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Showing posts with label insulin. Show all posts
Showing posts with label insulin. Show all posts

Thursday 28 April 2016

Intranasal Insulin for Some Autism vs IGF-1 and NNZ-2566

 

Very often the simplest solutions are the best and very often, when fault finding a problem, people overlook the obvious.  

I seem to be forever having to mend things and I find this all the time.

Back in 2013, when I knew much less about autism, I wrote about the experimental use of insulin like growth factor 1 (IGF-1) in autism.  

It’s a Small World – IGF-1 and NNZ-2566 in Autism


It turned out that in autism the many different growth factors can be disturbed (too much, or too little) and this variation does indeed define some specific types of autism.  For example in Rett Syndrome there are very low levels of Nerve Growth Factor (NGF); low levels of NGF in some older people is the cause of their dementia.  In more common types of autism NGF is actually elevated.

IGF-1 is very well studied.

 

IGF-1 is a primary mediator of the effects of growth hormone (GH). 

Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver,kidney, nerves, skin, hematopoietic cell, and lungs. This would explain why adults abusing GH may end up needing hip and knee replacements.

Before getting into the science, IGF-1 has long been available as a drug to treat children with growth delays.  In the US this drug is being used on children with a type of autism called Phelan-McDermid Syndrome.

Now, regular readers will recall from my last post on intranasal insulin that it was in this very syndrome that there was a successful intranasal insulin.

So most likely without delving into the science at all it looks like IGF-1 and intranasal insulin are both options to treat the same dysfunction.

Using IGF-1


Using Intranasal Insulin

Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.



NNZ-2566

This is an Australian drug that is a modified version of IGF-1 (a so called analog).  They modified it so that it can be taken orally rather than by injection.  The developer has a very thorough presentation showing why they think it should be effective in autism.  

  




The Science

The first thing to note is that insulin and IGF-1 act as messengers.  Disruption in growth factor signaling can have serious consequences.

Insulin and IGF-1 both activate the same insulin receptor (IR).

Most people think that insulin is a just a hormone produced in their pancreas that regulates the amount of glucose (sugar) in their blood.  It does of course do that, but it actually does much more.



  




Insulin receptors are expressed all over the body including the brain.

Here is a relatively simple presentation explaining the role of insulin signaling in the brain:-





Now for the diehard scientists among you that have been reading about all those signaling pathways that lie behind autism, cancer and many other hard to treat conditions, look at the graphic below.

We know the importance of RAS.  Impaired RAS signaling underlies the RASopathies, one feature of which is cognitive loss (MR/ID), another is autism.

We also know the importance of Akt (PKB/protein kinase B) in some types of autism.  PTEN appears again.










So irrespective of an undoubtedly important effect on glucose and insulin resistance, we should expect activation of insulin receptors in the brain, in some types of autism, to have a further positive effect.

It would seem to be a potential therapy for RASopathies.

As is often the case, there are extreme dysfunctions of RAS and I suggest there are more mild dysfunctions.

I suggest that some people with autism and some cognitive dysfunction have a partial RASopathy.

Since autism contains both extremes of many dysfunctions, there will undoubtedly be types of autism that respond negatively, or not at all, to activation of insulin receptors in the brain.



Practicalities

Nobody likes injections and that is necessary to give IGF-1.

NNZ-2566 is an experimental autism drug and on past performance that means it will take decades to reach the market, if ever.

That leaves insulin which was sitting all along in your local pharmacy.

Intranasal insulin was once investigated for use in diabetics, but it did not work.  It is not absorbed into the blood stream.

This is of course the huge advantage for people with autism, since we only want to activate the insulin receptors in the brain.  If you are not diabetic why would you want to have any effects in the rest of the body?

Indeed there are known major side effects of injecting IGF-1 or GH (growth hormone) into adults.  All kinds of things start growing and this can lead to terrible results.

The fact that all the studies show that intranasal insulin does not enter the blood stream and so lower blood glucose levels, makes it a much better drug for autism than IGF-1 or indeed NNZ-2566.


Insulin

There are various types of insulin and the main difference is that some are modified to be longer acting.

The basic insulin is soluble or clear insulin, and nowadays is synthetic rather than derived from pigs.  Examples include Humulin Regular/R/S by Lilly.

The standard concentration is 100 IU/ml.

The trials in Alzheimer’s and other conditions varied in dosage but generally used about 20 to 40 IU per day.

This is not a trivial dose.  If injected, rather than inhaled, that dose would have a significant effect on lowering blood sugar and would be dangerous.

My antihistamine nasal spray gives a metered dose of 0.14 ml.

So without any dilution, if filled with off the shelf insulin it would dispense 14 IU per spray.

So no special high tech drugs, dilutants/diluents or dispensers appear to be necessary. Some trials do use fancy inhalers, like the one in the video at the end of this post.

To be prudent it might be wise to dilute the insulin so as to gradually increase the dose.  Maybe in some people the nasal membrane is more permeable than in others.  Some of the trials did this, but most did not.

A fridge is required, because insulin needs to be kept chilled.

I do wonder why nobody seems to be researching this in autism.  Silly point, as one insulin researcher commented on the earlier post; there is no big money to be made, hence no interest.



Insulin & Alzheimer’s

The reasons that intranasal insulin improves Alzheimer’s, and likely will Down Syndrome, may differ to those help in (some) autism.

Beta amyloid is key to Alzheimer’s (and early onset Alzheimer’s in Down Syndrome) but is not a known issue in autism.  Central insulin resistance is an issue in Alzheimer’s and might well be in autism.  

Perhaps people with mitochondrial dysfunction (an energy conversion dysfunction) might particularly benefit from increased glucose uptake in the brain.  It appears that mitochondrial dysfunction plays a role in insulin resistance. 

Role of Mitochondrial Dysfunction in Insulin Resistance

The activation of the RAS pathway might be highly beneficial to some people with autism.  

Here is a good film, which refers to the studies from previous posts and shows the effect on one man with Alzheimer's. 





 You also see their fancy inhaler device.








Thursday 31 March 2016

Intranasal Insulin for Improved Mood and Cognition


  

This post follows on the previous one that raised the issue of brain-specific insulin sensitivity being a common feature of neurological diseases/disorders.

It appears to be much more than just a rare possibility.   There have been numerous studies and even more are ongoing.

Intranasal insulin has even been tried one single-gene type of autism (Phelan-McDermid Syndrome) and in autism’s big brothers, bipolar and schizophrenia.

I did look for trials in children with Down Syndrome, since here is a direct link to Alzheimer’s, but there is just a trial in adults in progress.

There was an early trial in typical adults which is interesting since it found not only a cognitive improvement but also improved mood, so perhaps it should be trialed in adults with depression.  In the US, interestingly, T3 thyroid hormone is sometimes given off-label for depression and some antidepressants increase the conversion of the pro-hormone T4 to T3 in the brain.  I think central hypothyroidism is likely a feature of some neurological disorders, as I proposed in an earlier post.

I think it would be well worth trialing intranasal insulin in idiopathic Autism and, separately, idiopathic Asperger’s.  I am surprised nobody has done it. I really think Autism and Asperger’s  should be separated, since while we sometimes see the same therapy helps in both, sometimes there are Asperger-specific therapies, like Baclofen.

A small number of readers of this blog do follow the science and engage in some experimentation at home.  I think given what some people have already tried, intranasal insulin is not at all far fetched, you just need a metered dose nasal spray, insulin and the correct amount of dilutant/diluent, as in the trials.


Insulin and IGF-1 (insulin-like growth factor 1)

There are autism trials underway using subcutaneous injections of IGF-1 and also oral IGF-1 analogs.


IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body,

Insulin levels affect levels of growth hormone (GH) and IGF-1.

We know that various growth factors (NGF, BDNF, IGF-1 etc.) in people with autism can be disturbed, but there is both hypo and hyper.

We also know that the level of hormones measured in the blood can be very different to those in the brain/CNS.  This means that having blood tests indicating  high serotonin, thyroid T3, IGF-1 etc. does not tell you anything about the level within the brain.  Quite possibly they may be the opposite.

It would seem to be hugely preferable to target the brain directly, rather than the whole body.

The lack of side effects in the numerous studies of intranasal insulin is very encouraging.




Healthy Neurotypical Adults



Declarative memory in humans without causing systemic side effects like hypoglycaemia. The improvement of memory in the eighth week of treatment corroborates previous findings of improved memory function following acute intravenous administration of the peptide both in healthy subjects (Kern et al., 2001) and in patients with Alzheimer’s disease (Craft et al., 1999). In addition, intranasal insulin positively affected mood in our subjects. The improving effect of subchronic intranasal insulin administration appeared to be specific for hippocampus dependent declarative memory.

Our subjects in the insulin group also expressed enhanced mood. Acute intranasal intake of insulin enhanced the feelings of well-being and self-confidence, which is in accordance with previous results (Kern et al., 1999).

In summary our data indicate that prolonged intranasal intake of insulin improves both consolidation of words and general mood. These beneficial findings suggest intranasal administration of insulin as a potential treatment in patients showing memory deficits in conjunction with a lack of insulin, such as in Alzheimer’s disease




Adults with Schizophrenia

No effect of adjunctive, repeated-dose intranasal insulin treatment on psychopathology and cognition in patients with schizophrenia.



Abstract

OBJECTIVE:

This study examined the effect of adjunctive intranasal insulin therapy on psychopathology and cognition in patients with schizophrenia.

METHODS:

Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder and been on stable antipsychotics for at least 1 month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale and the Scale for Assessment of Negative Symptoms. A neuropsychological battery was used to assess cognitive performance. The assessment for psychopathology and cognition was conducted at baseline, week 4, and week 8.

RESULTS:

A total of 45 subjects were enrolled in the study (21 in the insulin group and 24 in the placebo group). The mixed model analysis showed that there were no significant differences between the 2 groups at week 8 on various psychopathology and cognitive measures (P > 0.1).

CONCLUSIONS:

Adjunctive therapy with intranasal insulin did not seem to be beneficial in improving schizophrenia symptoms or cognition in the present study. The implications for future studies were discussed.


Adults with Bipolar


A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder.

 


Abstract

BACKGROUND:

Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder.

METHODS:

Sixty-two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of ≤ 3 on the seven-item Hamilton Depression Rating Scale (HAMD-7) and ≤ 7 on the 11-item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery.

RESULTS:

There were no significant between-group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test-Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task-Habit Estimate, suggesting an improved performance from baseline to endpoint with no between-group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns.

CONCLUSIONS:

Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between-group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre-existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup





22q13 deletion syndrome is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations typical of a terminal deletion should be diagnosed as 22q13 deletion syndrome. 22q13 deletion syndrome is often placed in the more general category of Phelan-McDermid Syndrome (abbreviated PMS), which includes some mutations and microdeletions. 

Physical
·         Absent to severely delayed speech: 99%
·         Normal to accelerated growth: 95%
·         High tolerance to pain: 77%
·         Hypotonia (poor muscle tone): 75%
·         Dysplastic toenails: 73%
·         Long eyelashes: 73%
·         Poor thermoregulation: 68%
·         Prominent, poorly formed ears: 65%
·         Large or fleshy hands: 63%
·         Pointed chin: 62%
·         Dolichocephaly (elongated head): 57%
·         Ptosis (eyelid) (droopy eyelids): 57%
·         Gastroesophageal reflux: 42%
·         Epileptic seizures: 27%
·         Kidney problems: 26%
·         Delayed ability to walk: 18%

Behavioral
·         Chewing on non food items: 85%
·         Delayed or unreliable toileting: 76%
·         Impulsive behaviors: 47%
·         Biting (self or others): 46%
·         Problems sleeping: 46%
·         Hair pulling: 41%
·         Autistic behaviors: 31%
·         Episodes of non-stop crying before age 5: 30%
·         Teeth grinding: (unknown) %



Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.

 

BACKGROUND:

The 22q13 deletion syndrome (Phelan-McDermid syndrome) is characterised by a global developmental delay, absent or delayed speech, generalised hypotonia, autistic behaviour and characteristic phenotypic features. Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease.

AIMS:

To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome.

METHODS:

We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year. Short-term (during the first 6 weeks) and long-term effects (after 12 months of treatment) on motor skills, cognitive functions, or autonomous functions, speech and communication, emotional state, social behaviour, behavioural disorders, independence in daily living and education were assessed.

RESULTS:

The children showed marked short-term improvements in gross and fine motor activities, cognitive functions and educational level. Positive long-term effects were found for fine and gross motor activities, nonverbal communication, cognitive functions and autonomy. Possible side effects were found in one patient who displayed changes in balance, extreme sensitivity to touch and general loss of interest. One patient complained of intermittent nose bleeding.

CONCLUSIONS:

We conclude that long-term administration of intranasal insulin may benefit motor development, cognitive functions and spontaneous activity in children with 22q13 deletion syndrome.


For intranasal administration, insulin (40 IU/ml; Actrapid, Novo Nordisk, Mainz, Germany) was diluted with 0.9% saline solution to a concentration of 20 IU/ml so that each 0.1 ml puff with the nasal atomizer (Aero Pump, Hochheim, Germany) contained a dose of 2 IU insulin. Subjects received one dose of 2 IU insulin per day during the first 3 days according to the standard subcutaneous insulin therapy in children with type 1 diabetes mellitus. In three-day intervals, administration was increased gradually, until the final dosage of about 0.5-1.5 IU/kg/d (TID)


As with idiopathic autism there is interest in using the related IGF-1 as a therapy.



A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome



Background

Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.

Methods

Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.

Results

Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.

Conclusions

This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.


Drug administration

IGF-1 (Increlex; Ipsen Biopharmaceuticals, Inc) is an aqueous solution for injection containing human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. Placebo consisted of saline prepared in identical bottles by the research pharmacy at Mount Sinai. We received an Investigational New Drug exemption from the Food and Drug Administration (#113031) to conduct this trial in children with PMS. Based on the package insert for Increlex, dose titration was initiated at 0.04 mg/kg twice daily by subcutaneous injection, and increased, as tolerated, every week by 0.04 mg/kg per dose to a maximum of 0.12 mg/kg twice daily. This titration was justified based on our preclinical data, which indicated that 0.24 mg/kg/day is effective in reversing electrophysiological deficits whereas 0.12 mg/kg/day was not as effective[21]. We aimed to reach the therapeutic dose as quickly as is safe and tolerated in order to allow maximum time for clinical improvement. Doses could be decreased according to tolerability by 0.04 mg/kg per dose. Medication was administered twice daily with meals, and preprandial glucose monitoring was performed by parents prior to each injection throughout the treatment period. Parents were carefully trained in finger stick monitoring, symptoms of hypoglycemia, and medication administration.



Down Syndrome

The ongoing Down Syndrome trial is in adults.  As mentioned earlier, a feature of the syndrome is the likely early onset of Alzheimer’s, so not surprisingly if intranasal insulin helps people with Alzheimer’s it makes sense to trial it on people with Down Syndrome.
I think it makes sense to trial it on young people with Down Syndrome, prior to the onset of Alzheimer’s.




This study is a single center, randomized, double-blind, placebo-controlled, cross-over pilot study designed to assess the safety of intranasally (IN) delivered glulisine versus placebo in patients with DS. Subjects will be randomized into this cross-over study and within subject comparisons conducted between single treatment of intranasal insulin glulisine and single treatment of intranasal placebo



The SNIFF (Study of Nasal Insulin in the Fight against Forgetfulness) Trials




The large clinical trials all relate to Alzheimer’s.  The big trial, SNIFF INI, will last for 18 months, but they are also making shorter trials using different types of insulin.  There is  SNIFF Quick to test fast acting insulin and SNIFF long to test the long acting type.







The big 18 month study.




Conclusion

I think in a couple of decade’s time, it will be widely recognized that various physiological states exist in many complex diseases and while it may not be possible to cure those conditions, you can treat those altered physiological states.

In the case of autism those states might include:-

·        Oxidative stress
·        Mitochondrial stress
·        Microglial activation
·        Central hormonal dysfunction
·        Reduced brain insulin sensitivity
·        Impaired remyelination
·        Faulty GABA switch


These altered states are in addition to the specific channelopathies and other dysfunctions a particular person might have.


By applying what is learnt from other diseases we can then better treat the autism variants.  So what eventually develops from MS research in regard to remyelination can be translated to some autism variants, quite possibly that of Hannah Poling (mitochondrial disease, triggered by vaccination).

Reduced brain insulin sensitivity, where present, appears very treatable today.  I suspect some variants of autism do indeed feature reduced brain insulin sensitivity, but others will not.  There is no clever way to predict this, but it looks simple to test.