Author: Gabor Varga | 25.10.2018.
INTRANASAL C-PEPTIDE IS A RESTORER AND A MAINTAINER OF HEALTHY BRAIN FUNCTIONS AND A PROMISING THERAPEUTIC INTERVENTION IN CHRONIC DISEASES, SUCH AS: AUTISM, TRAUMATIC BRAIN INJURY, CANCER, DIABETES MELLITUS, INFLAMMATORY DISEASES, ETC.
C-Peptide – formed in the biosynthesis of insulin - is released from pancreatic beta cells into the circulation in equimolar amounts of insulin. It has been considered as biologically useless. Many beneficial functions emerged in the past twenty years, an effect attributed to proinsulin c-peptide. I will primarily focus on its most important effects on the nervous system. Most of the clinical trials of c-peptide focused on investigating its support of the health of the peripheral nerves, primarily in diabetes mellitus type 1, where it is not produced endogenously. However, its main effect is related to the central nervous system, a fact that is unfortunately largely overlooked by the mainstream research community.
Proinsulin C-peptide has a crucial role in early brain development. One recent publication investigates how maternal type 1 diabetes – where c-peptide is completely lacking and is not supplemented – impacts the risk of autism in the offspring. The investigators are taken aback by the results: maternal type 1 diabetes increases the risk of autism in the offspring more than two times (2.5/ 250%) compared to healthy mothers, and significantly more than type 2 diabetes (1.5/150%) or gestational diabetes by 26 weeks of gestation (1.4/140%). http://diabetes.diabetesjournals.org/content/67/Supplement_1/117-OR
As usual, researchers are blaming hypo-or hyperglycemia in particular for similar results, never the lack of c-peptide (which is able to lessen the deleterious effects of both). Clinically relevant cognitive impairment is also prevalent (five times higher!) among middle-aged adults with childhood-onset type 1 diabetes.
Why am I interested in c-peptide and the autism connection?
C-peptide is a close relative of insulin: it helps the proper folding of insulin during biosynthesis. Over 10 years ago (2005) I have initiated the first intranasal insulin treatment for a genetically identified form of autism (deletion or mutation 22q13, or Everything Has Been Overlooked Syndrome/ EHBOS or sometimes called Phelan McDermid Syndrome or SHANK3 deletion, which is one of the genes responsible for the disease): https://vargagyogygomba.hu/upload/original/szakirodalom/insulin_to_improve_the_developmental_delay_in_children.pdf
Intranasal insulin treatment for EHBOS has also proven to be successful for children older than three years of age in a larger, placebo-controlled trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117914/
So, I know exactly the beneficial effects and the drawbacks of intranasal insulin, although in the first years – 13 years ago - it was a life-saving intervention for my family (for all of us!): https://vimeo.com/480278
At least 50 clinical trials of intranasal insulin have been registered for various neurodegenerative and neuropsychiatric problems. Most of them turned out to be disappointing. Some results point to a beneficial effect in Alzheimer's. http://www.ekjcp.org/journal/view.html?doi=10.24304/kjcp.2017.27.3.161 https://www.sciencedirect.com/science/article/pii/S002839081730566X https://www.ncbi.nlm.nih.gov/pubmed/28372335
However, intranasal insulin has its serious limitations. Its effectiveness in mental problems has a definite limit that cannot be overridden by the administration of larger doses. (Also an unpublished observation)
One common effect of brain insulin and c-peptide is that they increase the activity of the parasympathetic / vagus nerve system.
In this regard c-peptide seems to be significantly more potent. In animal and in human clinical trials, c-peptide could significantly increase the parasympathetic tone (measured by heart rate variability):
Centrally administered (directly into the brain), c-peptide (seems to be significantly more potent:
How important is all this?
Longevity, aging, cancer, neuropsychiatric disorders, autism, schizophrenia, depression, Alzheimer's, traumatic brain injury, inflammatory diseases, defense against bacterial and viral infections, even marital stress, violence, aggression, crime, creativity etc. can all be significantly influenced by the parasympathetic nerve activity and thus by the central/brain c-peptide. We are now on the threshold to combat all these problems by an effective therapy with virtually nonexistent side effects. This may potentially be a new opportunity to change mental health problems. If this should fail, we will all go down because we must prevent the deterioration of our brain due to stress and environmental pollution (detailed later) causing our main problems in this world.
Aging is associated with the progressive decrease of the parasympathetic activity which is measured by heart rate variability. People living more than 80 years experience the reversal of the decrease of heart rate variability. The investigators of this phenomenon conclude that „Persistently high HRV in the elderly represents a marker predictive of longevity.”
Vagus – that is, parasympathetic nerve stimulation, is a very promising treatment possibility for autism in general, not only for seizure control but, among others, for its significant anti-inflammatory characteristics.
It has beneficial effects in epilepsy and depression.
https://www.ncbi.nlm.nih.gov/pubmed/29459836 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084129/ https://www.ncbi.nlm.nih.gov/pubmed/26896810 https://www.ncbi.nlm.nih.gov/pubmed/27401807 https://www.ncbi.nlm.nih.gov/pubmed/28120052 .
It is a relatively new finding that vagus nerve activity predicts cancer survival and may decrease the probability/aggressivity of metastases. Scientists conclude that „vagus nerve activation improves cancer prognosis.”
Vagus nerve stimulation seems to decrease inflammatory processes in the brain
and may be beneficial for stroke,
sepsis, inflammatory bowel disease, arthritis, heart disease, artherosclerosis and for inflammatory or autoimmune diseases in general.
https://www.ncbi.nlm.nih.gov/pubmed/24095121 https://www.ncbi.nlm.nih.gov/pubmed/19461672 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735283/ https://www.ncbi.nlm.nih.gov/pubmed/27491814 https://www.ncbi.nlm.nih.gov/pubmed/25378088 https://academic.oup.com/neurosurgery/article/81/5/N38/4560068 http://www.japmnet.com/uploadfile/2017/0202/20170202103906240.full.pdf https://www.ncbi.nlm.nih.gov/pubmed/28766392 https://www.researchgate.net/publication/6696733_Vagus-brain_communication_in_atherosclerosis- related_inflammation_A_neuroimmunomodulation_perspective_of_CAD
Activating the vagus nerve may resolve sleep dysregulation problems. https://www.ncbi.nlm.nih.gov/pubmed/16257548
Parasympathetic activation may ameliorate high glucose, insulin resistance and high blood pressure disorders https://www.ncbi.nlm.nih.gov/pubmed?linkname=pubmed_pubmed_citedin&from_uid=24968966 https://www.ncbi.nlm.nih.gov/pubmed/18833640
and may prevent or slow down the obesity epidemic. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606212/ .
In summary, central c-peptide may have brain regenerating properties that affect the whole body, because centrally improving the parasympathetic functions presupposes the regeneration of complex brain pathways.
This may lead to the amelioration or a cure for a wide variety of human diseases, not only for the most feared epidemic: cancer.
What may be the specific biological signalling pathways in the brain that are responsible for the regenerating effects of c-peptide on the central nervous system?
In November 2016, I had a traumatic brain injury inflicted in Kaprun, Austria, as a consequence of a ski accident. Both of my hippocampi fell out, I had a 3-second memory for two days and for a few days I have lost all of my memory of the last three years. As a long- term consequence I had sleep disturbances, daily mild memory impairments and some mood dysregulation and irritability. After a short recovery period, starting in March 2017, I resumed doing research again – as I had done 13 years earlier for my child Gabor’s autism and severe intellectual disability problems, leading to the discovery of the beneficial effects of intranasal insulin. This time, I have researched for both of us. I had to research for my own problem/traumatic brain injury because 30 phase III. clinical trials designed for the effective treatment for this disease had failed. It took me 7 months and on October 23, 2017 I have found the most optimal solution: intranasal c-peptide. The research has been arduous, often forgetting papers I had already read, but at least I had some confidence, supported by my former success of finding some relief from a few symptoms of autism through intranasal insulin.
As mentioned, I had traumatic brain injury with a three-second memory for two to three consecutive days. That means that I probably had a severe bilateral hippocampus failure at least in the C1 region. https://www.ncbi.nlm.nih.gov/pubmed/8756452
Vulnerable dendritic spines are responsible for memory formation and maintenance; these are tiny protrusions – mushroom shaped in mature form – mostly on the dendrites of neurons.
Traumatic brain injury is able to reduce their number or impair their functions. https://www.researchgate.net/publication/251567869_Controlled_Cortical_Impact_Results_in_an_Extensive_Loss_of_Dendritic_Spines_that_Is_Not_Mediated_by_Injury-Induced_Amyloid-Beta_Accumulation
I had known these facts from my neuroscience research pursued 13 years ago. I had to dive even deeper into neuroscience to find the solution that nobody with a scientific background could find.
Dendritic spines are dynamic structures. Their shape may change continuously, what's more, they can grow or shrink and vanish. Their change in form and shape, or their growing and shrinking is mainly due to actin, discovered by Bruno Straub in the laboratory of Nobel laureate Albert Szent-Györgyi, in the University of Szeged/Hungary. (The author of this site is currently in cooperation with the same department of the University of Szeged, named after Albert Szent-Györgyi.)
https://en.wikipedia.org/wiki/Actin Actin can grow, „polymerize” or be chopped up by cofilin, https://en.wikipedia.org/wiki/cofilin, the molecular scissor of actin. When cofilin is active, the scissors are working very diligently, disrupting existing shapes and functions and supporting new actin pieces for new shapes and functions. When cofilin is too active, or „overactivated”, the shapes collapse and dendritic spines collapse, which seems to be a catastrophic event; Actin is overchopped, tiny actin pieces are abundant, their long structures are missing and mature, mushroom-shaped dendritic spines cannot be maintained, as they do not have endogenous, filamentous actin support. A delicate balance between activation and deactivation of cofilin has to be maintained. For this delicate balance, complex signaling mechanisms are responsible to regulate cofilin activation (dephosphorulation) or deactivation (phosphorulation of cofilin/ pCofilin). My traumatic brain injury had obviously overactivated cofilin, the actin scissor, which caused dendritic spine damage in the bilateral hippocampus that was mostly restored within one week. This is exactly what researchers have seen when investigating the hippocampus in the animal model of traumatic brain injury. https://www.ncbi.nlm.nih.gov/pubmed/21838518
This is the biological explanation of why I had a three-seconds-memory for two to three days. After that, I had mild, short- term memory impairment and severe sleep deprivation/disturbance. Interestingly, recent researchers have discovered that sleep deprivation causes memory deficits by a mechanism similar to traumatic brain injury: reversible dendritic spine number reduction and destabilization caused be cofilin overactivation in the hippocampus.
At this point I thought I have pinpointed a problem that must necessarily be resolved by a potential remedy for neurodegeneration and specifically traumatic brain injury.
Interestingly, in the above-mentioned genetically identified form of autism, in EHBOS/ SHANK3 deletion, the same is the case in the genetic disease affecting my son Gabor: Cofilin is overactivated, https://www.ncbi.nlm.nih.gov/pubmed/26027926 with the difference that this overactivation is continuous, leading to the devastating consequences we know of one of the most severe forms of autism, leading to continuous neurological deterioration and to very early Alzheimer’s: https://naucnamreza.me/sites/naucnamreza.me/files/multimedia/istrazivaci/1510/naucni_radovi/SHANK3_0.pdf
The long term effects of traumatic brain injury are also similar: they may lead to Alzheimer’s https://www.ncbi.nlm.nih.gov/pubmed/29396300
and increased rates of psychiatric illnesses: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2327235/.
Indeed, according to the latest research of Alzheimer’s and cofilin, highly oxidative environment and elevated levels of active cofilin are the main culprits of Alzheimer’s and probably of a host of neurodegenerative diseases. As the discoverer of cofilin, James Bamburg suggests, the inhibition of cofilin („activating LIM kinase”) should be the solution for Alzheimer’s and for a few other neurodegenerations. https://www.ncbi.nlm.nih.gov/pubmed/26873625
Other researchers recently supported this suggestion by showing that restoring cofilin phosphorulation (inactivating cofilin by overexpressing PAK), rescues Alzheimer’s disease and restores synaptic functions.
Cofilin inhibition even restores neuronal cell death in ischemic brain injury and stroke and for this reason it is suggested by scientists as a therapeutic intervention. https://www.ncbi.nlm.nih.gov/pubmed/25526862
As we will see, this is exactly what proinsulin c-peptide does.
I had to find something for preventing the deterioration of my brain and the brain of my son because therapeutic science had failed at that time, despite spending billions of dollars for the solution (for autism, traumatic brain injury, Alzheimer’s, aging, stroke etc.). This has happened on October 23, 2016. I have found c-peptide (I had earlier investigated dozens of growth factors, hormones, neuropeptides etc.). First, c-peptide is activating signaling pathways, ultimately leading to the non toxic deactivation of cofilin (Rac1-PAK-LIMK pathway): https://www.ncbi.nlm.nih.gov/pubmed/19373435
This cofilin deactivation happens through multiple pathways: the above-mentioned sleep deprivation-induced cofilin activation, for example, is dependent on PDE4A5, which is downregulated by c-peptide by MAPKAPK2 (MK2) https://www.ncbi.nlm.nih.gov/pubmed/21323643
„Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A.” https://www.ncbi.nlm.nih.gov/pubmed/12059784
„(MAPKAP-K2) was induced after stimulation with c-peptide.”
Second, c-peptide, always present in combination with insulin in the body and brain, has also neuroprotective effects through other pathways, for example, by decreasing the toxic nitrotyrosine that is increased in various neurodegenerative diseases (e.g. Alzheimer’s, T1d, T2d, EHBOS, traumatic brain injury):
It has worked for me in vivo. I had the right to help myself when clinical science has failed.
But what about the case with autism, with EHBOS. As scientists found, EHBOS/ SHANK3 failure (not necessarily deletion or mutation!) is characterized by overactivated cofilin. SHANK3 or cofilin disregulation can be caused by several environmental factors, not only by genetic diseases, deletions, or mutation.
Aging downregulates SHANK3, along with some of the most important excitatory receptors that SHANK3 regulates: AMPA, NMDA making the brain vulnerable to neurodegenerative diseases, because, e.g., evoked AMPA contributes to the clearance of the toxic amyloidal beta in the brain.
and activated cofilin is more prone to oxidative damages, leading to cell death. https://www.ncbi.nlm.nih.gov/pubmed/19734890
Toxic materials, like aluminum, or amyloid beta, may induce inflammation that dowregulates SHANK3 and activates cofilin. Dowregulated shank3 is implicated not only in Alzheimer’s, but in autism, schizophrenia, bipolar depression and the list will be growing. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732231/
Children exposed to severe stress, maternal deprivation or the loss of their families are vulnerable to stress and to neuropsychiatric disorders by upregulation of mir-504, which leads to the downregulation of shank3.
Exposure to environmental pollution in early childhood can lead to autism by inflammation and shank3 downregulation.
Indeed, in brain tissues of autism, SHANK3 was epigenetically downregulated. https://www.ncbi.nlm.nih.gov/pubmed/24186872
Returning to our initial thread of the parasympathetic nervous system activation by intranasal proinsulin c-peptide, it is not surprising that even this procedure may lead to, among others, the solution of both autism and traumatic brain injury epidemic,, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496407/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247460/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211199/
leading to the resolution of aggressive behaviours and neuroticism: https://www.ncbi.nlm.nih.gov/pubmed/22067596
and increasing creative thinking: https://www.researchgate.net/publication/221629576_Correlation_between_coherent_heart_rate_variability_and_divergent_thinking
As we have seen, inflammation and pathogens play a major role in the development of neurodegenerative problems. Growing concern is the increasing number of bacteria resistant to antibiotic treatment. C-peptide, in combination with zinc, (zinc increases c-peptide activity significantly) may help in this respect, among others, by activating the anti-inflammatory parasympathetic pathway defeating pathogen-induced sepsis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968544/
Unfortunately, there is no worldwide intranasal c-peptide spray registered as a medicament.
Because c-peptide promotes the nutritional microcirculation in the skin at c-peptide deficient states (not only in type 1 and late type 2 diabetes but also in smokers and in the aging), I have registered the first c-peptide spray in the world as a cosmetic spray . https://dm5migu4zj3pb.cloudfront.net/manuscripts/2000/2147/JCI9802147.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015664/ https://www.ncbi.nlm.nih.gov/pubmed/12485807
The deodorant for the skin is/ will be available at: www.vargapeptide.com
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