Galantamine, Diabetes and the Vagus Nerve.

Remy

Administrator
Looks like the metabolic disease, T2 diabetes, is also modulated by acetylcholine and the vagus nerve. Many of us struggle with higher than *should be* blood glucose despite an excellent diet and intractable weight gain. Maybe this is part of the reason why...and maybe galantamine can offer some relief?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532414/

Galantamine is available as an rx or OTC supplement, strangely enough. It's typically used for Alzheimer's disease though the relevant applications may be much more widespread.

The cholinergic anti-inflammatory pathway is one of the putative biochemical pathways that link diabetes with Alzheimer disease. Hence, we aimed to verify the potential antidiabetic effect of galantamine, unveil the possible mechanisms and evaluate its interaction with vildagliptin.

The n5-STZ rat model was adopted and the diabetic animals were treated with galantamine and/or vildagliptin for 4 weeks.

Galantamine lowered the n5-STZ-induced elevation in body weight, food/water intake, serum levels of glucose, fructosamine, and ALT/AST, as well as AChE in the tested organs. Moreover, it modulated successfully the lipid profile assessed in serum, liver, and muscle, and increased serum insulin level, as well as % β-cell function, in a pattern similar to that of vildagliptin.

Additionally, galantamine confirmed its antioxidant (Nrf2, TAC, MDA), anti-inflammatory (NF-κB, TNF-α, visfatin, adiponectin) and anti-apoptotic (caspase-3, cytochrome c) capabilities by altering the n5-STZ effect on all the aforementioned parameters.

On the molecular level, galantamine/vildagliptin have improved the insulin (p-insulin receptor, p-Akt, GLUT4/GLUT2) and Wnt/β-catenin (p-GSK-3β, β-catenin) signaling pathways.

On almost all parameters, the galantamine effects surpassed that of vildagliptin, while the combination regimen showed the best effects.

The present results clearly proved that galantamine modulated glucose/lipid profile possibly through its anti-oxidant, -apoptotic, -inflammatory and -cholinesterase properties. These effects could be attributed partly to the enhancement of insulin and Wnt/β-catenin signaling pathways.

Galantamine can be strongly considered as a potential antidiabetic agent and as an add-on therapy with other oral antidiabetics.
 

Remy

Administrator
Galantamine at 8 mg/day in CFS found to improve cholinergic transmission and improve symptoms.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796068/pdf/pi-6-204.pdf

Hypocortisolism
Many studies of patients with CFS have found HPA axis dysregulation and hypocortisolism. In these studies cortisol levels were decreased in 24-hour urine,7 serial blood samples,10 or saliva,11 as seen in our study, but it is not clear whether low cortisol levels and HPA hypo- function in CFS are a cause or result of the illness. Tak- ing into account the finding of this study of the reduced cortisol levels of the pre-and post-treatments, we can infer that HPA alterations in CFS are the persisting fea- tures of the disease, although we do not make any sug- gestions as to whether it is a cause or a consequence of the illness. Reduced HPA axis functioning6 has also been suggested to cause some of the symptoms, like re- duced energy, post-exertional malaise, and headaches1 seen in CFS patients. In a previous study 5-10 mg/d hy- drocortisone therapy resulted in a fall in fatigue scores of 34%.33 One explanation for hypocortisolism in CFS may be increased glucocorticosteroid receptor sensitivity.34

The finding of unchanged cortisol level after galanta- mine treatment of this study is consistent with a recent study by Blacker et al.26

How can we explain the finding of the study that while cortisol levels remained lower throughout the galantamine treatment some patients showed symptomatic improve- ment at partial level? It has been suggested that a func- tional deficiency of cholinergic neurotransmission may result in hypoactive HPA axis under stress conditions35
and may have a role at pathophysiology of CFS. Cho- linergic neurotransmission stimulates growth hormone and insulin-like growth factor I secretions, which plays an important role in the regenerative functions of the pe- ripheral nerves and skeletal muscles.35 Taking together these findings, increased cholinergic activity by galanta- mine treatment might trigger well-being independently of cortisol levels in some patients. This means, at least in some patients, that it may not be necessary to normalize cortisol levels for an improvement to be achieved. How- ever, if we followed the patients in the long-term we could have a better idea about cortisol levels. As a con- clusion we can suggest that in some patients with CFS there may be dysregulation in other systems like the cholinergic system along with the HPA axis.

Dehydroepiandrosterone sulfate levels and dehydroepiandrosterone sulfate/cortisol molar ratios

Given the findings of lower pre- and post-treatment cortisol levels, higher pre-treatment DHEAS levels com- pared to post-treatment, and higher DHEAS/cortisol mo- lar ratios in the patient group, we can suggest that there may be a disturbance in the ‘metabolic shift’ from an- drogens to glucocorticoids.

DHEA/cortisol or DHEAS/cortisol molar ratios were used in many studies as variants that reflected the home- ostasis between androgens and glucocorticoids at adrenal level.17,36 Scott et al.37 performed a study in CFS patients without any psychiatric comorbidity. They found that DHEA and DHEAS levels were lower than in healthy controls and explained this finding with mild adrenal cortical atrophy (failure) secondary to ACTH deficiency. Scott et al.37 also did not identify any difference between CFS patients, depressives, and healthy controls with res- pect to basal cortisol levels. De Becker et al.38 demons- trated that basal DHEA levels were normal, but DHEA responses to ACTH stimulation were blunted in CFS patients. No cortisol levels were reported in that study.

Cleare et al.36 found higher basal DHEA levels in CFS patients with no psychiatric comorbidity compared to healthy controls; however, they did not report any differ- ence in DHEAS levels. In the same study, they did not find any difference between patients and controls with respect to cortisol/DHEA molar ratio. In addition, the investigators administered low dose (5-10 mg/d) hydro- cortisone to CFS patients and determined significant de- creases in DHEA levels in patients who reported declin- ed fatigue scores with treatment. They found significant reductions in DHEAS after hydrocortisone treatment. Similarly, we also found decreased DHEAS levels after galantamine treatment in CFS patients. This may be interpreted as the fact that the acetylcholinergic effect of galantamine facilitates the release of CRH hormone and in turn, causes elevated DHEAS levels to decrease th- rough recovering the existing tentative disturbance in metabolic shift from cortisol to DHEAS.

Some studies have reported low39,40 or normal36,41 mor- ning DHEAS levels in CFS patients. An investigator re- ported a slightly high DHEA levels in CFS patients.18 Si- milarly, Goldberg and Lichten42 reported DHEAS levels above the reference limit in 20% of their patient group, made up of 140 females with CFS. In our study increa- sed pre-treatment DHEAS/cortisol molar ratio may have been due to impaired HPA axis activity and decreased cortisol levels or a defect in metabolic shift from andro- gen to glucocorticoid production. It was proposed that the literature findings about higher cortisol/DHEA molar ratios in major depression were the most important indica- tors of excessive cortisol exposure of the brain.43,44 On the other hand, our finding of high DHEAS/cortisol molar ratios might lead to further decreases in the low cortisol effects on the brain. However, only basal levels were in- vestigated in this study. Circadian measurements might provide further information on this subject.

The controversies in all these studies might be explained by the differences in clinical characteristics (psychiatric comorbidity, medicines), methodological discrepancies (differences in the timing of blood sampling or laboratory techniques), and other factors that might affect functions of the HPA axis, like inactivity. Our study had the advantages of including pure and untreated CFS patients.

In conclusion, decreases in basal DHEAS levels and DHEAS/cortisol molar ratios in CFS patients with gal- antamine treatment may somewhat support the hypothe- sis that cholinergic deficit may be present in CFS. On the other hand, DHEAS findings of responders suggest that high pre-treatment values of this hormone may be an indicator of the treatment responsiveness. If DHEA and DHEAS levels play an important role in CFS phy- siopathology, we think that, in addition to the employ- ment of non-invasive techniques like the measurement of cortisol levels in the saliva, the evaluation of DHEA (-S) levels with response to naturalistic stressors (chal- lengers) like exercise or social stress in future studies will be beneficial.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Looks like the metabolic disease, T2 diabetes, is also modulated by acetylcholine and the vagus nerve. Many of us struggle with higher than *should be* blood glucose despite an excellent diet and intractable weight gain. Maybe this is part of the reason why...and maybe galantamine can offer some relief?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532414/

Galantamine is available as an rx or OTC supplement, strangely enough. It's typically used for Alzheimer's disease though the relevant applications may be much more widespread.
Wow - Alzheimer's, diabetes, acteylcholine and the vagus nerve - that's quite a combination.

One of the reasons Ron Davis doesn't want ME/CFS moved into the neurological institute (NINDS) is that he's not sure that its primarily a nervous system disorder at all. If the metabolomics data he's getting is validated it could be a metabolic disorder and would be better off with diabetes in the diabetes Institute - the name of which escapes me.

It's nice to see the acetylcholine and vagus nerve connection :)
 

Remy

Administrator
which do you like better - ibudilast or galantamine?
So I finished out the galantamine bottle...tried 4 mg and 8 mg twice a day.

I can honestly say I felt nothing from the galantamine at any dose.

So I switched to huperzine A...and I can definitely feel that at 200 mcg twice a day. I got a little blurry vision the first couple of days but that seems to have cleared up now. My HRV is also a little higher in the morning since I started and last night my HF (parasympathetic) was actually dominant, just relaxing and reading, as it should be.

So I'll stick with that for a bit and see how it goes.
 

ankaa

Well-Known Member
@Remy

What's HRV and HF?

Do you like ibudilast better than Huperzine? Is ibudilast cholinergic, or does it work on increasing blood flow to the brain (ie, a vascular agent)?
 

Remy

Administrator
@Remy

What's HRV and HF?

Do you like ibudilast better than Huperzine? Is ibudilast cholinergic, or does it work on increasing blood flow to the brain (ie, a vascular agent)?
HRV is heart rate variability.

HF is high frequency which is one of the parameters that makes up HRV. LF, or low frequency, is the other arm that represents the sympathetic activation.

Ibudilast and huperzine do different things. I think that they may work well together but we will see!

Ibudilast is not cholinergic, it is a phosphodiesterase inhibitor, mainly.
 

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