Friday, June 30, 2017

Heal Your Mind, Rewire Your Brain

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Heal Your Mind, Rewire Your Brain: Applying the Exciting New Science of Brain Synchrony for Creativity, Peace and Presence Paperback – July 15, 2010,by Patt Lind-Kyle  (Author)

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"Understanding how your mind can heal your brain."

Hope for brain injury.

What is "brain?"
-Chemicals and electrical signals in that lump of
meat that sits in our skulls.
-A part of the nervous system that is distributed
throughout the body.

What is "Mind?"
An embodied relational process that regulates the flow of information and energy. -Dan Seigel

Mindfulness is the mind's ability to be gently aware of this process.

Two key ways the mind can help the brain rewire:
Neuroplasticity

Neurogenesis

What is neuroplasticity?
"Neuro" Greek for nervous system "Plasticity" means plastic or malleable (like clay, it can be shaped).
Thus neuroplasticity is having a malleable nervous system (brain) - for better or worse (eg. kindling vs the dalai lama).

What is neurogenesis?
"Neuro" = Brain/Nervous system
"Genesis" = to be born
Neurogenesis is the birth of new brain cells.

Yes it's possible!

What is Reptilian Brain?
Image result for reptilian brain

Image result for reptilian brain

Image result for reptilian brain


Image result for reptilian brain

Image result for reptilian brain

What is the job of the reptilian brain?
"The reptilian brain was the first part of the 
modern brain to develop in evolution. It 
operates behind the scenes, regulating our 
survival needs: food, oxygen, heart rate, 
blood pressure and reproduction, among 
many others.
The brainstem is like a bodyguard who's always
watching your back, constantly scanning the
environment for potential threats. The reptilian
brain also decides whether you will move into 
fight or flight."

What is the limbic brain?
The emotional brain or the "seat of the
unconscious" holds the amygdala and the
hippocampus.
The amygdala (size and shape of an almond)
can often be overactive in MTBI and PTSD. It
plays a role in emotional learning as well as
procedural memory.

The Hippocampus
The hippocampus regulates cortisol, a hormone
that is elevated by stress and fear/anxiety.
Too much stress leads to imbalances in cortisol
that can be related to the shrinking or lessoning
of the hippocampus (atrophy).

The Unhappy Hippocampus and the
Overactive Amygdala
The hippocampus is responsible for memory to
have a sense of past, present and future.
It is the seat of declarative/explicit memory
(factual information).
It is important in filtering what information is
important and what is irrelevant.

Image result for brain mirror view brain waves

Image result for brain mirror view brain waves

Image result for brain mirror view brain waves


The Hippocampus and Neurogenesis
 We once thought that the brain cells one is
born with were all that you had to work with and
that they died off as one aged.

By tagging thymadine with a dye we have
discovered that the hippocampus is where new
brain cells are first born.

Even in 90 years olds and even with brain
injury.


The Power of the Mind
By using our mind (spirit/will) to
effort calming ourselves the new
cells born in the hippocamus can
help the brain forge new pathways
(neuroplasticity).

How to help new cells not do the
same old thing.

One way in which the mind can help heal the
brain can be found in developing a strong skill
set of mindful based tools.

Mindfulness is one powerful way to help the
brain (part of the nervous system) to regulate
cortisol levels and achieve homeostasis.

The Mindful Brain: A Key
Having mastery over ways to be calm is one
way to help new brain cells being born in the
hippocampus not be drenched in cortisol so
that they do the same ole thing.

Mindfulness is a key to reverse atrophy in the
hippocampus so it can be robust and an ally.

Mindfulness assists the emotional
brain in regulating.

A happy hippocampus:
-helps with working memory,
-differentiation between the past and present
-filtering important vs ineffective information
-keeps the amygdala from going bonkers
-constructs a resilient narrative

How to develop a mind that can help
heal the brain:

1. Research shows changes in the brain after
ten hours of focusing on the breath in short
sittings (fifteen minutes).

2. Being successful does not require being
focused. Rewiring happens each time we bring
the wandering mind back to the breath.

PT for the brain!

When your mind wanders come back
to the breath.

Inhale 1 2 3 4 5
Exhale 1 2 3 4 5

Being with the Breath
Inhale (count), hold, exhale (count). 

Don't feel defeated every time you
catch your mind wandering.

That's the important part. When you catch
yourself and come BACK to the breath you
strengthen the brain muscle.

Brain muscle?

Mindfulness exercises help strengthen muscles
for positive neuroplasticity like the insula which
is part of the prefrontal cortex.

The dalai lama has Arnold Shwartzeneger
muscles in the insula.

The neocortex embraces the
emotional and reptilian brain.

When the limbic brain is flooded then the
neocortex cannot be accessed.

When this happens guess what we lose?

Executive function.

Executive Function tasks include:

Planning
Working Memory
Attention
Problem Solving
Verbal Reasoning
Inhibition
Mental Flexibility
Task Switching

Executive function is sometimes
called a non-cognitive skill.

This is because emotional regulation (noncognitive
skill) is the balance between a happy
hippocampus and a hearty prefrontal cortex.

Multiple variables that can make
executive function difficult to use.

1. Developmental obstacles (eg SES factors)
2. Attachment (e.g. caregivers with depression,
substance abuse, a hx of trauma)
3. PTSD/dissociation
4. MTBI/TBI

These are all ways the brain can be injured

Indeed MTBI and PTSD symptoms
are often the same.

Common examples of PTSD include:
AVOIDANCE
-Avoiding things that bring up memory such as
movies or tv that have images that remind you
of something
-Avoiding peole with red beards or hamburger
joints if something distressing happened. 

The dark side of neuroplasticity

The limbic system can kindle. Or one fear
based or avoidant thought re-enforces another.

This can lead to isolation because men with red
beards and hamburger joints can lead to
avoiding all men with facial hair and all public
eatery.

Thus fear and anger can wire our brains in a
way that is a disservice to our well being.

Thankfully our mind does not only exist in the
brain but just as much in the heart.

And there is a lot of of science to this statement
specific to the vagal nerve and to
neuropeptides such as oxytocin and
vassopresin but let me cut to the chase.

The Heart is an Intelligence
Processing Center

It's electromagnetic field is measured at five
times greater then that of the brain!

http://www.youtube.com/watch?
v=1XqPhoRKPWw

One amazing tool of mindfulness practice is
cultivating heart intelligence.

For example, the heart may have a habit of
racing when introduced to a stressor. (Low
heart rate variance [HRV]).

By working with the breath and slowing down a
frantic brain the heart's intelligence can be
accessed (High HRV).

Mindfulness repatterns the heart.

Research finds the more steady and even your
attention can make the heart the more willpower
rather then impulsivity can guide your
life.

Will power is intrinisic to agency (person-hood),
volition (choice). These "non-cognitive skills"
are at the "heart" of executive function.

The Reflective Self

Becoming heart centered means we are able to
feel with others in a way science calls "Flow"
that is at the heart of healthy relationships.

The mind is responsbile for flow. The brain and
heart are the minds "helpers."

Lovingkindness

Another major way the mind can
heal the brain with the heart's help is
through a practice called loving
kindness.

What is lovingkindness?

Lovingkindness is a practice in which we wish
others and ourselves well being. Practiced by
the dalai lama.

You don't have to be the dalai lama
to know this kind of happiness.

Research (Richard Davidson) shows that eight
minutes a day of loving kindness practice
rewires the brain.

Let's practice together now.

Sharing my experience of rewiring

I was first introduced to the ways the mind can
heal the brain through a neuro-scientist named
Dr. Jeffrey Schwartz. Dr. Schwartz discovered,
with brain imaging, the ways in which 21 days
of mindfulness based behavioral therapy and
his own process called "The Four Steps" could
rewire the brain.

The seed was planted

I was so impacted by Dr. Schwartz I gave up a
successful career in the film industry to study
psychology, particularly the field of trauma.

Thus I came into my experience with
a deep certainty that I was not stuck.

This is the first step to share with you:
To believe in your own potential to transform
and to perservere in trying and trying and
trying.

Here are are some keys tools that helped me
rewire.

Somatic Experiencing

Created by Peter Levine, this is a form of
therapy that helps the nervous system calm
and heal. It is not talk therapy. It is a subtle
and powerful tool.

The person I worked with:

There are different styles and ways to offer S.E.
My experience was lying on a massage table
and being well nurtured by someone named
Sally Thomas, an OT who was trained in a four
year program by Peter Levine. I asked Sally to
be available today so that, if you are interested
you can connect with her. Sally, will you stand
up?

Neurofeedback

Neurofeedback is a kind of therapy in which
electrodes are put on your head. They do not
stimulate you, they read your brainwaves.

Then you listen to tones and watch a computer
screen for feedback This feedback teaches
your brain when it's in it's optimal zone. 

The qEEG controversy.

There are lots of ways to do neurofeedback but
if you have TBI you know your brain is not
typical. Thus it is important to take great care
before you start altering the electromagnetic
field of your brain.

It's important to have your brain
imaged with a qEEG.

Although many wonderful programs exist that
are automatic, when using neurofeedback with
TBI, though it is an expense, it is not safe or
wise to work with a practitioner who is not
reviewing your qEEG and tailoring treatment to
your own unique brain's needs.

Crystal Bowl Meditation

I also utilzyed a form of sound therapy in which
someone played large bowls for one hour each
week to help me repattern my nervous system.
Crystal bowls are not just sound therapy.
Being lined with crushed quartz they have a
strong electromagnetic vibration. Not for the
faint of heart but very powerful.

Crystal Bowl Resource

I asked Kelly Maccinnis to be here today so
that you can find him as a resource.

Kelly plays weekly at Om Time and Body
Dynamics. He has a table out in the resource
area.

So, as we conclude let's revisit
where we began.

We began by taking a moment to connect with
one another. We then talked about the ways
the brain can wire/connect in new and
constructive ways you can direct with your
mind.
Revisiting Mind

Mind REGULATES information and energy.
This is a Relational Embodied Process. -Dan Siegel

MINDFULNESS

By following the guidelines of mindfulness practice (slowing down, focusing on the breath), the brain can learn to make new
CONNECTIONS.

LOVING KINDNESS

By becoming heart centered we get out of our
miserable egos and learn how to be more fully
and vitally connected to the world around us.

Having a "broken brain" does not
mean having a diminished heart.

If anything, those who have been through the
hardship of TBI have a much bigger and more
generous heart.

Loving kindness helps us CONNECT to the
world around us in constructive and meaningful
ways.

As you can see, it is all about
CONNECTION.

Suffering comes from a sense of isolation.

As we conclude, look around you. Think back
to the beginning of this presentation when you
connected with a neighbor.

As you go into your day, connect with one
another with a generous spirit. See what new
connections might be possible.

Yes, you can teach your old brain new tricks! Breakthroughs in the scientific understanding of how the brain works have shown us that our brains are constantly rewiring themselves in response to events in our lives. This handbook applies this new science in practical ways, by giving us a training program to re-pattern our behavior and thereby change the ways our brain is wired. It interrupts our suffering, sharpens our mental abilities and corrects our cognitive imbalances. As we learn these mental skills, the neural patterns of our brains begin to change and we literally reprogram the neural networks through which information and energy flows. If you've heard about neuroplasticity, epigenetics, psychoneuroimmunology and other scientific advances, but didn't know how you could apply these breakthroughs to improve your life, you will find Heal Your Mind, Rewire Your Brain a treasure trove of resources. It provides a clear, step-by-step program that shows you how to correct the imbalances of the stressed-out brain, and install a peaceful state of mind.

Heal Your Mind, Rewire Your Brain: Applying the
Exciting New Science of Brain Synchrony for
Creativity, Peace and Presence
Author: Patt Lind-Kyle
Publisher: Energy Psychology Press
ISBN: 978-1-60415-056-8

The Brain : Is there a more fascinating and complex organ in the body? Often studied and just as often misunderstood, science, medicine and psychology have made great strides in the study of the brain.

Author Patt Lind-Kyle offers the reader a fascinating and indepth look at the last decade of the scientific breakthroughs in brain studies. The reader is given a better understanding of how the brain works and how it is constantly evolving. New studies have shown that by using mental training practices, we can transform our life and increase our emotional balance and wellbeing.

The first part of the book serves as a strong starting point to understanding the human brain, how it developed and how it affects all aspects of our lives. Part two teaches the reader meditations and tools to deal with challenges and changes. You will get a thorough understanding of brain wave patterns, the key neurotransmitter chemicals and the various brain centers.


The author has presented this work in an engaging and well organized style. Written with the layperson, student and professional in mind, it will be of tremendous aid to understanding how to help your mind work for you, your needs and areas you may feel weak in. Anyone with an interest in how our brain works and how thought processes can change our lives will thoroughly enjoy this book, and find a vast amount of new knowledge.

Author Lind-Kyle takes the reader on an extensive neuro-anatomy expedition; introduces Enneagram personality typing, and some eastern thought, before getting into the actual meditation exercises she recommends to alter brain wave function. Carefully omitting the word yoga, Lind-Kyle explains the physiology of meditation by exploring its chemical and physical substrates. The last third of the book explores the meditation exercises that Lind-Kyle recommends for balancing brain patterns based on her work with meditation techniques and the electroencephalograph. The author recommends the methods to reduce stress, alter obsessive thoughts and correct personality anomalies.
The scientifically minded will be annoyed at her continued use of the word evolution both as a word to describe the true Darwinian “survival of the fittest” and the chemical changes that take place in the individual human brain as a result of learning. They will also be put off by Lind-Kyle’s reference to DNA and genes as separate units of heredity. However, anyone truly interested in neuroplasticity and meditation will be fascinated by the effort to bring healing and change to the average person.


Easy to understand, explains evolution, function, and patterns of different areas of the brain, neurotransmitters' impact on behavior, electro-chemical processes, and the mind-brain relationship. "The mind is what the brain does." Still reading . 

The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science
by Norman Doidge

An astonishing new science called neuroplasticity is overthrowing the centuries-old notion that the human brain is immutable. Psychiatrist and psychoanalyst, Norman Doidge, M.D., traveled the country to meet both the brilliant scientists championing neuroplasticity and the people whose lives they've transformed people whose mental limitations or brain damage were seen as unalterable. We see a woman born with half a brain that rewired itself to work as a whole, blind people who learn to see, learning disorders cured, IQs raised, aging brains rejuvenated, stroke patients learning to speak, children with cerebral palsy learning to move with more grace, depression and anxiety disorders successfully treated, and lifelong character traits changed. Using these marvelous stories to probe mysteries of the body, emotion, love, sex, culture, and education, Dr. Doidge has written an immensely moving, inspiring book that will permanently alter the way we look at our brains, human nature, and human potential.
The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science

Tuesday, June 27, 2017

Curing Type 1 Diabetes

Within the pancreas there are areas that are called the islets of Langerhans. The beta cells constitute the predominant type of cell in the islets. The beta cells are particularly important because they make insulin. Degeneration of the beta cells is the main cause of type I (insulin-dependent) diabetes mellitus.

How do beta cells produce insulin?

The primary function of a beta cell is to store and release insulin. Insulin is a hormone that brings about effects which reduce blood glucose concentration. Beta cells can respond quickly to spikes in blood glucose concentrations by secreting some of their stored insulin while simultaneously producing more.

What is an islet cell?

Pancreatic islets, also called islets of Langerhans, are tiny clusters of cells scattered throughout the pancreas. Pancreatic islets contain several types of cells, including beta cells, that produce the hormone insulin. Insulin helps cells throughout the body absorb glucose from the bloodstream and use it for energy.

Which cells do not need insulin?

It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.

What is beta cell strain?

Beta cells produce insulin, and also secrete insulin when they are signaled to do so by an increase in glucose levels in the blood. Without adequate insulin, blood glucose levels rise too high, a defining characteristic of any type of diabetes.

Where are the islets of Langerhans located and what is their function?

Image result for islets of Langerhans

The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (i.e., hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans.

Image result for islets of langerhans diabetes

Image result for islets of langerhans diabetes

Image result for islets of langerhans diabetes

Image result for islets of langerhans diabetes

Image result for islets of langerhans diabetes

Image result for islets of langerhans diabetes


Image result for islets of langerhans diabetes

How Insulin is synthesized?
Insulin is synthesized in significant quantities only in beta cells in the pancreas. ... When the beta cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity.

Can the beta cells regenerate?

A chemical found in ayahuasca has the potential to regenerate pancreas cells that have been lost to diabetes. New research published in Nature Medicine may have unlocked a new line of treatment for diabetes. The researchers honed in on the main culprits in diabetes: beta cells. Ayahuasca is an Amazonian plant mixture that is capable of inducing altered states of consciousness, usually lasting between 4 to 8 hours after ingestion.

What are the alpha cells?

Alpha cells (more commonly alpha-cells or α-cells) are endocrine cells in the pancreatic islets of the pancreas. They make up to 20% of the human islet cells synthesizing and secreting the peptide hormone glucagon, which elevates the glucose levels in the blood.

Physiologic Effects of Insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?"

Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues.

The Insulin Receptor and Mechanism of Action

Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.


The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.

Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects. A more detailed look at these processes is presented in the section on Insulin Signal Transduction.

Insulin and Carbohydrate Metabolism

Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are:

1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.

When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.

It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.


2. Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.

Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.

3. A well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves.

When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon, which is secreted when blood glucose levels fall below the normal range.

Insulin and Lipid Metabolism

The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following:


1. Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.

When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.

2. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.

From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.

Other Notable Effects of Insulin

In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation.

Insulin also increases the permiability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.

Insulin Deficiency and Excess Diseases

Diabetes mellitus, arguably the most important metabolic disease of man, is an insulin deficiency state. It also is a significant cause of disease in dogs and cats. Two principal forms of this disease are recognized:

Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin. The onset of this disease typically is in childhood. It is due to destruction pancreatic beta cells, most likely the result of autoimmunity to one or more components of those cells. Many of the acute effects of this disease can be controlled by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life.
Type II or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the onset of this disease is in adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is normal. Because there is not, at least initially, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy. Rather the disease is controlled through dietary therapy and hypoglycemic agents.

Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for energy (insulin shock).

Physiologic Effects of Insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?"

Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues.

The Insulin Receptor and Mechanism of Action

Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.


The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.

Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects. A more detailed look at these processes is presented in the section on Insulin Signal Transduction.

Insulin and Carbohydrate Metabolism

Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are:

1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.

When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.

It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.


2. Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.

Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.

3. A well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves.

When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon, which is secreted when blood glucose levels fall below the normal range.

Insulin and Lipid Metabolism

The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following:


1. Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.

When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.

2. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.

From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.

Other Notable Effects of Insulin

In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation.

Insulin also increases the permiability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.

Insulin Deficiency and Excess Diseases

Diabetes mellitus, arguably the most important metabolic disease of man, is an insulin deficiency state. It also is a significant cause of disease in dogs and cats. Two principal forms of this disease are recognized:

Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin. The onset of this disease typically is in childhood. It is due to destruction pancreatic beta cells, most likely the result of autoimmunity to one or more components of those cells. Many of the acute effects of this disease can be controlled by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life.
Type II or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the onset of this disease is in adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is normal. Because there is not, at least initially, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy. Rather the disease is controlled through dietary therapy and hypoglycemic agents.

Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for energy (insulin shock).

CURE
For those who have been diagnosed with type 1 diabetes, JDRF is funding research towards curing the disease by replacing or renewing insulin-producing cells, and also stopping the body from attacking these cells.

THE BASIC CHALLENGES OF CURING TYPE 1 DIABETES

Type 1 diabetes occurs when the body’s immune system mistakenly attacks itself and destroys beta cells in the pancreas. Beta cells normally produce insulin, a hormone that helps the body turn sugar from food sources into energy for cells throughout the body. But when the immune attack destroys the beta cells, insulin is no longer produced and the sugar stays in the blood where it can cause serious damage to body organs. Because of this, people with type 1 diabetes have to regularly inject insulin in order to stay alive.

To cure someone with type 1 diabetes, two aspects of the disease need to be corrected. 

We need to stop the mistaken immune system attack on the insulin-producing beta cells, as well as protecting new beta cells from this ongoing attack (encapsulation).
We need to restore the body’s ability to produce its own insulin, either by making new beta cells from other remaining healthy cells in the pancreas (regeneration) or by making them in a lab or obtaining them from other animals and putting them into the body (replacement).
We have made good advances in identifying new ways to regenerate beta cells, and encapsulating beta cells in a barrier that protects them from further immune attack. Our cure research priorities in FY14 focus on:

Generating new beta cells from alternative cell sources that can be shielded from the immune system
Blocking the autoimmune response

Obtaining new markers to detect the disease at early stages