Metformin linked to higher incidence of AD & Parkinson's

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Julie G
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Metformin linked to higher incidence of AD & Parkinson's

Postby Julie G » Mon Apr 10, 2017 7:46 am

A new paper was recently presented at the International Conference on Alzheimer’s and Parkinson’s Diseases that indicated metformin may increase the incidence of both Alzheimer's and Parkinson's in those with T2D. This contradicts earlier research. The authors suggest that a B12 deficiency may be at play. You can read a press release here.

As you'll recall, previous research has suggested that metformin inferes with mitochondrial efficiency. I can't help but wonder if that's the real MOA behind this finding. Here's an excellent link that summarizes the risks posed by metformin, including mitochondrial damage. Given that ApoE4 carriers already exhibit decreased mitochondrial efficiency, we may want to think twice about this medication.
At the center of metformin’s mitochondrial damage is its affect on the most basic of mitochondrial functions – ATP (cellular energy) production. Metformin reduces mitochondrial ATP production in skeletal muscle by as much as 48%. Sit with that one for a moment, a 48% reduction in cell fuel. Imagine functioning at only half capacity. This would make basic activities difficult at best and exercising to lose weight a very unlikely proposition. Imagine similar reductions in ATP production were observed in the brain or the heart or the GI tract (which, when on Metformin are likely), the types of disturbances we might see become quite clear: neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction, is an overwhelming sense of fatigue and malaise.[Emphasis mine.]

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Re: Metformin linked to higher incidence of AD & Parkinson's

Postby circular » Mon Apr 10, 2017 10:11 am

Wow, it must be complicated (knock me over with a wet noodle). I can't delve into it but I recalled this older thread suggesting it may have longevity benefits.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Metformin linked to higher incidence of AD & Parkinson's

Postby KatieS » Mon Apr 10, 2017 2:07 pm

Thanks, Julie for the metformin warnings. Such as contrast to the hyper we heard a few years ago when my A1c was 5.8. Fortunately, the endocrine consult thought I was not pre-diabetic, quickly dismissing my suggested metformin prophylaxis. Losing exercise's insulin sensitivity benefits, being exhausted with ATP depletion and elevating Hcy/decreasing B12 might underlie the increase in AD. The Taiwanese study was over 12 years of 9k, reviewing metformin Rx logs with AD & PD. I wonder if metformin's negative effect would be greater in countries with higher E4 incidence.

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Re: Metformin linked to higher incidence of AD & Parkinson's

Postby aphorist » Sat Jul 08, 2017 5:51 pm

I don't take metformin regularly, but I've trialed it a few times. I think a low dose metformin (500-750 mg/d), immediate release is probably fine. The primary reason I don't take it, is because I think I can probably achieve most of the outcome I desire through diet/lifestyle decisions. But I remain interested in it as an option for AMPK activation, insulin sensitivity and other aspects like the capacity to possibility offset the ills of being an office deskworkerhttps://www.hindawi.com/journals/jdr/2016/8274689/.

There is a point Chen makes at the end of his 2008 paperhttp://www.pnas.org/content/106/10/3907.full, which seems to demonstrate that Metformin (and likely its mechanism of action AMPK activation) potentiate insulin in a result that ultimately lower ABeta.

Image


Whether or not that AMPK activation is best achieved through metformin or other means (exercise, fasting, etc.), probably depends a bit on the individual.

Unless you are hypoinsulinemic, taking significant/continuous amounts (constant exposure) of metformin, I think metformin can be useful. I'm not taking it (yet), but I'm more inclined to find it beneficial at the appropriate dosage and context, such that the dose makes the poison. The B12 issue can be navigated.

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Re: Metformin linked to higher incidence of AD & Parkinson's

Postby Julie G » Sun Jul 09, 2017 11:52 am

I fall into the diet/lifestyle camp on this myself, but found this new paper interesting:

Metformin - a Future Therapy for Neurodegenerative Diseases
https://www.ncbi.nlm.nih.gov/pubmed/28589443
Abstract
Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin's role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson's disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin's advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aβ (β-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.


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