2 to PIP 3.
Binding to PIP3 activates PDK1, which phosphorylates and activates PKB
PKB diffuses through cell and actibates processes such as glucose transport and glycogen synthesis.

Question 13

where is glucose moved to when insulin stimulates transport

Answer 13

it triggers cells to remove glucose from blood inyo adipocytes and skeletal muscle (used for energy)

Question 14

how does insulin stimulate glucose transport into aipocytes and skeletal muscle

Answer 14

Glut 4 is contained inside cell in storage vesicles which is help inside the cell by AS160.
AS160 is phosphorylated by PKB (produced from insulin) which inactivates it - allowing glut 4 vesicles to fuse to the membrane so tjat it can transport more glucose into the cell.

Question 15

How does insulin repress gluconeogenesis

Answer 15

it inhibits the transcription factor called FOX01

Question 16

FOX 01 mechanism

Answer 16

synthesised in the cytosol - but targeted to the nucleus - where it regulates exression of genes which mediate gluconeogenesis eg PEPCK or g6pase

Question 17

How does insulin inhibit gluconeogenesis

Answer 17

Insulin signalling leads to activation of PKB, which phosphorylates FOX01
Phosphorylation of FOX01 stops it from entering nucleus -> loss of gene expression for gluconeogenesis so loss of glucose production

Question 18

loss of insulin leads to hyperglycaemoa asd a result of (think cellular processes eg)

Answer 18

loss of insulin stimulated glucose uptake into target cells or loss of insulin mediated repression of gluconeogenesis ( and glycogen breakdown) in the liver

Question 19

what are the target cells for glucose uptake

Answer 19

skeletal muscle and adipocytes

Question 20

what factors can increase risk of developing T1DM

Answer 20

genetic variations and environmental triggers ( eg autoimmune disease genes and infection triggers)

Question 21

first degree relative with diabetes increase risk by

Answer 21

15x higher risk

Question 22

which region of which chromosome is linked to susceptibility of developing T1DM

Answer 22

HLA region of chromosome 6 - this contains genes which encodes components of major histocompatability complexes

Question 23

HLA region is the

Answer 23

human leukocyte antigen

Question 24

WHich antibodies, which target pancreatic beta cells, are a significant risk factor for T1DM development

Answer 24

GAD 65, insulin, IA-2, ZnT8

Question 25

presence of 2 antibodies against beta cell antigens increases risk by

Answer 25

increases risk of developing type 1 within next 10yrs to 75%

Question 26

Example of a virus which may cause T1DM

Answer 26

enteroviruses- especially coxsackie viruses. This is due to the 2c protein of a coxsakie virus being very similar to GAD65

Question 27

what encodes the main components of the immune system

Answer 27

Chromosome 6

Question 28

what are GAD

Answer 28

enxymes found within beta cells

Question 29

how many beta cells tend to be lost by the time of diagnosis

Answer 29

90% of them

Question 30

what causes high blood glucose levels in type 2 diabetes

Answer 30

insulin resistance of target tissues or insufficient production/ secretion of insulin ( beta cell dysfunction)

Question 31

When is diabetes usually diagnosed

Answer 31

type 1- earlier in life type 2 - later in life

Question 32

what is causing the increase in type 2 diabetes

Answer 32

increased obesity/lack of exercise/poor diet/ageing population

Question 33

how does obesity cause T2DM

Answer 33

amount of triacylglycerols exeeds the storage capacity of adipose tissues - so ft starts to accumulate in other tissues eg liver and muscle. The excess fat leads to increased levels of itracellular lipid signalling intermediates in the cytoplasm oc cells which are fored from fatty acids ( DAG and ceramide)

Question 34

fatty acids broken down to

Answer 34

DAG - further proken down to PKC - serine phosphorylation then effects IRS Ceramide - effects PKB Both these lead to insulin resistance

Question 35

how do adipocytes contribute to insulin resistance

Answer 35

obesity - increased circulating levels of pro-inflammatory cytokines adipose tissue from lean individuals secrete anti-inflamatory and insulin-sensitising adipokines (adiponectin) obese people release more pro-inflammatory cytoskines (tnfalpha) so less adiponectin is released, leading to insulin resistance TNFalpha also induces ecpression of PTP1B - which dephosphorylates IR so less IRS binding

Question 36

what does complex polygenic mean

Answer 36

caused by combination of genetic and lifestyle factors)