Case the cell, this depolarizes the cell membrane.

Case study: Diabetes

 

1.

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The gold standard test for diabetes is the
Oral Glucose Tolerance Test or OGTT. This test a 12-hour fast prior to blood
sample. Post bloods being taken, the patient ingests 75grams of glucose and
their blood is further recorded 2 hours’ post. Had the fasting serum glucose be
less than 6.1mmol/l, the patient is within the normal range, and suggests that
they are not diabetic.

 

 A
random blood sugar test is also a diagnostic tool is troubleshooting diabetes.
This can be taken at any time, regardless of fasted state. The patient takes a
blood sample, and if their glucose level is beyond 11.1mmol/1, it would suggest
they are possibly diabetic.

A fasting blood sugar test is when a blood
sample is taken after a person has not eaten overnight. Blood glucose levels
less than 5.6mmol/l are in the normal range.

 

A glycated haemoglobin test, or A1C test is
another method that requires fasting of the patient. As Erythrocytes lifespan
is of three months within the blood, the test measures blood glucose levels for
the past three months by measuring glucose attached to haemoglobin. This
average number gives an accurate idea in theory, however had the person only be
very recently affected, it will give inaccurate information. An A1c level of
5.7% means blood glucose levels are normal (Diabetes.co.uk, 2017)

 

2.

 Insulin’s role in the body is to reduce the
level of blood glucose as a means of regulation.

The standard
level of blood glucose in the body is 5 mM/L, this rises if a person has just
eaten a meal. Glucose levels are detected by the pancreatic beta cells like so;
glucose levels balance out very quickly across the membrane of the beta cells
due to the expression of glucose transporter 2 (GLUT2). GLUT2, via mediated
facilitated diffusion, allows glucose to enter the beta cells. As glucose
enters the cell it is converted to glucose-6-phosphate because in this form, it
is prevented from leaving the cell (Sherwood, 2016). Glucose-6-phosphate is
oxidised, producing ATP. When the
ATP/ADP ratio increases in beta cells, it causes the ATP-sensitive
K+ (KATP) channels to close consequently less k+ leaves the cell, this
depolarizes the cell membrane. This depolarization changes the voltage of the
cell’s membrane. Calcium channels called Cell-surface voltage-dependent Ca2+
channels (VDCC) respond to this voltage change by opening. Calcium then rapidly
diffuses into the beta cell down its concentration gradient. The rise of
intracellular calcium causes exocytosis of granules that roughly contain 40mM’s
concentration of insulin.

Fig1(Sherwood,
2016)

Fig1. Glucose enters the cell via
GLUT2 (1) glucose converted into glucose 6 phosphate as it enters the cell and
ATP is generated (2&3) ATP sensitive k+ channels close due to ATP (4)
membrane is depolarized (5) voltage gated calcium channels open (6) calcium
influx (7) exocytosis of insulin vesicles (8&9)

 

Insulin
secretion is also regulated by ingested nutrients via the work of incretins. Incretins
are a group of metabolic hormones that work to reduce blood glucose levels. K
cells (found in the proximal GI tract) and L cells (found in the distal GI
tract) are stimulated by nutrients to secrete incretins known as Gastric
inhibitory polypeptide (GIP) and glucagon like peptide 1 (GLP1). These hormones
work in an anticipatory fashion, when they detect nutrients, they let the beta
cells know that blood glucose levels are about to rise thus increasing insulin
levels by increasing cyclic AMP which augments calcium induced release of
insulin.

 

 

3.

Insulin,
like many molecules, binds to a receptor to activate a signalling pathway that
will bring about the desired effect. The insulin receptor is a dimerized
receptor tyrosine kinase (RTK), it has two alpha and two beta subunits held
together by disulphide bonds. As insulin is secreted, it binds to the
extracellular part of the RTK which in this case are the alpha subunits. As
insulin binds to the receptor it induces a conformational change that changes
the structure of the receptor. In doing so the shape of the cytoplasmic domain
changes as well. This series of events cause autophosphorylation of specific
tyrosine residues, which then serve as binding sites to be used in the
cytoplasmic domain of the receptor. These events lead to activation of the
insulin receptor but after this, there are two cell signalling pathways that
take place; the PI3K/AKT pathway and RAS pathway

 

After
activation, the PI3K/AKT pathway starts off (see fig 2) with insulin receptor
substrates (IRS) binding to the phosphorylated tyrosine residues. The reason
these IRS proteins bind is because they contain an SH2 domain which is
attracted to the phosphorylated tyrosine. Once these bind to the tyrosine
kinases, they too become phosphorylated due to the intrinsic tyrosine kinase
activity of the receptor. As the IRS proteins become phosphorylated they act as
a link between the receptor and the PI3 kinase (PI3K). PI3K becomes active and
migrates to the inner side of the cell membrane and phosphorylates a second
messenger embedded in the cell membrane, a lipid called Phosphatidylinositol 2,3,4-triphosphate (PIP3). This action attracts AKT,
a serine/threonine kinase, to the receptor signalling complex and it is then phosphorylated
by PI3K. This then releases AKT from PIP3 and it is now active, and carries out
different effects throughout the cell; AKT translocates GLUT4, a protein
responsible for glucose uptake into the cell, to the cell membrane. AKT also
activates Glycogen synthase 3 (GSK3), a protein that catalyses the
transformation of glucose into glycogen. AKT can phosphorylate a transcription
factor responsible for gluconeogenesis, its blocks it from entering the nucleus
therefore transcription cannot take place and consequently gluconeogenesis does
not occur (Slack, 2017)

 

Fig2(Oregon
state, 2017)

Fig2-  A schematic representation of the PI3K/AKT
pathway showing the steps in the signalling cascade from the point insulin
binds to the receptor.

 

The RAS/ERK pathway is the second signalling pathway to be discussed; After
insulin receptor activation, a protein called Growth factor receptor-bound
protein 2 (Grb2) is attracted to the phosphorylated tyrosine kinase residues
via its SH2 domain. Grb2 acts as a connection between the receptor and another
protein called SOS, a guanine nucleotide exchange factor (GEF). GEFs act as
molecular switches by activating GTPases- they do so by phosphorylating GDPs to
GTPs on the GTPases. SOS in this case activates RAS. Once active, RAS starts a
phosphorylation cascade which begins with a protein known as RAF that in turn
phosphorylates the protein MEK which does the same to the protein ERK. Erk
serves as the downstream effector and carries out a few functions; ERK inhibits
IRS proteins mentioned in the first pathway, reducing insulin signalling.  PPAR gamma, a protein which regulates fatty
acid differentiation and glucose metabolism is also inhibited by ERK,
discouraging adipocyte differentiation. ERK inhibits mTOR which is vital
protein in the process of protein synthesis, thus downregulating protein
synthesis. (Slack,
2017)

 

4.

 Insulin is released into the blood in response
to blood glucose levels higher than 5mM/L. It stimulates the uptake, usage and
storage of glucose. The way insulin works to enable the uptake of glucose into
cells is by the use of a hexokinase transporter known as GLUT4. This
transporter is translocated to the plasma membrane of cells by action emerging
from insulin. GLUT4 proteins are normally stored in vesicles in the cytoplasm
of cells, the binding of insulin to receptors on cells causes the vesicles to
fuse with the cell membrane allowing GLUT4 to perform its function as a glucose
transporter. The transport of glucose into the cells by GLUT4 is not a
mechanism than all types of tissues use, for example brain and liver tissue use
other mechanisms for glucose uptake (Vivo.colostate.edu, 2017). As glucose leaves the blood
and enters cells, the levels of blood glucose decrease. As soon as glucose
enters the cell it is phosphorylated to glucose-6-phosphate by the enzyme
hexokinase, and in this form, it is prevented from leaving the cell (Sherwood,
2016)

 

Fig3 (GLUT4, 2017)

 

Fig3- this figure diagrammatically represents the way
insulin influences GLUT4 to translocate to the cell membrane to facilitate the
uptake of glucose into cells

 

As nutrients
are ingested and make their way through our digestive system, they are broken
down and absorbed by the small intestine. A great amount of glucose absorbed
this way is taken up by the hepatocytes in the liver and is converted into
glycogen for storage. Insulin in the liver works in the way mentioned above,
recruiting glucokinase instead of hexokinase to trap glucose within hepatocytes
by converting it into glucose-6-phosphate, therefore aiding reduction of blood
glucose levels. There is a limit of how much glycogen can be stored in the
liver, when the liver can no longer store glycogen, glucose is converted to
fatty acids.  (Vivo.colostate.edu, 2017)

 

Adipocytes
among other cells are stimulated by insulin to uptake glucose. Glucose taken
into adipocytes is converted into glycerol which along with the fatty acids
from the liver are converted into triglycerides in fat cells and stored.

 

Insulin also
prevents glycogenolysis to allow glucose to be converted to glycogen for
storage (glycogenesis). ‘Activated PP1 directly dephosphorylates glycogen
phosphorylase a, reforming the inactive glycogen phosphorylase b, whereas
phosphodiesterase converts cAMP to AMP, thus inactivating PKA and its ability
to phosphorylate (activate) glycogen phosphorylase’. (diapedia.org, 2017)

 

5.

If a person
has been diagnosed with type 1 diabetes, it means the body does not produce
enough insulin. This cannot be cured but it can be treated; a person in this
position will have to inject insulin into their body directly. Insulin cannot
be taken in form of a tablet because it will get broken down and not enter the
bloodstream (nhs.uk, 2017).

 

If a person
is diagnosed with type 2 diabetes it means the body has become resistant to
insulin. There are several treatments for this; people are generally advised to
increase fibre and reduce fats and sugars in their diets, this is to prevent
insulin spikes. Loss of weight and exercise is also vital in terms of treating
type 1 diabetes as obesity contributes to the body’s resistance to insulin.

 

People with
type 2 diabetes generally take medication after being diagnosed. Metformin is a
tablet that is taken which reduces the amount of glucose that the liver sets in
the bloodstream. It also makes cells less resistant to insulin. Another group
of medications, in the form of tablets, called Sulphonylureas are prescribed to
increase the amount of insulin produced by the pancreas (nhs.uk, 2017).

 

 

References:

Diabetes.co.uk.
(2017). Normal and Diabetic Blood Sugar Level Ranges
– Blood Sugar Levels for Diabetes. online Available at:
http://www.diabetes.co.uk/diabetes_care/blood-sugar-level-ranges.html Accessed
11 Dec. 2017.

 

Fu, Z., R. Gilbert, E. and Liu, D. (2013).
Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell
Dysfunction in Diabetes. Current Diabetes Reviews, online 9(1),
pp.25-53. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934755/
Accessed 11 Dec. 2017.

GLUT4.
(2017). image Available at: http://proteopedia.org/wiki/index.php/GLUT4
Accessed 12 Dec. 2017.

 

Mayoclinic.org.
(2017). Diabetes – Diagnosis and treatment – Mayo
Clinic.
online Available at: https://www.mayoclinic.org/diseases-conditions/diabetes/diagnosis-treatment/drc-20371451
Accessed 11 Dec. 2017.

 

nhs.uk.
(2017). Treatment. online Available at:
https://www.nhs.uk/conditions/type-2-diabetes/treatment/ Accessed 13 Dec.
2017.

 

Oregon state (2017). Insulin Signalling.
image Available at:
http://oregonstate.edu/instruct/bb450/fall14/stryer7/14/figure_14_21.jpg
Accessed 12 Dec. 2017.

 

Sherwood, L. (2016). Human physiology from cells to stems.
9th ed. cengage learning, pp.690-700.

 

Slack, C. (2017). Panopto Viewer. online
Panopto. Available at:
https://astonreplay.cloud.panopto.eu/Panopto/Pages/Viewer.aspx?id=b9ceb60c-27f5-4dec-8b39-d4f127b03823
Accessed 11 Dec. 2017.

 

Vivo.colostate.edu.
(2017). Insulin Synthesis and Secretion. online Available at: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html
Accessed 11 Dec. 2017.

 

Ward, C.
(2017). Glycogenolysis and glycogenesis – Metabolism, insulin and other
hormones – Diapedia, The Living Textbook of Diabetes. online Diapedia.org.
Available at:
https://www.diapedia.org/metabolism-insulin-and-other-hormones/51040851111/glycogenolysis-and-glycogenesis
Accessed 13 Dec. 2017.

 

 

 

 

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