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.



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


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.


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).


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.




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.


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.


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.


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. 

·         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%

·         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.



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.


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


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.


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.


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


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.


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.


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.


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.


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.

Tuesday, 29 March 2016

Verapamil use in Autism – Request for Case Reports from Parents

 By Agnieszka Wroczyńska, MD, PhD, 
Medical University of Gdansk, Poland

In June 2014 my son with severe autism was given verapamil as an emergency mast cell stabilizer according to Peter’s blog, as we run out of other medication ordered from abroad. This turned out to be a life changing moment for him and my family. Two days later his chronic diarrhea resolved completely and soon after we also saw improvements in other symptoms and behaviors.

Several months, blog entries and papers read later my son still uses verapamil and now also other medications targeting autism, most of them being included into Peter’s PolyPill. He is still significantly affected by ASD, but his quality of life improved much, thanks to this blog.

Recently I have visited a very open-minded pediatrician, the first one who suspected medical issues behind challenging behaviours in my son and she asked me about papers on verapamil use in ASD, possibly to include it into her clinical practice. Unfortunately I have nothing to recommend although the use of calcium channel blockers for autism had been suggested long before my son was born as in this paper written in 2004: “These findings hint at a potential mechanism that might underlie autism. Future studies will focus on the genetic analysis of Cav1.2 and other calcium channels in the disorder and the potential application of calcium channel blocker therapy” [1]. This did not happen and no clinical trials were done.

Calcium signalling role in ASD is well backed by science [2-5] as Peter described in many excellent posts here, but not a single case report of such treatment was published. That’s why I would like to invite readers who use or used verapamil (short or long term with or without effects) to jointly publish an article on this treatment in a peer-reviewed medical journal as a case series description.  

According to what Peter suggested before, I wrote a questionnaire including basic clinical data and - if available - tests results suggested by Peter and Nat, as a first step to this article. I would really appreciate your contribution, comments or questions about this idea.

There is no deadline date so you are welcome to join if you start verapamil treatment for you or your child in the future. You may consider to do some lab tests according to the questionnaire then.

If you have not used verapamil, but would like to join this idea in other way, please feel free to contact me.

Before the collective article is ready let me quote a recent paper on another class of calcium channel blocking drugs in autism: “Given the excellent toxicity profile of dihydropyridine LTCC blockers, long-term off-label treatment of patients with ASD appears justified based on our robust in vitro findings.” [6]

If you have not used verapamil, but would like to join this idea in other way or just discuss autism treatment without participating in this case series report, please feel free to contact me.

Thank you!


Agnieszka Wroczyńska, MD, PhD
Medical University of Gdansk, Poland

The questionnaire can be downloaded from here:

The questionnaire filled with my son’s details as an example:

Friday, 25 March 2016

“Type 3” Diabetes in Alzheimer’s, but maybe also in some Autism

Intranasal insulin, for cognitive enhancement in Alzheimer’s and …

Today’s post was sparked by another little experiment of mine; no, not intranasal insulin.

Recently I have been using a reduced number of therapies on Monty, aged 12 with ASD.  Some people think there are just too many pills.

I wrote many posts last year about something called PPAR gamma (Peroxisome proliferator-activated receptor gamma, PPAR-γ or PPARG, also known as the glitazone receptor).

As you can read in Wikipedia:-

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia andhyperglycemia. PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells. PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.
Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.

What we found out in earlier posts that PPAR-gamma can be used to reduce microglial activation, which should turn down the body’s “immunostat”.  A key feature of many people’s autism appears to be an over-activated immune system, reflected by activated microglia.

PPAR-gamma agonists as regulators of microglial activation and brain inflammation.

The present review summarizes the several lines of evidence supporting that PPAR-gamma natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. 
Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-gamma agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.


The potent PPAR-gamma agonist drugs like Rosiglitazone, have side effects which I think make them unsuitable for autism.  I use a flavanol called Tangeritin, in the form of a supplement called Sytrinol.

For two months we have not used Sytrinol, but yesterday Monty had one pill after lunch.

The piano lesson was great and then Monty had three hours with his Assistant, doing academic work and then some more piano practice.

Before she went home, Monty’s Assistant spent ten minutes telling me, and Monty’s big brother, just how great the afternoon had been.

“Monty was amazing today”

“When he was doing math, it was like he wasn’t autistic”

(we live in a country where autism means strict definition autism, what in the US is called severe autism)

“Did you hear how he played the piano?”

I told Monty’s brother to make a mental note of this and tell it to Mum/Mom later.

The next day the effect of Sytrinol was not as profound.

This actually is a recurring theme, the effect of various interventions is the greatest at the beginning  and then, as the body’s feedback loops get involved, the effect reduces.  

The same is true with cinnamon, another food-based intervention, that also helps people with diabetes.  The effect in (some) autism is greatest when you start.

It would be great if it was possible to keep the full initial effect of both Sytrinol and Cinnamon, and avoiding the dampening reaction caused by feedback loops.

I think if this is possible, it will be via targeting the therapy directly at the brain, rather than the entire body.  This can be achieved via the intranasal route, as used with oxytocin.

What to put in the spray?  This would be a very personalizable solution, since different people have different dysfunctions and to varying degrees.  Some possibilities might include:-

·        Insulin  (read on to learn why)
·        IGF-1
·        T3 thyroid hormone
·        TRH
·        Type 2 iodothyronine deiodinase (D2) 
·        Oxytocin
Fine tuning Cognition

It is difficult to be certain what therapy is responsible for what effect.

I recently told one researcher/parent that interventions in autism seem to take effect very quickly and so you can pretty rapidly run through a series of mini-trials to see what helps, what makes things worse and what does nothing.  Being a researcher, his view is that you need to try things for much longer.

One problem of trials lasting months is that external factors may then change, that cause behavior to change and distort the result. This is why I try to avoid trials from May to October, the allergy season.

Many people do find that some supplements help a lot for a week or two and then make things worse.  This includes things like some B vitamins and carnitine.  For other people continued use keeps giving a positive effect.

Previous Experience with Sytrinol

Monty’s assistant at school last year thought Sytrinol made him cleverer.

She also thought the PAK inhibiting propolis (BIO 30) had a similar effect.  This propolis is quite expensive and I concluded the effect was small and this might be because it just was not potent enough. 

One reader of this blog is using a much more potent PAK inhibitor, FRAX486, and some people in the US use Ivermectin.

Ivermectin is an anti-parasite drug which also happens to be a PAK inhibitor.  It is not suitable for long term use.

 Why would Sytrinol improve cognition?

I have written a lot about PPAR gamma in the past, so today has a new angle on the subject.

I did a quick check on PPAR gamma and cognition.

I was surprised what I found.



PPARγ Recruitment to Active ERK during Memory Consolidation Is Required for Alzheimer's Disease-Related Cognitive Enhancement

Cognitive impairment is a quintessential feature of Alzheimer's disease (AD) and AD mouse models. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Tg2576 cognitive enhancement occurs through the induction of a gene and protein expression profile reflecting convergence of the PPARγ signaling axis and the extracellular signal-regulated protein kinase (ERK) cascade, a critical mediator of memory consolidation. We therefore tested whether PPARγ and ERK associated in protein complexes that subserve cognitive enhancement through PPARγ agonism. Coimmunoprecipitation of hippocampal extracts revealed that PPARγ and activated, phosphorylated ERK (pERK) associated in Tg2576 in vivo, and that PPARγ agonism facilitated recruitment of PPARγ to pERK during memory consolidation. Furthermore, the amount of PPARγ recruited to pERK correlated with the cognitive reserve in humans with AD and in Tg2576. Our findings implicate a previously unidentified PPARγ–pERK complex that provides a molecular mechanism for the convergence of these pathways during cognitive enhancement, thereby offering new targets for therapeutic development in AD.

Cognitive Enhancementwith Rosiglitazone Links the Hippocampal PPAR gamma and ERK MAPK Signaling Pathways

Pathogenesis of Alzheimer’s and Diabetes

The pathogenesis of a disease is the biological mechanism (or mechanisms) that lead to the diseased state.

I am not suggesting that autism leads to Alzheimer’s.  (We do though know that most people with Down Syndrome will develop early Alzheimer’s in their 40s or 50s)

Many complex diseases like Alzheimer’s, cancer and indeed autism have multiple biological mechanisms behind them.

By studying the molecular pathways involved in one disease it may help understand another disease.  This is why some readers of this blog follow the cancer/oncology research.

For some time I have been intrigued at the overlap between diabetes and autism.  What is good for autism really does seem to be good for diabetes and vice versa.

Alzheimer’s Disease as Type 3 Diabetes

I was surprised to learn that some clinicians now consider Alzheimer’s Disease as Type 3 Diabetes.           

You will recall that Type 1 diabetes is when your pancreas packs up making insulin and then you have to inject yourself with supplementary insulin.

Type 2 diabetes occurs in late middle age, often linked to obesity, and is characterized by high blood sugar, insulin resistance (insulin sensitivity), and relative lack of insulin.

Insulin resistance (IR) is generally regarded as a pathological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin. When the body produces insulin under conditions of insulin resistance, the cells in the body are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to a diagnosis of Type 2 diabetes.  Despite the ill-effects of severe insulin resistance, recent investigations have revealed that insulin resistance is primarily a well-evolved mechanism to conserve the brain's glucose consumption by preventing muscles from taking up excessive glucose.[

Eventually Type 2 diabetes may progress to Type 1 diabetes mellitus, where the body's own immune system attacks the beta cells in the pancreas and destroys them. This means the body can no longer produce and secrete insulin into the blood and regulate the blood glucose concentration. We saw how the use of Verapamil can stop beta cells being destroyed.

Some clinicians/researchers propose that diabetes of the brain should be called Type 3 diabetes.

The research does support the view that Alzheimer’s does incorporate this brain-specific type of diabetes.  But I know wonder if this applies to some autism.

Alzheimer’s disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain

The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM

Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production.

At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance.

Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or  a PPAR agonist

Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease

 Although many classes of drugs are now approved for management of diabetes, a primary focus of efforts to treat insulin-signaling dysfunction in AD has been the administration of exogenous insulin. There is abundant anecdotal evidence that insulin administration in people with diabetes may acutely affect mood, behavior, and cognitive performance.

Results of recent pilot studies of intranasal insulin in mild cognitive impairment (MCI) and AD have been encouraging. The most notable of these studies was a doubleblind, randomized trial of 104 older adults with MCI or AD who received placebo, low-dose (20 IU), or high-dose (40 IU) intranasal insulin for 4 months

In 2012, the U.S. National Institutes of Health allocated $7.9 million for a pivotal trial of intranasal insulin called the Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF; ClinicalTrials identifier: NCT01767909). This multicenter phase 2/3 study will be conducted by the ADCS. It is expected to recruit 250 participants with AD or MCI and to randomize them for 12 months to intranasal insulin or placebo, followed by an open-label extension of 6 months in which all participants will receive intranasal insulin. The study should be completed in late 2014.  The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)

In preclinical studies, TZDs improved biomarkers of AD as well as memory and cognition (31). The first pilot studies in humans were also generally encouraging, including a study by Watson et al. (32) that showed improved memory and modulation of amyloid-b levels in CSF compared with placebo after 6 months of treatment with rosiglitazone. On the basis of these preliminary studies, the maker of rosiglitazone sponsored two adequately powered phase 3 studies of rosiglitazone in AD as monotherapy or as adjunctive therapy to acetylcholinesterase inhibitors in mild to-moderate AD. These larger trials failed to replicate the positive findings of the smaller pilot studies (33).

Many explanations have been proposed for why rosiglitazone does not appear to be effective as a treatment for AD in cognitively impaired adults. Perhaps the most convincing explanation is that rosiglitazone has only modest blood-brain barrier penetration, and in fact, rosiglitazone is actively pumped out of the brain by an endogenous efflux system (34). Therefore, rosiglitazone should be expected to have only a mild insulin-sensitizing effect in the human brain.



The type 2 diabetes drugs like Rosiglitazone/Pioglitazone have been trialed in both autism and Alzheimer’s.  The results in autism with pioglitazone were positive, in Alzheimer’s they used Rosiglitazone, due to the adverse side effects of pioglitazone, and the results were very mixed.  Rosiglitazone has only modest blood-brain barrier penetration so it looks a poor choice.

In the autism trial they measured "autism" rather than cognitive function.

Effect of pioglitazone treatment on behavioral symptoms in autistic children 

In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3–4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.
Conclusion  Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.

One to watch is the effect of the standard type 2 diabetes treatment Metformin on cognition in Alzheimer’s.  Nobody really knows the mode of action of Metformin.

Intranasal insulin is very interesting and not just in Alzheimer’s.

Intranasal insulin improves memory in humans

Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

I will add it to my growing list of therapies for mild cognitive impairment, in case I need it in the future.

·        Nerve growth factor (NGF) eye drops
·        Lions Mane Mushrooms (that increase NGF)
·        Cocoa Flavanols (increase cerebral blood flow)
·        Intranasal insulin or just Tangeritin/Sytrinol

I do not know if intranasal insulin would be a safe long-term therapy for children, but it would be a good diagnostic tool.  Once large numbers of older people start using intranasal insulin for cognition, we will find out how well it is tolerated.  Older people seem far more prone to side effects than younger people.

For now I think Tangeritin/Sytrinol is the best choice.