Blood Sugar Variability Linked With Alzheimers

[centralcoastinvestor]

Mike C. just tweeted this out and Sportsrancho found it and posted it.  I think this is worthy a thread of its own.  Someday we can say; "Use Afrezza to stay in range and reduce Alzheimer's risk."  Very nice.

www.diabetes.co.uk/news/2017/aug/blood-sugar-and-hba1c-variations-linked-with-alzheimers-in-type-2-diabetes-98343355.html

[peppy]

hmmmm, diabetes a disability and blood sugar variation may lead to Alzheimer's.
A letter for insurance coverage to an insurer becoming more interesting.

(Mango, where is your unbelievable Alzheimer's work?)

[sportsrancho]

Aug 17, 2017 14:27:27 GMT -5 peppy said:

hmmmm, diabetes a disability and blood sugar variation may lead to Alzheimer's.
A letter for insurance coverage to an insurer becoming more interesting.

(Mango, where is your unbelievable Alzheimer's work?)

Mango is in heaven right now. He just now saw the Vdex video on Metformin. (That I looked through 30 posts to find for him:-)

[dreamboatcruise]

Aug 17, 2017 14:24:52 GMT -5 centralcoastinvestor said:

Mike C. just tweeted this out and Sportsrancho found it and posted it.  I think this is worthy a thread of its own.  Someday we can say; "Use Afrezza to stay in range and reduce Alzheimer's risk."  Very nice.

www.diabetes.co.uk/news/2017/aug/blood-sugar-and-hba1c-variations-linked-with-alzheimers-in-type-2-diabetes-98343355.html

This study wasn't directly looking at time in range, but I'd think it would be logical conclusion that there would be a direct link between having variable FPG and having more volatile swings in BG including out of range excursions.  Hopefully a study like this will be done using CGM to establish the direct link between time out of range and dementia now that CGMs are readily available.

[thall]

I stopped reading at "China Medical University."

[falconquest]

Aug 17, 2017 16:34:51 GMT -5 thall said:

I stopped reading at "China Medical University."

Actually, I own shares in another company that while working on Alzheimer's treatment has discovered this link. It should not be ignored.

[falconquest]

Ok, they actually obtained the rights to the compound. Note the source. Here's the detail......


Anavex Awarded New U.S. Patent

New York — June 4, 2014 — Anavex Life Sciences Corp. (“Anavex” or the “Company”) (OTCQB: AVXL), a clinical-stage biopharmaceutical company developing novel drug candidates to treat Alzheimer’s disease, other diseases of the central nervous system (CNS) and various types of cancer, is pleased to announce that it has been issued U.S. Patent No. 8,673,931 (the “Patent”). The composition and method Patent covers ANAVEX 3-71 (formerly AF710B) for treating Alzheimer’s disease (AD), type 2 diabetes and insulin resistance. ANAVEX obtained exclusive rights to worldwide patents and patent applications for ANAVEX 3-71 and related compounds in March 2014 from Life Science Research Israel, a subsidiary of the Israel Institute for Biological Research. The Patent has a term that expires no earlier than April 29, 2030.

“We are delighted to strengthen our intellectual property position with the issuance of this U.S. patent,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “We believe the issuance of this patent validates the novelty of our platform. Additionally, we consider it to be an important step in our strategy to build and protect strong and highly differentiated small molecule therapeutics for Alzheimer’s and other neurodegenerative diseases. We believe these indications are an area of significant opportunity in drug development and we look forward to leveraging our unique technology to address such therapeutic needs.”

About U.S. Patent No. 8,673,931

The invention in this Patent covers certain bicyclic heterocyclic spiro compounds, which are thought to be ligands for G-protein coupled receptors. The active compounds function as muscarinic receptor agonists and are candidates for pharmaceutical use. There is particular emphasis on a method for the treatment of Alzheimer’s disease as well as treating type 2 diabetes and insulin resistance syndrome.

[sayhey24]

Years ago Itell was following what was being called Type 3 diabetes very closely. Hopefully he still has all his research. Mango has also done some research in this area.

The one question I always had was what would be the absorption rate of afrezza if snorted. I am not sure if anyone knows. I am assuming MNKD did some analysis which should be available.

[mango]

peppy I sent some stuff in PM.

Metformin induces a range of effects that can facilitate and even induce neurodegeneration. One in particular is, Metformin induces mitochondrial dysfunction. Mitochondria contain DNA. Mitochondria produce ATP via the Krebs cycle > intracellular energy transfer. This drug, Metformin, harms mitochondria, rendering it dysfunctional. This could be looked at as disrupting energy flow (homeostasis), which effects overall homeostasis and becomes imbalanced. Screw up homeostasis > you will have health consequences.

There's a lot, but to just name a few things mitochondria regulate (via the endocannabinoid system within a mitochondrion) is: cell metabolism, programmed cell death, and calcium signaling (in the brain, CB1 receptor regulates GABA by inhibiting calcium from entering into the presynaptic axon terminals. So, you are talking about a very sophisticated homeostatic regulatory system becoming dysfunctional via Metformin).

There is a gut-pancreas axis and there is a gut-brain axis. I think it's all just one axis. Mitochondria in the brain regulate systemic glucose. The liver has an ECS too, everything does, and all talking to one another to regulate homeostasis. So go figure.

Metformin directly alters gut microbiota — Bingo.
Metformin upregulates BACE1 and APP > induces beta amyloid aggregates — Bingo.
Metformin induces mitochondrial dysfunction and neuronal cell death (TOM40, VDAC1, and HKI) — Bingo.

Did I mention mitochondria (via the ECS) in the brain regulates systemic glucose (via ECS)? Bingo.

Left our vitamin b12 deficeincy (essential for RBC production and DNA synthesis) — Bingo.

[peppy]

Aug 17, 2017 18:22:07 GMT -5 sayhey24 said:

Years ago Itell was following what was being called Type 3 diabetes very closely. Hopefully he still has all his research. Mango has also done some research in this area.

The one question I always had was what would be the absorption rate of afrezza if snorted. I am not sure if anyone knows. I am assuming MNKD did some analysis which should be available.

sports posted a tweet weeks back; An afrezza forgot her dreamboat, and used a straw.

(Up your nose with a rubber hose.)

[dreamboatcruise]

Aug 17, 2017 19:10:55 GMT -5 mango said:

peppy I sent some stuff in PM.

Metformin induces a range of effects that can facilitate and even induce neurodegeneration. One in particular is, Metformin induces mitochondrial dysfunction. Mitochondria contain DNA. Mitochondria produce ATP via the Krebs cycle > intracellular energy transfer. This drug, Metformin, harms mitochondria, rendering it dysfunctional. This could be looked at as disrupting energy flow (homeostasis), which effects overall homeostasis and becomes imbalanced. Screw up homeostasis > you will have health consequences.

There's a lot, but to just name a few things mitochondria regulate (via the endocannabinoid system within a mitochondrion) is: cell metabolism, programmed cell death, and calcium signaling (in the brain, CB1 receptor regulates GABA by inhibiting calcium from entering into the presynaptic axon terminals. So, you are talking about a very sophisticated homeostatic regulatory system becoming dysfunctional via Metformin).

There is a gut-pancreas axis and there is a gut-brain axis. I think it's all just one axis. Mitochondria in the brain regulate systemic glucose. So go figure.

Metformin directly the alters gut microbiota — Bingo.
Metformin upregulates BACE1 and APP > induces beta amyloid aggregates — Bingo.
Metformin induces mitochondrial dysfunction and neuronal cell death (TOM40, VDAC1, and HKI) — Bingo.

Did I mention mitochondria (via the ECS) in the brain regulates systemic glucose (via ECS)? Bingo.

Left our vitamin b12 deficeincy (essential for RBC production and DNA synthesis) — Bingo.

Though, millions upon millions of people have used it for long periods of time without safety concerns.  The evidence is growing, the topic of this thread, that poor blood sugar control definitely has consequences.  I'm not arguing against Afrezza as a better, though significantly more expensive treatment vs Metformin, but all of these theoretical speculations about Metformin don't outweigh that it is widely used, does have meaningful results in controlling BG and has proven itself safe.

Speaking of speculative research there is some that suggests Metformin may be useful in preventing dementia for non diabetic individuals, though I wonder whether that is simply linked to its BG lowering given that many people not diagnosed as diabetic probably have poor BG control none the less.

[mango]

Aug 17, 2017 19:22:33 GMT -5 dreamboatcruise said:

Aug 17, 2017 19:10:55 GMT -5 mango said:

peppy I sent some stuff in PM.

Metformin induces a range of effects that can facilitate and even induce neurodegeneration. One in particular is, Metformin induces mitochondrial dysfunction. Mitochondria contain DNA. Mitochondria produce ATP via the Krebs cycle > intracellular energy transfer. This drug, Metformin, harms mitochondria, rendering it dysfunctional. This could be looked at as disrupting energy flow (homeostasis), which effects overall homeostasis and becomes imbalanced. Screw up homeostasis > you will have health consequences.

There's a lot, but to just name a few things mitochondria regulate (via the endocannabinoid system within a mitochondrion) is: cell metabolism, programmed cell death, and calcium signaling (in the brain, CB1 receptor regulates GABA by inhibiting calcium from entering into the presynaptic axon terminals. So, you are talking about a very sophisticated homeostatic regulatory system becoming dysfunctional via Metformin).

There is a gut-pancreas axis and there is a gut-brain axis. I think it's all just one axis. Mitochondria in the brain regulate systemic glucose. So go figure.

Metformin directly the alters gut microbiota — Bingo.
Metformin upregulates BACE1 and APP > induces beta amyloid aggregates — Bingo.
Metformin induces mitochondrial dysfunction and neuronal cell death (TOM40, VDAC1, and HKI) — Bingo.

Did I mention mitochondria (via the ECS) in the brain regulates systemic glucose (via ECS)? Bingo.

Left our vitamin b12 deficeincy (essential for RBC production and DNA synthesis) — Bingo.

Though, millions upon millions of people have used it for long periods of time without safety concerns.  The evidence is growing, the topic of this thread, that poor blood sugar control definitely has consequences.  I'm not arguing against Afrezza as a better, though significantly more expensive treatment vs Metformin, but all of these theoretical speculations about Metformin don't outweigh that it is widely used, does have meaningful results in controlling BG and has proven itself safe.

Speaking of speculative research there is some that suggests Metformin may be useful in preventing dementia for non diabetic individuals, though I wonder whether that is simply linked to its BG lowering given that many people not diagnosed as diabetic probably have poor BG control none the less.

What I said is not speculation.

[agedhippie]

Aug 17, 2017 19:53:43 GMT -5 mango said:

Aug 17, 2017 19:22:33 GMT -5 dreamboatcruise said:

Though, millions upon millions of people have used it for long periods of time without safety concerns.  The evidence is growing, the topic of this thread, that poor blood sugar control definitely has consequences.  I'm not arguing against Afrezza as a better, though significantly more expensive treatment vs Metformin, but all of these theoretical speculations about Metformin don't outweigh that it is widely used, does have meaningful results in controlling BG and has proven itself safe.

Speaking of speculative research there is some that suggests Metformin may be useful in preventing dementia for non diabetic individuals, though I wonder whether that is simply linked to its BG lowering given that many people not diagnosed as diabetic probably have poor BG control none the less.

What I said is not speculation.

And yet there is no evidence in the field...  If metformin was this dangerous, and given that huge quantities consumed, there should be far higher rates than are seen.

There is evidence that metformin improves brain function in Alzheimer's patients although there have only been small trials to date - it's difficult to get funding for drugs that are free to a first approximation since there are no big profits.

[peppy]

Aug 17, 2017 20:28:59 GMT -5 agedhippie said:

Aug 17, 2017 19:53:43 GMT -5 mango said:

What I said is not speculation.

And yet there is no evidence in the field...  If metformin was this dangerous, and given that huge quantities consumed, there should be far higher rates than are seen.

There is evidence that metformin improves brain function in Alzheimer's patients although there have only been small trials to date - it's difficult to get funding for drugs that are free to a first approximation since there are no big profits.

mnkd.proboards.com/post/113602

mnkd.proboards.com/post/113585

mnkd.proboards.com/post/104515

mnkd.proboards.com/post/103820

mnkd.proboards.com/post/101126

mnkd.proboards.com/post/98907

mnkd.proboards.com/post/111617

mnkd.proboards.com/post/96942

mnkd.proboards.com/post/96983

mnkd.proboards.com/post/93302

[mango]

Aug 17, 2017 20:28:59 GMT -5 agedhippie said:

Aug 17, 2017 19:53:43 GMT -5 mango said:

What I said is not speculation.

And yet there is no evidence in the field...  If metformin was this dangerous, and given that huge quantities consumed, there should be far higher rates than are seen.

There is evidence that metformin improves brain function in Alzheimer's patients although there have only been small trials to date - it's difficult to get funding for drugs that are free to a first approximation since there are no big profits.

That's a fine statement of opinions.

Metformin causes mitochondrial dysfunction. If you want to argue this fact, then perhaps you have already take too much Metformin.


Endocrinology & Metabolism International Journal

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

Optimal control of diabetes can reduce the progression of cognitive deficits in patients with AD. The use of drugs such as rioglitazone, pioglitazone has demonstrated to have a positive impact upon cognition and memory in patients with mild to moderate AD. While metformin by itself increases the formation of Β-amyloid, combined with insulin it enhances the effects of insulin in reducing amyloid levels.

medcraveonline.com/EMIJ/EMIJ-04-00091.pdf

While metformin by itself increases the formation of Β-amyloid

Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

RESEARCH DESIGN AND METHODS
Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n = 480) or mild cognitive impairment (n = 187) and those who were cognitively intact (n = 687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n = 104) or impaired glucose tolerance (n = 22).

RESULTS
Participants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).

CONCLUSIONS
Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12and calcium use on cognition in older people with diabetes who are taking metformin.

The amyloid plaques seen in the brains of patients with AD are formed by aggregation of Aβ peptides. In cell cultures, Chen and colleagues (21) reported that activation of AMP–activated protein kinase by metformin increased the expression of β-secretase, an enzyme that increases the formation of Aβ peptides.

One recent case-control study that included 14,172 participants 65 years of age or older reported that taking metformin over the long term increased the risk of AD (odds ratio [OR] 1.71 [95% CI 1.12–2.60]) (22).

Among participants with diabetes, cognitive performance was worse in patients who were taking metformin (adjusted OR 2.23 [95% CI 1.05–4.75]). MMSE scores were lower in participants with diabetes who used metformin (mean score ± SD 22.8 ± 5.5) than in those who did not use metformin (24.7 ± 4.4). Participants with diabetes who had vitamin B12 levels <250 ρmol/L also had worse cognitive performance (2.29 [1.12–4.66]). MMSE scores were lower among those with serum vitamin B12 <250 ρmol/L (22.9 ± 4.7) than those with higher levels (25.0 ± 4.7).

CONCLUSIONS
In our series, patients with diabetes who were taking metformin had worse cognitive performance than participants who were not taking metformin. Our observations agree with those previously reported by Imfeld and colleagues (22), in particular that patients who are taking metformin may be at an increased risk for cognitive impairment.

Metformin is a widely prescribed first-line monotherapy for type 2 diabetes but is associated with vitamin B12 deficiency and peripheral neuropathy. A case-control study of more than 14,000 patients reported that long-term metformin use was associated with an increased risk for AD in those ≥65 years old (22). Metformin at pharmacological doses was reported to increase the expression of β-secretase in cell culture; this may be a possible disease mechanism (21). Alternatively, metformin also impairs absorption of vitamin B12 via a drug interaction that occurs at the distal ileum. Low serum vitamin B12 levels are associated with AD and other neurodegenerative diseases (38).

This study was presented at the 2012 Smart Geelong Network Research of the Year Awards, Victoria, Australia, 26 October 2012, for which it was awarded the Population Health Researcher of the Year Award.

www.ncbi.nlm.nih.gov/pmc/articles/PMC3781568/pdf/2981.pdf


Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study

Objectives
To explore the risk of developing Alzheimer's disease (AD) in individuals with diabetes mellitus treated with metformin or other antidiabetic drugs.

Design
Case–control study.

Setting
The United Kingdom–based General Practice Research Database (GPRD), a well-established primary care database.

Participants
Seven thousand eighty-six individuals aged 65 and older with an incident diagnosis of AD identified between 1998 and 2008 and the same number of matched controls without dementia. Matching criteria were age, sex, general practice, calendar time, and years of history in the database.

Measurements
Comparison of previous use of metformin or other antidiabetic drugs between cases and controls and calculation of corresponding odds ratios (ORs) with 95% confidence intervals (CIs), using conditional logistic regression. Risk estimates were stratified according to duration of use and adjusted for potential confounders.

Results
As compared with nonusers, long-term users of 60 or more metformin prescriptions were at greater risk of developing AD (adjusted OR (AOR) = 1.71, 95% CI = 1.12–2.60), but there was no consistent trend with increasing number of prescriptions. Long-term use of other antidiabetic drugs such as sulfonylureas (AOR = 1.01, 95% CI = 0.72–1.42), thiazolidinediones (AOR = 0.87, 95% CI = 0.31–2.40), or insulin (AOR = 1.01, 95% CI = 0.58–1.73) was not related to an altered risk of developing AD.

Conclusion
Long-term use of sulfonylureas, thiazolidinediones, or insulin was not associated with an altered risk of developing AD. There was a suggestion of a slightly higher risk of AD in long-term users of metformin.

Discussion
The findings of this large case–control study do not provide evidence that use of metformin is associated with lower risk of developing AD. The findings even suggest that long-term use of metformin may be associated with a slightly higher risk of developing AD than nonuse of this drug, whereas such a finding was not seen for use of other antidiabetic drugs such as sulfonylureas, thiazolidinediones, or insulin.

In summary, the findings of this large observational study do not provide evidence that use of metformin reduces the risk of developing AD but even suggest that long-term use of metformin, as opposed to use of other antidiabetic drugs, is associated with greater risk, although there was not a consistent trend with increasing number of prescriptions, and the result was not confirmed in a subgroup analysis of individuals prescribed metformin only. Long-term use of sulfonylureas, thiazolidinediones, or insulin was not associated with an altered risk of developing AD in individuals with DM[/font[.

www.medscape.com/viewarticle/764413


Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial

While the mechanisms for the action of metformin are not completely understood [26], it clearly reduces insulin levels[25], inflammation and thrombosis[75], and the risk of the metabolic syndrome[76] and T2D[77] in persons at risk. Metformin is usually the first step in pharmacological treatment of T2D [78], but it is increasingly used for T2D prevention based on the findings of the landmark Diabetes Prevention Program (DPP)[77], the largest trial of metformin among persons without T2D.

Our biomarker analyses did not provide insight into the potential impact of metformin on neurodegeneration. Future studies should ideally include AD biomarkers in CSF or imaging markers such as PET with an amyloid ligand. Future studies should also include systematic measures of cerebrovascular disease, which were not part of our protocol. Among the strategies related to insulin resistance that could potentially be used for AD prevention, metformin seems to be the safest, cheapest, and most sustainable. In addition, since metformin is so widely used, it is important to establish its cognitive safety in light of conflicting evidence about its effect on AD.

Our main imaging outcome did not show statistically significant differences. It has been estimated that sample sizes of several hundred persons with prodromal AD are needed to detect appreciable differences in rCMRgl at longer follow-up periods than our trial [93]. Thus, we were not powered to detect significant differences, but our results were not inconsistent with those showing benefit for the SRT.

It seems safe and feasible to conduct a randomized trial of metformin among persons with MCI although we encountered important challenges. These challenges included a long recruitment period due in part to a large number of subjects needed to be screened, the inability to achieve the maximum metformin dose in the majority of participants, and the inability of some participants to tolerate metformin at all.

We acknowledge that our results must be interpreted with caution because of the inconsistency of the results for the SRT and ADAS-cog, because the results of post-hoc analyses are are subject to chance.

Our biomarker analyses did not provide insight into the potential impact of metformin on neurodegeneration. Future studies should ideally include AD biomarkers in CSF or imaging markers such as PET with an amyloid ligand. Future studies should also include systematic measures of cerebrovascular disease, which were not part of our protocol.

www.ncbi.nlm.nih.gov/pmc/articles/PMC5079271


• Editorial Related to that Study

Type 2 diabetes and dementia: is there a substantial link?

Additionally, there is an ongoing Phase II trial of metformin (NCT00620191) testing whether metformin can decrease cogni­ tive decline and dementia in individuals with MCI. The results of this trial will be reported in 2012. A study in cellular models demonstrated that metformin increases the production of amyloid­b through upregulation of b­secretase [17], thus raising the concern that metformin could increase the risk of Alzheimer’s disease. However, the relevance of these findings to humans is not clear and the study needs to be replicated in other models.

www.openaccessjournals.com/articles/type-2-diabetes-and-dementia-is-there-a-substantial-link.pdf


• Metformin up-regulates BACE1 transcription via AMP-Kinase depended pathway. Metfomin does much of its work through AMPK.
• Up-regulation of BACE1 transcription = faciliting amyloid precursor protein processing. Amyloid plaques are largely made up of amyloid beta peptides, which are DERIVED from amyloid precursor proteins, which are PROCESSED by BACE1.
• Amgen's patent on BACE inhibitors gives DIRECT EVIDENCE that Metformin induces aggregation of beta amyloid. 


• Amgen Patent

Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

Beta amyloid plaques are primarily composed of amyloid beta peptide (A-beta peptide). A-beta peptide is derived from the proteolytic cleavage of a large transmembrane amyloid precursor protein (APP)

The fact that BACE initiates the formation of beta-amyloid, and the observation that BACE levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE inhibition thus reducing beta-amyloid and its associated toxicities.

It has been proposed that A-beta peptide accumulates as a result of APP processing by BACE. Moreover, in vivo processing of APP at the beta secretase cleavage site is thought to be a rate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis. Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity is desirable for the treatment of AD.

The BACE enzyme is essential for the generation of beta-amyloid or A-beta. BACE knockout mice do not produce beta-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. Cole, S. L., Vasser, R., Molecular Degeneration 2:22, 2007.

patents.justia.com/patent/9611261


Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription

Metformin Up-Regulates BACE1 Promoter Activity

BACE1 transcription has recently been reported to be regulated by the PPARγ pathway (36). We now demonstrate that the diabetes drug metformin can also modulate BACE1 transcription, likely independently of the PPARγ pathway despite the presence of several PPAR/RXR binding sites in the promoter (31, 32). Metformin-mediated transcriptional activation of BACE1 appears to depended on a pathway involving AMPK. Recently, the AMP-activated protein kinase (AMPK) has been identified as one of the molecular targets of metformin, accounting for the majority of its pleiotropic effects.

Indeed, our study using a comparable dose (2 mg/mL is equivalent to a clinical dosage of 300 mg/kg/day) indicates that systemically administrated metformin for 6 days increases brain AMPK activation and BACE1 protein levels (Fig. 5). A direct measurement of the metformin concentration in these mice showed that it reaches 2 μM and 1 μM in the plasma and forebrain region, respectively (Table S1); Considering that the steady-state plasma level of metformin in patients is reported to be from 10 μM to as high as 40 μM (32) and we achieved the maximum effect of metformin on BACE1 levels and AMPK activation in primary cultured neurons at 1–10 μM, the potential side-effects of metformin on accelerating AD pathogenesis must be taken seriously.

Metformin Up-Regulates BACE1 Promoter Activity. As correlated with its increased protein level (Fig. 1D), metformin increased the total BACE1 enzymatic activity by 2-fold (Fig. 2A). BACE1 mRNA was also increased by metformin in a time-dependent manner in both N2a695 and primary cortical neurons (Fig. 2B), as measured by semiquantitative RT-PCR. A luciferase reporter assay on a 1.5-kb BACE1 promoter (35) showed that metformin increased promoter activity by >5-fold whereas insulin had no effect (Fig. 2C).

www.ncbi.nlm.nih.gov/pmc/articles/PMC2656178


Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation

we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation.

Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.

content.iospress.com/articles/journal-of-alzheimers-disease/jad151200


Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates

Within this context, antidiabetic drugs, including metformin, are investigated for their effect on AD. We report that in the C57B6/J mice, metformin is delivered to the brain where activates AMP-activated kinase (AMPK), its molecular target. This drug affects the levels of β-secretase (BACE1) and β-amyloid precursor protein (APP), promoting processing and aggregation of β-amyloid (Aβ), mainly in the cortex region. Moreover, metformin induces mitochondrial dysfunction and cell death by affecting the level and conformation of Translocase of the Outer Membrane 40 (TOM40), voltage-dependent anion-selective channels 1 (VDAC1) and hexokinase I (HKI), proteins involved in mitochondrial transport of molecules, including Aβ. By using biophysical techniques we found that metformin is able to directly interact with Aβ influencing its aggregation kinetics and features. These findings indicate that metformin induces different adverse effects, leading to an overall increase of the risk of AD onset.

www.ncbi.nlm.nih.gov/pmc/articles/PMC5032692/


Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect

This study demonstrates the effect of metformin, a therapeutic biguanide administered for T2DM therapy, on β-amyloid precursor protein (APP) metabolism in in vitro, ex vivo and in vivo models.

Furthermore, the protective role of insulin against metformin is also demonstrated. In LAN5 neuroblastoma cells, metformin increases APP and presenilin levels, proteins involved in AD.

Overexpression of APP and presenilin 1 (Pres 1) increases APP cleavage and intracellular accumulation of β-amyloid peptide (Aβ), which, in turn, promotes aggregation of Aβ. In the experimental conditions utilized the drug causes oxidative stress, mitochondrial damage, decrease of Hexokinase-II levels and cytochrome C release, all of which lead to cell death. Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect.

Finally, the involvement of NF-κB transcription factor in regulating APP and Pres 1 expression was investigated. Upon metformin treatment, NF-κB is activated and translocates from the cytoplasm to the nucleus, where it induces increased APP and Pres 1 transcription. The use of Bay11-7085 inhibitor suppressed the effect of metformin on APP and Pres 1 expression.

ac.els-cdn.com/S0167488915000324/1-s2.0-S0167488915000324-main.pdf?_tid=e6fc40ce-29d7-11e7-9e89-00000aab0f6b&acdnat=1493139472_2e9f328d1f039184db772c4cd00a4fa5


To finish, I present a True Diabadass—Mr. McCullough of VDEX

"Damn near irresponsible to prescribe it"