Tatum homeostasis regulated and what are the

 

 

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                                                                                                                Biochemistry 201

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How is glucose homeostasis regulated and what are the detrimental
effects of high glucose levels for the brain?

Individuals
may have heard the age-old myth that eating too much sugar causes diabetes.
This is not true. Diabetes is
diagnosed from the body’s inability to utilize insulin, where Type 1 Diabetes
is caused by an autoimmune attack on insulin-producing cells and Type 2
Diabetes is the result of down-regulation in insulin receptors. There is much
confusion about the effects of high glucose levels and this essay will focus on
how glucose is regulated, issues that arise from dysfunction in this regulatory
process related to high glucose levels, and new methods of treatment. First,
the process of glucose homeostasis will be explored. Next, the effects of a
disruption in this glucose regulatory process and lack of relationship between
high glucose levels and insulin resistance will be addressed. Third, issues in
the brain that arise from high glucose levels – caused by the narrowing of
blood vessels – will be examined. Fourth, mechanisms in which high glucose
levels indirectly cause hypothalamic inflammation will be investigated. Lastly,
treatments for issues arising from high glucose levels, specifically through NF-?B inhibition, will be
examined. It is essential to understand the process of glucose homeostasis and
what occurs in the body when this system fails, because high glucose levels can
lead to a range of harmful issues within the brain.

In a normal body, the body will
prevent glucose levels from becoming too high through insulin secretion, a
process vital to prevent metabolic disorders such as diabetes. Insulin
secretion begins with glucose uptake in the hepatocytes, facilitated through
GLUT2. Within the hepatocytes, glucose becomes converted to glucose-6-phosphate
through phosphorylation. Afterwards, G6P is oxidized and turned into ATP. This
increases the ATP:ADP ratio within the cell, thereby closing the ATP-sensitive potassium
channels when ATP binds to it. When the channel is closed, potassium ions are
unable to leave the cell, causing the inside of the cell becomes less negative
compared to the outside. This leads to depolarization of the cell surface
membrane. In response to this, calcium channels will open allowing calcium ions
to move through the cell during facilitated diffusion. The calcium influx
stimulates exocytosis, whereby insulin vesicles fuse with the cell membrane,
allowing it to enter the bloodstream. When blood glucose levels are too high,
insulin signals the liver, muscle, and fat cells to absorb glucose from the
bloodstream to use for energy (Hames and Hooper, 2005). Understanding the homeostatic
process of insulin secretion is extremely important because failure of insulin
usage relates to a number of diseases, including Type 1 and Type 2
Diabetes. 

While high glucose levels may lead to
a range of issues within the brain, it does not trigger the insulin resistance
that is characterized in Type 1 and Type 2 Diabetes. A 2006 article from Nature
explores the failure of the homeostatic insulin feedback loop that diabetic
individuals suffer from and demonstrates how it is unrelated to high glucose
levels (Kahn, Hull and Utzschneider, 2006).

 

 

Figure 1: The graphs below show the
relationship between insulin sensitivity and insulin release in health and
disease. The relationship within normal bodies is hyperbolic, where the product
of the X and Y axis is 1. The regions are differentiated by color: green demonstrate
regular levels of glucose tolerance, yellow shows impaired glucose tolerance,
and red describes those suffering from Type 2 Diabetes mellitus (Kahn, Hull and Utzschneider, 2006).

 

 

 

The graphs shown in Figure 1 show the
relationship between insulin response and sensitivity. In normal bodies, a
decline in insulin sensitivity is matched with an increase in insulin response.
This is because a feedback loop exists between insulin sensitive tissues and ?
cells, stimulating the ? cells to increase their insulin supply in response to
liver, muscle, and adipose tissue demand. Individuals with Type 2 Diabetes
demonstrate a decline in  ? cell function
and failure of this important feedback loop. A lack of insulin sensitivity is
not matched with an increase in
insulin, resulting in the high blood glucose levels characterized by Type 2
Diabetes (Kahn, Hull and Utzschneider, 2006).

The same Nature article explains that
failure of this feedback loop – where a decline in insulin sensitivity is not matched
with an adaptive increase in insulin – has nothing to do with increased glucose
levels. Experimental data demonstrated that insulin levels increased with an
increase in insulin resistance in both fasting and post-activity, while the
fasting plasma glucose levels did not rise. Strangely for animals, there is a
direct correlation between increasing glucose levels, decreased insulin
sensitivity, and a subsequent rise in insulin. Increased citrate levels from
glucose metabolism resulted in more malonyl-CoA and therefore an increase in
long chain acyl-CoA and diacylglycerol, stimulating protein kinase C activation
and insulin release (Kahn, Hull and Utzschneider, 2006). This leads to the
question, what detrimental effects does high glucose levels actually cause in humans?

First
of all, high blood glucose is shown to have extremely harmful effects in
regards to people’s cognitive abilities and the brain’s access to blood supply.
Scientists from the University of Montreal and Boston College conducted an
animal study in 2009 proving that the excessive consumption of glucose is
linked to memory and cognitive deficiencies (Edwards, 2017). Another study by
the University Medical Center Utrecht showed that when suffering from blood
glucose levels past 15 mmol/L, those suffering from Type 1 and Type 2 Diabetes
received lower cognitive scores and individuals with Type 2 diabetes
demonstrated worse learning and memory abilities. They also suffered likelihood
of neural slowing, attention deficit, and issues with executive functioning (Mukherji, Jacobson and Holt,
2014).  These studies show that problems related to
cognition may be a direct result of one’s excessive glucose consumption. 

Complications
within the brain occur because high glucose levels can reduce the levels of
nitric oxide, a vasodilator, which causes the blood vessels to become narrower.
Consequently small-vessel disease may occur, where small arteries in the heart
are damaged and there is restricted blood flow to the brain, inhibiting the
brain’s ability to process information. When small-vessel disease escalates,
vascular dementia may arise which is caused by lack of proper blood supply to
the brain. There can even be fatal effects of this blood vessel narrowing: when
areas of the brain do not receive blood, they will rapidly begin to die,
causing atrophy and potentially death (Edwards, 2017). It is therefore essential to maintain glucose
homeostasis because high glucose levels can disrupt the brain’s access to
blood, inhibiting cognitive processing and stimulating the neurodegeneration of
brain cells.

 

 

 

Figure 2: Increased
projections of DNI?B?-htNSCs cells versus non DNI?B?-inducted-htNSCs are shown
over a period of 30 days (Li et al., 2014).

Figure 3: The graph showcases
the increased cell survival of DNI?B?-inducted-htNSCs cells. Additionally, some
of the DNI?B?-htNSCs differentiated into cells which expressed POMC in chow-fed
mice, reversing the effects of POMC loss from high fat diet (Li et al., 2014).

High glucose levels also harm
the body by increasing insulin secretion which stimulates the absorption of
glucose as fat; high fat diets (HFD) may lead to hypothalamic inflammation,
harming proopiomelanocortin cells (POMCs) and hypothalamic neural stem cells (htNSCs).
POMCs are essential to glucose metabolism because they help regulate body
weight and glucose metabolism in the mediobasal hypothalamus. Under high fat
diet conditions however, these POMCs have reduced responsiveness to central
insulin and leptin, providing a neural mechanism for Type 2 Diabetes. The
physiological relevance of htNSCs remain unclear. However, from a 2014 animal
study, scientists determined that a loss in htNSCs and POMCs in mice results in
metabolic issues. They discovered this by injecting lentiviruses
expressing Sox2 promoter driven Herpes simplex virus type-1 thymidine kinase
(Hsv1-TK) into the medial basal hypothalami of adult mice. Hsv1-TK turns
ganciclovir (GCV), a nucleoside analog, into a toxic product that acts as a
chain terminator during DNA replication, thereby killing Sox2 positive cells
that would otherwise reproduce. After four months, mice suffered from a 10%
reduction in POMC and a partial loss in htNSCS within the arcuate nucleus
(ARC). The mice demonstrated a range of metabolic issues, including
hyperinsulinemia, glucose intolerance, increased food intake, and slight weight
gain (Li et al., 2014). The experiment suggests that both htNSCs and POMCs play
a role in the regulatory process of glucose and loss of these cells result in
glucose intolerance related issues.

Furthermore, inhibition of NF-?B appears
to be a promising new method to promote POMCs neurogenesis and battle
complications involving glucose intolerance. Scientists knew that NF-?B
disrupted htNSCs and wanted to see if POMC/htNSC growth would occur in the
presence of inhibited NF-?Bs. They went about this by engineering a line of
htNSCs with engineered NF-kB inhibition, by inducing lentiviral induction of
dominant negative I?B? (DNI?B?-htNSCs). These cells were then put into the MBH
of mice under high fat diet feeding condition. This resulted in a number of
positive effects: the survival rate of implanted DNI?B?-htNSCs cells
dramatically rose and even migrated, implicating neurogenesis occurred, shown
in Figure 2. Figure 3 demonstrates how some of the DNI?B?-htNSCs differentiated
into cells that expressed POMC in chow-fed mice, suggesting a method of
amending POMC losses through inhibition of NF-kB. Implantation of DNI?B?-htNSCs
resulted in major reductions in body weight, glucose intolerance, food intake,
and blood insulin levels in the HFD-fed mice as well as POMC neurogenesis,
suggesting a groundbreaking new method for fighting high glucose complications
(Li et al., 2014).

A number of detrimental effects in
the brain can occur as a result of high glucose levels, so it is imperative
that the homeostasis of blood glucose is maintained. High levels of glucose can
cause blood vessels to become narrower, leading to a range of complications in
the brain including cognitive difficulties, vascular dementia, atrophy, and
even death (Edwards, 2017).
Additionally, a high fat diet from excessive glucose intake may lead to
hypothalamic inflammation, causing a disruption of htNSC and POMC cells, which
can lead to glucose intolerance related issues. Nonetheless, scientists may be
able to combat these disruptions through new forms of treatment, such as nf-KB
inhibition (Li et al., 2014). Understanding the process of glucose homeostasis and how it
is disturbed is essential for scientists to discover new methods of alleviating
the negative effects related to high glucose levels. This is particularly
important as so many people suffer from issues related to a failures in this
regulatory process, such individuals with diabetes, a disease that affects over
361 people in the world (Obateru, Olokoba and Olokoba, 2012). Typically, high
glucose levels are prevented through the secretion of insulin, however when the
body is unable to maintain glucose homeostasis, this may lead to a range of
detrimental issues in the brain including narrowed blood vessels, cognitive
failure, hypothalamic inflammation from fat buildup, and thereby disruption of
important cells such as htNSCs or POMCs.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REFERENCES

 

Edwards, S. “Sugar
and the Brain.” Harvard Medical
School Department of Neurobiology, On the Brain News, http://neuro.hms.harvard.edu/harvard-mahoney-neuroscience-institute/brain-newsletter/and-brain-series/sugar-and-brain

Hames, D. and Hooper, N. “Carbohydrate
Metabolism.” Biochemistry, 3rd ed. New York: Taylor & Francis, 2005,
pp.300-345.
Kahn, S., Hull,
R. and Utzschneider, K. “Mechanisms linking obesity to insulin resistance
and type 2 diabetes.” Nature News,
Nature Publishing Group, 14 Dec. 2006, http://www.nature.com/articles/nature05482

Li, J., Tang,
Y., Purkayastha, S., Yan, J. and Cai, D. “Control of obesity and glucose
intolerance via building neural stem cells in the hypothalamus.” Molecular Metabolism, Elsevier, 4
Feb., 2014, http://www.sciencedirect.com/science/article/pii/S2212877814000179

Mukherji, S.,
Jacobson, A. and Holt, R. “Effects of glucose on the brain – Associated
disorders – Diapedia.” The Living
Textbook of Diabetes, Diapedia, 13 Aug., 2014, https://www.diapedia.org/associated-disorders/61047161570/effects-of-glucose-on-the-brain

6.     Obateru O.,
Olokoba, A. and Olokoba, L. “Type 2 Diabetes Mellitus: A Review of Current
Trends.” Oman Medical Journal, U.S. National Library of Medicine, 28 Jul., 2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC3464757/

Röder, P., Wu, B., Liu, Y.
and Han, W. “Pancreatic regulation of glucose homeostasis.” Experimental and Molecular Medicine,
Mar. 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892884/