Case with type 2 diabetes your blood glucose

Case study 2: Type 2 Diabetes

1.       What
commonly performed tests would be able to confirm the likely diagnosis of this
patient, and what would normal results for those tests be? (5 marks)

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The
HbA1c test is the most commonly used test to identify type 2 diabetes and is
recommended by WHO now to help diagnose type 2 diabetes (WHO, 2011). The test shows your average plasma glucose levels over the
past 8 to 12 weeks. The value to diagnose diabetes is around 6.5% but if you
fall below 6.5% you are not guaranteed to not be diabetic. At least 2 HbA1c
tests must be done with both showing diabetic values for you to then be
diagnosed with type 2 diabetes (WHO, 2011).

The
OGTT test is another commonly used test to diagnose type 2 diabetes. You must
avoid food and drinks for 8-12 hours before having the test. They will measure
your blood glucose before the test and after the test when you’re given a sweet
glucose drink. They measure again after 2 hours (NHS, 2016). The test will determine whether you have impaired glucose
tolerance (IGT) or diabetes (NHS, 2016). The values for someone without diabetes should be less than
6mmol/l before the test and less than 7.8mmol/l two hours after the test. With
IGT the blood glucose levels should be 6-7mmol/l before the test and
7.9-11mmol/l two hours after the test (NHS, 2016). To be diagnosed with type 2 diabetes your blood glucose levels
will be more than 7mmol/l before the test and more than 11mmol/l two hours
after the test (NHS, 2016).

 

2.       Describe the endocrinological axis that regulates the release of insulin including details of
the cells/tissues involved. (15 marks)

Insulin
secretion is primarily controlled by a direct negative feedback system between
the pancreatic ?
cells and the concentration of glucose in the blood flowing to them (Sherwood, 2016). ? cells
are in islet clusters and have capillaries surrounding them called fenestrae
which allow for unrestricted nutrient access and therefore allow for ? cells to sense changes in glucose levels
quickly (Fu, et al., 2016) (Sherwood, 2016). When insulin is at high levels it will promote blood glucose
levels back to normal and storage of glucose. On the other hand, when blood
glucose levels are low insulin secretion is directly inhibited. Metabolism of insulin
secretion is shifted from being absorptive to post absorptive. This is the
negative feedback loop which maintains glucose levels without nerves and other
hormones being involved (Sherwood, 2016). Glucose stimulates insulin secretion through changing the
membrane potential of ? cells, which eventually lead to insulin secretion.
GLUT2 which is expressed in ? cells is the first glucose sensor to be
interacted with. Glucose enters the ? cells via GLUT2-mediated diffusion (Fu, et al., 2016). The glucose is then phosphorylated to glucose-6-phosphate by
glucokinase. Glucose-6-phosphate undergoes oxidation which then generates ATP.
The ATP generated causes the usually open K+ channels to close as
ATP binds to them. The voltage-gates Ca2+ channel is open at resting
potential. The decreased permeability of K+ ions leads to
depolarization of ? cells due to the positively charged K+ being in
high quantity (Sherwood, 2016). The depolarization of the membrane causes the voltage-gated Ca2+
channel to open. Ca2+ enters the ? cells eventually triggering
exocytosis of secretory vesicles containing insulin. Insulin is then secreted.

There are
other inputs which are involved in the regulation of insulin secretion. When you
have eaten a high protein meal your bloods amino acid level is high. This will
directly stimulate the ? cells and increase insulin secretion. Amino acid entry
into cells increases as high insulin levels enhance this. This lowers blood
amino acid levels and promotes protein synthesis. Amino acids generate ATP like
glucose does, so they increase insulin secretion the same way, using a negative
feedback loop.

Incretins
like glucose-dependent insulinotrophic peptide (GIP) and glucagon-like peptide
1 (GLP-1) stimulate pancreatic insulin secretion. This comes after there has
been a presence of food in the gastrointestinal tract (Sherwood, 2016).

The
autonomic nervous system directly influences insulin secretion (Sherwood, 2016). The parasympathetic and sympathetic nerve fibres innervate the
islets. The presence of food in the digestive tract stimulates increased
parasympathetic activity and increased insulin secretion. Acetylcholine acts
through the IP3-Ca2+ pathway. This and the GIP, GLP-1
pathways are feedforward responses due to their anticipation of nutrient
absorption (Sherwood, 2016). Sympathetic stimulation and the increase in epinephrine inhibit
insulin secretion by decreasing cAMP. Allowing for blood glucose levels to rise (Sherwood, 2016).

 

3.       Describe the cell signalling pathway activated by insulin during blood glucose regulation. (10 
marks)

The
insulin receptor (IR) is a heterotrimeric bifunctional complex, consisting of 2
extracellular ? subunits that bind insulin and 2 transmembrane ? subunits with
tyrosine kinase activity (Chang, et al., 2005). When insulin binds to a ? subunit it will induce
transphosphorylation of one ? subunit by another on specific tyrosine residues
in an activation loop. This results in increased catalytic activity of the
kinase (Chang, et al., 2005). The next step is for the IR to undergo autophosphorylation which
is in the juxtamembrane regions and intracellular tail. The insulin receptor
becomes activated and then phosphorylates tyrosine residues on intracellular
substrates like insulin receptor substrates (IRS), Shc isoforms and Gab-1. When
phosphorylated these substrates will interact with the SH2 domains that
specifically recognize different phosphotyrosine motifs. Glucose uptake by
insulin will be mediated by phosphatidylinositol (PI) 3-kinase dependent and
independent pathway (Chang, et al., 2005). After the tyrosine is phosphorylated IRS proteins will interact
with the p85 regulatory subunit of PI3k which activate small G proteins by
binding to nucleotide exchange factors (Saltiel & Kahn, 2001). Phosphatidylinositol-3,4,5-triphosphate (PIP3) is phosphorylated
by PI3K. It will regulate the localization and activity of many proteins. PI3K
is essential to glucose uptake and GLUT4 translocation. If it is blocked
glucose uptake is no longer stimulated. PIP3 recruits and can
activate pleckstrin homology (PH) domain containing proteins like adapter
molecules, enzymes and their substrates. Ser/Thr kinase PDKI is one of these.
It phosphorylates and activates kinases like AKT1. PIP3 helps AKt
travel to the plasma membrane using the PH domain. Akt will then phosphorylate
other proteins at other subcellular locations Overexpression of a membrane
bound form of AKT in 3t3L1 adipocytes resulted in increased glucose transport
and localization of GLUT4 to the plasma membrane (Chang, et al., 2005). Akt if interfered with inhibits GLUT4 translocation. Reducing
AKT2 decreases insulin sensitivity and decreases glucose disposal (Chang, et al., 2005).

The
Ras-MAPK pathway is also essential in the insulin signalling pathway. Shc
activates the Ras-MAPK pathway and this Shc-Grb2-SOS-Ras-Raf-MAPK pathway
controls cellular proliferation and gene transcription ( Boucher, et al., 2014). The activated receptors and IRS proteins will have docking sites
for adaptor molecules that have SH2 domains like Shc and Grb2. Gab-1 can be
bound by the carboxy terminal SH3 domain of Grb2. The protein Son of the
Sevenless (SOS) will be bound by the amino terminal SH3 domain in proline-rich
regions. SOS is a guanine nucleotide exchange factor for Ras ( Boucher, et al., 2014). SOS will catalyse the switch of membrane bound Ras from its
inactive state being bound to GDP (Ras-GDP) to its active state bound to GTP
(Ras-GTP). Ras-GTP will interact with and stimulate downstream effectors like
Ser/Thr kinase Raf ( Boucher, et al., 2014). This stimulates the downstream target MEK1 and 2 which will
phosphorylate and activate the MAP kinases ERK1 and 2. ERk1 and 2 are essential
to cell proliferation or differentiation, regulating gene expression or
extranuclear events, such as cytoskeletal reorganization through
phosphorylation and activation of targets get in the cytosol and nucleus ( Boucher, et al., 2014).

4.       What are the physiological effects of insulin signalling activation that contribute to blood glucose regulation?
(15 marks)

Insulin
is important to glucose, fatty acids and amino acids as it lowers their
presence in blood and promotes their storage. When they enter the blood during
the absorptive state, insulin promotes their cellular uptake and conversion
into glycogen, triglycerides and proteins. Insulin will increase the activity
of glycogen synthase to achieve these effects. Insulin will also inhibit
enzymes like hormone sensitive lipase which breakdown triglycerides back into
free fatty acids and glycerol (Sherwood, 2016).

Insulin
has 4 effects on carbohydrates to lower blood glucose levels and promote
carbohydrate storage. Insulin facilitates glucose transport into most cells
glucose transport into most cells. Glycogenesis, the production of glycogen
from glucose, in both skeletal muscle and liver is stimulated by insulin.
Insulin will inhibit glycogenolysis, the breakdown of glycogen into glucose. It
will also inhibit gluconeogenesis. This is the conversion of amino acids into
glucose in the liver. The amino acids present in blood will be decreased, so
less is available for gluconeogenesis and the hepatic enzymes needed for
converting amino acids into glucose inhibited.

To
lower blood fatty acid levels and promote triglyceride storage insulin uses 4
methods to this. Fatty acid entry from blood into adipose tissue cells is
enhanced. Using GLUT4 the transport of glucose into adipose tissue cells will
increase. Glucose is a precursor for the formation of fatty acids and glycerol,
which are used for triglyceride synthesis. Lipolysis will be inhibited to
reduce the number of fatty acids releasing into blood. They all promote fatty
acid and glucose removal and storage of triglycerides (Sherwood, 2016).

To
lower blood amino acid levels and enhance protein synthesis insulin will
promote 3 effects. Active transport of amino acids from the blood into muscles
and other tissues is promoted. This will decrease the blood amino acid level
and aid protein synthesis inside cells. Protein synthesizing machinery is
stimulated so more amino acids are incorporated into protein. Protein
degradation is inhibited. This leads to a protein anabolic effect and shows
insulin is essential for growth (Sherwood, 2016).

5.       What initial treatments would be recommended for this patient? How do these treatments
work? (5 marks)

For
this patient initially, they will be recommended to eat more healthily to
control their glucose levels without medication if possible. So, they should
eat more fibre and fruit and vegetables to lower their glucose levels. They
will be recommended to lose 5-10% of their body fat as well if they’re
overweight, this again can lower blood glucose levels.  The first medication they are prescribed if
this doesn’t work is metformin. This reduces the amount of glucose released by
the liver. Sulphonylureas (NHS, 2016) can be used to increase insulin secretion from the pancreas.
Examples include gliclazide. Gliptins (DPP-4 inhibitors) can be prescribed too.
They prevent the breakdown of GLP-1 which helps the body produce insulin. This
prevents high blood glucose levels. Insulin injections can be used too with
usually 2-4 injections a day lowering blood glucose levels. If hypoglycaemic,
glucagon can be administered to help with tiredness and to increase blood
glucose levels (NHS, 2016). These treatments can help relieve symptoms like tiredness,
excessive thirst and frequent urination at night. This is because they
are mainly due to high blood glucose levels.

Bibliography

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