My Complicated Relationship With My MannKind Stock

[Deleted]

silentknight Do other forms of insulin prevent diabetics conditions from worsening? I believe the answer is no for numerous reasons. Therefore, other forms of insulin are NOT controlling glucose levels.

[traderdennis]

Jul 11, 2017 8:02:34 GMT -5 @kastanes said:

traderdennis "About the worst side effect with Metformin is having to poo too many times a day.  It also costs less than $5 bucks per month as a generic rx."

Tell that to my landlord on Metformin that requires his big toe to be amputated!

Your landlord had uncontrolled blood sugar over a very long period of time to have his big toe amputated.  

My dad died of a stroke.  Was it his diabetes, or was it because he was overweight, smoked for 30+ years, or had a high carb  diet at times.

One data point does not confirm efficacy of a drug.

Metformin is an aid, as all drugs are an aid and will not solve the complications of diabetes.  

[traderdennis]

Jul 11, 2017 8:24:24 GMT -5 @kastanes said:

silentknight Do other forms of insulin prevent diabetics conditions from worsening? I believe the answer is no for numerous reasons. Therefore, other forms of insulin are NOT controlling glucose levels.

Other diabetes drugs give the user the ability to lower their A1cs.  It is up to the patient to control their disease.

[Deleted]

traderdennis A1C can be misleading, it is an average. Averages can have large ranges yet produce the appearance of a "normal" A1C.

That is what is occurring with other forms of insulin.

[sportsrancho]

Another highjacked thread.
Metformin is crap! So are all diet pills.

What happened to Roll Call:-)

[lojothehus]

Back to Roll Call. I have been with Mankind for about 2 years now, primarily investing my personal savings which is not as significant as my retirement funds. I bought in at the worse possible time but has been able to average down quite a bit. If you are familiar with any of my post, I tend to beat down Mankind about their advertising and about their website. In my opinion, if this is a non-traditional, state of the art, contemporary type of insulin; it should be portrayed and advertised in that manner. The web site should be full of information, full of technology, and full of interactive depictions of the administration of Afrezza outweighing the ancient needle.

Remember this, if a small dog barks loud enough; you will be cautious in your dealings with it.

[promann]

Jul 11, 2017 9:15:40 GMT -5 sportsrancho said:

Another highjacked thread.
Metformin is crap! So are all diet pills.

What happened to Roll Call:-)

Exactly enough said. :-)

[mango]

Jul 10, 2017 8:09:14 GMT -5 derek2 said:

If you're asking to learn, then here are a few reasons

(Answering as a T2 for 17 years. Currently well controlled (A1C 6.2) on Metformin, Forxiga and Basal & Mealtime insulin.) 

1. Because after diet and exercise, Metformin is what most doctors recommend, adding a second therapy (in this case GLP-1) if necessary.
2. If that works, your doctor will not want to change. 
3. Metformin is quite safe and well tolerated, despite some rather tin foil claims to the contrary 'round here.

Insulin has far more health risk, regardless of administration route (hypo, weight gain, increased LDL, increased BP) than Metformin, and initiating insulin therapy can impact your ability to obtain or retain life insurance. Obviously, it's eventually necessary for many T2s, but where applicable, therapies like Metformin that increase insulin sensitivity allow the body to properly regulate blood glucose instead of the blunt tool of exogenous insulin.

Contrary to your tin foil hat claim about Metformin, here is what science has to say:

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.

Source
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.

Source
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[.

Source
www.medscape.com/viewarticle/764413


• A Metformin Clinical Trial—Why Understanding a Drug's MOA Should be Important and Necessary

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.

Source
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 ndings to humans is not clear and the study needs to be replicated in other models.

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



• Remember what was said in the International Endocrinology Journal?

While metformin by itself increases the formation of Β-amyloid

Metformin up-regulates BACE1. Here, Amgen's patent on BACE inhibitors further illustrates that up-regulating BACE1 (what Metformin does) = neurodegeneration. You're defending a drug that was approved without having the proper research done beforehand. Do you know Metformin's precise MOA in the CNS? It is still unknown. Are you suggesting that is acceptable?

• 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.

Source
patents.justia.com/patent/9611261


• Here is the science to back that up:

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

Although the precise mechanism of action of metformin in the CNS remains largely unknown, recent studies (39, 40), together with ours, suggest that metformin crosses the blood brain barrier and exerts specific pharmacological effects in rodent brains upon chronic administration. 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 M and 1 M 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 M to as high as 40 M (32) and we achieved the maximum effect of metformin on BACE1 levels and AMPK activation in primary cultured neurons at 1–10 M, the potential side-effects of metformin on accelerating AD pathogenesis must be taken seriously.

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


Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system

The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.

Conclusions
Since activity of complex I is decreased in parkinsonian patients, and considering metformin produces the inhibition of this multienzyme complex, our results suggest that treatment with this drug in diabetic patients might accelerate the onset and/or progression of the disease. Further studies should be carried out on the use of metformin at clinical doses.
Our results show that metformin is able to decrease the inflammatory response in the animal model of PD used in this study. However, despite the decrease in inflammatory parameters, metformin not only fails to decrease death of dopaminergic neurons in the SNpc, but increases neuronal damage in this structure. Thus, our results suggest that metformin, probably through inhibition of mitochondrial complex I, increases the vulnerability of these neurons which, as already mentioned, are particularly sensitive to inhibition of complex I of the electron transport chain. Therefore, our results suggest that treatment with metformin in diabetic patients may be considered as a risk factor for PD. Considering that neurodegenerative diseases are a frequent complication in patients with diabetes mellitus, and given the few epidemiological studies on the subject, it seems necessary to deepen the impact that treatment with metformin or other oral antidiabetic agents may have on the development of PD.

Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system


• Metformin

—Metformin is a fluorescent molecule able to reach the brain

—Chronic metformin treatment stimulates APP processing mainly in brain cortex region

—Metformin induces accumulation of Aβ aggregates mainly in brain cortex region

—Metformin induces mitochondrial dysfunction by impairing MPT pores and membrane channels

—Metformin induces neuronal apoptosis

—Metformin directly interacts with Aβ peptide influencing its aggregation kinetics in vitro

—Metformin treatment changes the levels of expression of TOM40, VDAC1 and HKI, proteins involved in mitochondrial import and export of molecules and metabolites, in cortex region where Aβ aggregates are mainly present. Studies on human brain biopsies have demonstrated that TOM40 pore mediates the internalization of Aβ and APP

—Metformin Increases Aβ Generation

—Metformin Up-Regulates BACE1 Promoter Activity

—Metformin's Effect Is Independent of Glucose Metabolism and Insulin Signaling

—Metformin's Effect Is Mediated by Activation of the AMP Kinase (AMPK) in Vitro and in Vivo.

—Antagonizing Effect on Intracellular Aβ Generation

—Metformin induces APP expression and processing via oxidative stress

—Insulin plays a protective role against metformin by oxidative stress inhibition

—Metformin triggers APP and presenilin via NFκB activation

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


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

m.pnas.org/content/106/10/3907.long?view=long&pmid=19237574

ac.els-cdn.com/S0167488915000324/1-s2.0-S0167488915000324-main.pdf?_tid=5796efb8-f4c3-11e6-9ea2-00000aab0f01&acdnat=1487303230_c084c701970fe76391f9a5ac2de3d152

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

[jmkopp]

Been in MNKD for 7 years.  Loss on paper of 160k on 170k investment.  My average is about 4.50 pre-split.  After split = 22.5.  I have never believed in the potential success of a company as much as I have with MNKD.  I have never done as much research on anything else in my life.  This has been a terrible ride with the most usual circumstances arising throughout the years.  I sincerely believe that this company is actively being manipulated and other BP Companies are trying to bury it.  I am in for the duration.

[traderdennis]

Jul 11, 2017 9:15:40 GMT -5 sportsrancho said:

Another highjacked thread.
Metformin is crap! So are all diet pills.

What happened to Roll Call:-)

Unsubstantiated claims that Insulin is a poison to the system (k)
Tinfoil hat claims that metformin is crap 

[sportsrancho]

Jul 11, 2017 10:38:50 GMT -5 traderdennis said:

Jul 11, 2017 9:15:40 GMT -5 sportsrancho said:

Another highjacked thread.
Metformin is crap! So are all diet pills.

What happened to Roll Call:-)

Unsubstantiated claims that Insulin is a poison to the system (k)
Tinfoil hat claims that metformin is crap 

Oh thank you for that. My feelings about Metformin have nothing to do with tinfoil hats, MNKD stock or Afrezza. I saw first hand what it did to my mother and my cousin.
Go talk about it on the Metformin thread.

[mango]

@sportsrancho back to Roll Call—

My name is mango and I became a MannKindaholic beginning January 2016.

Sports was kind enough to say hello when I joined here. One of my first questions to her was, "Hey, this is the first stock I have ever invested in and I am new to all of this, is it normal to become obsessed with the company?"

Sports said, "No."

It was then I knew I found something special 🙃

[seanismorris]

clinicaltrials.gov/ct2/show/NCT02432287

The Metformin debate goes on...

In other news...

www.bbc.com/news/health-40567047

Coffee drinkers live longer.... I assume they removed the people that drink the sugar loaded crap sold by Starbucks from the study.

----

Without Clinical Trial results I assume everything is snake oil.  But I might pick up some dark chocolate covered espresso beans.  Even if they do nothing for my health, they're still worth it.

[mango]

Jul 11, 2017 11:29:45 GMT -5 seanismorris said:

clinicaltrials.gov/ct2/show/NCT02432287

The Metformin debate goes on...

In other news...

www.bbc.com/news/health-40567047

Coffee drinkers live longer.... I assume they removed the people that drink the sugar loaded crap sold by Starbucks from the study.

----

Without Clinical Trial results I assume everything is snake oil.  But I might pick up some dark chocolate covered espresso beans.  Even if they do nothing for my health, they're still worth it.

• Here's your clinical trial:


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.

• Source
www.ncbi.nlm.nih.gov/pmc/articles/PMC5079271/#!po=50.0000


• Editorial Related to that Metformin Clinical Trial

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 ndings to humans is not clear and the study needs to be replicated in other models.

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


• More Metformin Human Studies:

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.

• Source
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[.

• Source
www.medscape.com/viewarticle/764413

[peppy]

mango, that was some fine research (regarding metformin) you found and pointed out.
Dick Tracey. This information is not widely disseminated.
A bit of, "for your eyes only"
It makes me wonder what a physician would do if a patient brought that information in with medication requests.

"Before setting out on an assignment, Heap would invariably get the "word on the street" from a bongo-pounding beatnik (named "Nick") who communicated solely by beating coded messages on his drums."