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State precisely, where in the pancreas is insulin produced?

B cells in islets of Langerhans

Identify the specific sites on the cell surface membrane that insulin binds to.
Extracellular ligand binding site of receptor tyrosine kinase

Describe how rER is involved in the production of insulin.

rER has bound ribosomes for protein synthesis
chemical modification/ post-translational modification of polypeptide (glycosylation/folding)

Insulin is released by pancreatic B-cell. Outline the route taken by proinsulin.

from rough ER, a transport vesicle takes the pro-insulin to the Golgi apparatus (GA) (pro-insulin is synthesized
at rER!!!)
after chemical modification and packaging, a secretory vesicle buds off from GA
the transport of secretory vesicles aided by microtubules in the cytoplasm, until they fuse with the plasma
Secretory vesicles fuses with the cell surface membrane before releasing insulin by exocytosis.

Describe how Golgi body is involved in the secretion of insulin.

Golgi body further chemically modifies insulin (glycosylation/folding)
packages insulin into secretory vesicles which move towards the cell surface membrane with the aid of
microtubules and fuses with it, to release insulin out of the cell by exocytosis

Explain how B-cell specific transcriptional factors will lead to high level of insulin gene expression.
B-cell specific transcriptional factors are activators, that bind to the enhancer region found in the insulin
promoter region (specify what they are!)
binding of B-cell specific transcription factors will lead to increase in the formation of transcription initiation
complex at the promoter
B-cell specific transcription factors may also lead to chromatin remodelling to increase rate of transcription e.g.
via histone acetylation to allow greater accessibility to RNA polymerases for transcription to occur.

Explain what may have caused the difference in efficency of insulin promoters.
gene mutation in the insulin promoter sequence result in changes in base sequence of the promoter sequence
this change will cause the structure of the promoter to be of less complementary to the DNA binding site of the
RNA polymerase to the promoter sequence
methylation of the promoter region also affects the binding of RNA polymerases

Suggest how a change in the amino acid sequence (start point) of the receptor found in the plasma cell
membrane of the muscle cell could make the cell resistant to insulin (basically means insulin can't bind to receptor).
different amino acid sequence leads to different R group interactions (hydrogen bonds, disulfide bonds and
hydrophobic interactions) between R groups of amino acids
leading to different tertiary structure of receptor
so insulin does not fit/ shape of binding site is not complementary

Suggest why incidence of diabetes shows an increasing trend over the years worldwide.
changing lifestyles leading to increasing in incidence of obesity
high sugar diet leading to high frequency of high blood glucose levels --> stress pancreas

With reference to table, explain the difference in glucose production from glycogen and gluconeogensis in
patients with type II diabetes and those without.
patients with type II diabetes produce less glucose from glycogenolysis than control group (QV)
patients with type II diabetes produce more glucose from gluconeogenesis than control group (QV)
diabetic patients cannot respond to insulin to increase cellular glucose uptake when blood glucose is high
thus cannot have much glycogen store and have to produce glucose from non-carbon sources

Explain the importance of values of signifant levels to the experiment.

it indicates the probability that the values obtained for patients and control groups are deviating by chance

Using type II diabetes as an example, explain how environment affects phenotype.

people with functional pancreas have functional genes which codes for insulin release
overeating of sugary foods for a long period of time causes repeated stimulation of the pancreas
which responds by secreting high levels of insulin
repeated exposure of the target cells to large amounts of insulin desentisizes the target cells' responsiveness to
insulin (RTK will be removed from membrane by endocytosis so not respond to insulin)
result in target cells failing to take in glucose --> results in type II diabetes
With ref to fig 6.1, explain how activation of IRS-1 can lead to an increase in glucose permeability of muscle
IRS-1 activates PI3K which catalyses conversion of PIP2 to PIP3
PIP3 activates AKT/PDK1 which in turn activates PKC
which results in vesicles carrying GLUT4 glucose transporters to migrate towards plasma membrane and fuse
with the plasma membrane to embed within the plasma membrane, thus increasing glucose permeability of
muscle cells

With ref. to fig. 1 (shows glucose entering cell then forming glycogen), how binding of insulin to RTK receptors
on muscle cells leads to a lowering of blood glucose concentration.
insulin binding results in the entry of glucose into the muscle cell by faciliated diffusion via glut4 protein
glucose used to form glycogen in the muscle cell

Describe how the number of GLUT4 molecules are increased and removed from the cell surface membrane of
target cells.
vesicles with GLUT4 embedded in membrane translocate to cell surface membrane with aid of microtubules
and fuse with cell surface membrane to increase number of GLUT4
Invagination of cell surface membrane with GLUT4
to take in GLUT4 via endocytosis

Explain why removing GLUT4 molecules would make the cell surface membrane impermeable to glucose.
glucose is a polar molecule
that is repelled by the hydrophobic core of the phospholipid bilayer
requires a protein transporter/carrier
to provide a hydrophilic channel

Explain why gene mutations do not always produce mutated insulin protein whereas mutations of the splicing
sites involved in RNA splicing will produce mutated insulin.
gene mutations that involve substitution may result in the same amino acid being encoded an due to the
degenerate code
gene mutation could occur at the intron region instead of exons
mutation at the splice site will affect the binding of spliceosome and will affect the removal of introns and exons,
hence giving rise to a mutated protein with a loss of function.
eg: diff combination of exons produced => diff primary seq of amino acids=> diff protein (mutated)
eg: wrong excision of exons=> large number of bases and hence amino acids is lost
eg: introns not removed by spliceosome=> introns translated, became additional amino acids which will lead to
changes in the protein structure

Describe how amino acid residues at different positions in the polypeptide may be brought together in the
receptor site when the glucagon receptor is synthesized.
each protein contains a precise number, type and sequence of amino acids that are held together by peptide
bonds in a linear strand of polypeptide chain
the polypeptide chain will coil and fold into a-helices (in the transmembranal region) and B pleated sheets (in
the extracellular and intracellular binding domains) respectively due to hydrogen bonding between C=O and N-
H groups of the amino acid residues
the polypeptide chain will undergo further folding, bending and coiling to form the tertiary structure giving rise to
a globular protein
tertiary structure is held by ionic bonds, hydrogen bonds and disulfide bonds formed between the R groups of
amino acid residues
all these levels of folding would enable the amino acid residues at different positions in the polypeptide to be
brought together in the receptor site when the glucagon receptor is synthesized.

'In 2-8% of white populations, a mutation was incorporated in exon 2 of the glucagon receptor gene that changes a glycine to a serine
resulting in a Gly40Ser mutant receptor.. which was found to bind glucagon with an approximately 3-fold lower affinity... mutation
located in the extracellular region..' (the figure shows the structure of glycine and serine including their R groups)
With reference to the info provided and fig 1.3, describe the effects of the mutation of the glucagon receptor
gene. (4)
A single base-pair substitution of the glucagon receptor gene causes:
1) the DNA triplet to be changed in the gene
2) and one of the codons to be changed in the mRNA formed
resulted in a non-polar glycine being substituted by a polar serine at position 40 of the glucagon receptor
polypeptide chain
this substitution changes the 3D conformation of the binding site of the receptor, resulting in glucagon unable to
recognise and bind to the receptor.
Less cAMP activated, less protein kinase A activated, less phosphorylase kinase activated
less glycogen phosphorylase activated --> decreases breakdown of glycogen to glucose
Describe the significance of having a cell signalling system.
it is an efficient cascade system whereby a very low concentration of signal molecules, insulin, that bind to the
plasma membrane receptors initially is able to result in a much greater cellular response through multiple signal
cascades (signal amplification)
the binding of the ligand to receptors on the cell surface membrane is able to activate genes in the nucleus.
Therefore, the ligand does not need to cross the phospholipid bilayer to effect an cellular response.