27 replies to this topic

[Logan]

Is it reasonable that we could use things like cinnamon and r lipoic acid as a substitute for Metformin when trying to improve insulin sensitivity for longevity purposes?

Is there anything else out there supplement wise that could increase insulin sensitivity.

I know Pycnogenol lowers glucose levels but it has not been shown to increase insulin sensitivity.

Edited by morganator, 10 February 2010 - 10:39 PM.

[shaggy]

Is it reasonable that we could use things like cinnamon and r lipoic acid as a substitute for Metformin when trying to improve insulin sensitivity for longevity purposes?

Is there anything else out there supplement wise that could increase insulin sensitivity.

I know Pycnogenol lowers glucose levels but it has not been shown to increase insulin sensitivity.

Might be worth looking at curcumin, arginine and resveratrol for this too, sure I read they help wit blood glucose/insulin sensitivity.

Edited by shaggy, 10 February 2010 - 10:52 PM.

[Logan]

Yeah evidently chromium and milk thistle can help as well.

So far, cinnamon interests me the most. I don't often hear about people taking cinnamon supplements or adding it to their diet around here. It seems like it has several benefits and very little or no risks, so why not include it into a daily regimen.

[tunt01]

im pretty sure there were comments in the "500 mg" resveratrol club thread by a diabetic patient, indicating their anecdotal experience was improved glucose sensitivity since using resveratrol. you may want to search around.

you can probably find several research studies on pubmed.com discussing the value of resveratrol with regard to insulin sensitivity. it's not something i've looked into specifically, but resveratrol comes to mind first when thinking of a supplement that improves glucose sensitivity.

[tintinet]

Am J Clin Nutr. 2008 Mar;87(3):778-84.
Green tea extract ingestion, fat oxidation, and glucose tolerance in healthy humans.
Venables MC, Hulston CJ, Cox HR, Jeukendrup AE.

Human Performance Laboratory, School of Sport and Exercise Sciences, The University of Birmingham, Birmingham, United Kingdom.
BACKGROUND: Green tea consumption is reportedly associated with various health-promoting properties. For example, it has been shown to promote fat oxidation in humans at rest and to prevent obesity and improve insulin sensitivity in mice. OBJECTIVE: We investigated the effects of acute ingestion of green tea extract (GTE) on glucose tolerance and fat oxidation during moderate-intensity exercise in humans. DESIGN: Two studies were performed, both with a counter-balanced crossover design. In study A, 12 healthy men performed a 30-min cycling exercise at 60% of maximal oxygen consumption (VO2max) before and after supplementation. In study B, 11 healthy men took an oral-glucose-tolerance test before and after supplementation. In the 24-h period before the experimental trials, participants ingested 3 capsules containing either GTE (total: 890 +/- 13 mg polyphenols and 366 +/- 5 mg EGCG) or a corn-flour placebo (total: 1729 +/- 22 mg). RESULTS: Average fat oxidation rates were 17% higher after ingestion of GTE than after ingestion of placebo (0.41 +/- 0.03 and 0.35 +/- 0.03 g/min, respectively; P < 0.05). Moreover, the contribution of fat oxidation to total energy expenditure was also significantly higher, by a similar percentage, after GTE supplementation. The insulin area under the curve decreased in both the GTE and placebo trials (3612 +/- 301 and 4280 +/- 309 microIU/dL . 120 min, respectively; P < 0.01), and there was a concomitant increase of 13% in insulin sensitivity. CONCLUSIONS: Acute GTE ingestion can increase fat oxidation during moderate-intensity exercise and can improve insulin sensitivity and glucose tolerance in healthy young men.

PMID: 18326618 [PubMed - indexed for MEDLINE]

[tintinet]

Abstract
EYJOLFSON, V., L. L. SPRIET, and D. J. DYCK. Conjugated Linoleic Acid Improves Insulin Sensitivity in Young, Sedentary Humans. Med. Sci. Sports Exerc., Vol. 36, No. 5, pp. 814-820, 2004.

Background: Preliminary evidence in obese diabetic rats suggests that conjugated linoleic acid (CLA) may have antidiabetic properties, based on reductions in fasting glucose and insulin concentrations. However, in lean rats, CLA causes hyperinsulinemia. Furthermore, experiments in humans also suggest that CLA may worsen insulin sensitivity.

Objectives: The present study examined whether CLA supplementation can improve insulin sensitivity in humans.

Design: Sixteen young sedentary individuals (age, 21.5 ± 0.4 yr (mean ± SEM); body mass, 77.6 ± 3.4 kg) participated in this study. Ten subjects received 4 g·d-1 of mixed CLA isomers (35.5%cis-9, trans-11; 36.8%trans-10, cis-12) for 8 wk, whereas six subjects received placebo (safflower oil). Oral glucose tolerance tests were performed at baseline (0), 4 and 8 wk of supplementation.

Results: After 8 wk of CLA supplementation, insulin sensitivity index (ISI) increased (14.4 ± 1.0, 8 wk vs 11.3 ± 1.3, 0 wk; P < 0.05), which corresponded to a decrease in fasting insulin concentrations. Six of the 10 subjects showed large increases in their ISI (range, +27 to 90%), whereas two demonstrated essential no change (+3 to 5%), and two had a decrease in insulin sensitivity (-12 to -13%). ISI was unchanged over 8 wk in the placebo group.

Conclusions: Our results indicate that a common dosage of a commercially available CLA supplement can improve ISI in young, sedentary individuals. However, there is considerable individual variability in the response. Additional studies are required to identify underlying metabolic changes in human skeletal muscle.

©2004The American College of Sports Medicine

[tintinet]

BMC Endocr Disord. 2009; 9: 3.
Published online 2009 January 28. doi: 10.1186/1472-6823-9-3.

PMCID: PMC2640399

Copyright © 2009 Babraj et al; licensee BioMed Central Ltd.
Extremely short duration high intensity interval training substantially improves insulin action in young healthy males


John A Babraj,#1 Niels BJ Vollaard,#1 Cameron Keast,1 Fergus M Guppy,1 Greg Cottrell,1 and James A Timmonscorresponding author1,2
1Translational Biomedicine, School of Engineering and Physical Sciences, Heriot-Watt University Edinburgh, Scotland, UK
2The Wenner-Gren Institute, Arrhenius Laboratories, Stockholm University, Sweden
corresponding authorCorresponding author.
#Contributed equally.
John A Babraj: j.babraj@hw.ac.uk; Niels BJ Vollaard: n.vollaard@hw.ac.uk; Cameron Keast: ck51@hw.ac.uk; Fergus M Guppy: fmg1@hw.ac.uk; Greg Cottrell: gc29@hw.ac.uk; James A Timmons: jamie.timmons@gmail.com
Received September 10, 2008; Accepted January 28, 2009.


"Results
Following 2 weeks of HIT, the area under the plasma glucose, insulin and NEFA concentration-time curves were all reduced (12%, 37%, 26% respectively, all P < 0.001). Fasting plasma insulin and glucose concentrations remained unchanged, but there was a tendency for reduced fasting plasma NEFA concentrations post-training (pre: 350 ± 36 v post: 290 ± 39 μmol·l-1, P = 0.058). Insulin sensitivity, as measured by the Cederholm index, was improved by 23% (P < 0.01), while aerobic cycling performance improved by ~6% (P < 0.01)."

[Apchi]

Cinnamon should be consumed in moderation
There are some reports that the common variety(Cassia) is toxic

http://en.wikipedia.org/wiki/Cinnamon
"Due to the presence of a moderately toxic component called coumarin, European health agencies have recently warned against consuming large amounts of cassia.^[18] This is contained in much lower dosages in Cinnamomum burmannii due to its low essential oil content. Coumarin is known to cause liver and kidney damage in high concentrations. True Ceylon cinnamon has negligible amounts of coumarin."

[Ben K]

Cinnamon should be consumed in moderation
There are some reports that the common variety(Cassia) is toxic

http://en.wikipedia.org/wiki/Cinnamon
"Due to the presence of a moderately toxic component called coumarin, European health agencies have recently warned against consuming large amounts of cassia.^[18] This is contained in much lower dosages in Cinnamomum burmannii due to its low essential oil content. Coumarin is known to cause liver and kidney damage in high concentrations. True Ceylon cinnamon has negligible amounts of coumarin."

It's my impression that the beneficial compounds in cinnamon are water-soluble, but coumarin isn't. So you can avoid most of the coumarin by taking a cinnamon-extract supplement such as Cinnulin. Or, as a much more economical alternative, you can brew cinnamon powder in hot water and filter out the solids.

[e Volution]

Cinnamon should be consumed in moderation
There are some reports that the common variety(Cassia) is toxic

http://en.wikipedia.org/wiki/Cinnamon
"Due to the presence of a moderately toxic component called coumarin, European health agencies have recently warned against consuming large amounts of cassia.^[18] This is contained in much lower dosages in Cinnamomum burmannii due to its low essential oil content. Coumarin is known to cause liver and kidney damage in high concentrations. True Ceylon cinnamon has negligible amounts of coumarin."

It's my impression that the beneficial compounds in cinnamon are water-soluble, but coumarin isn't. So you can avoid most of the coumarin by taking a cinnamon-extract supplement such as Cinnulin. Or, as a much more economical alternative, you can brew cinnamon powder in hot water and filter out the solids.

Or is it possible some of cinnamon's benefits are from a hormetic type response which has been overlooked (newbie here)?

[niner]

Cinnamon should be consumed in moderation
There are some reports that the common variety(Cassia) is toxic
http://en.wikipedia.org/wiki/Cinnamon
"Due to the presence of a moderately toxic component called coumarin, European health agencies have recently warned against consuming large amounts of cassia.^[18] This is contained in much lower dosages in Cinnamomum burmannii due to its low essential oil content. Coumarin is known to cause liver and kidney damage in high concentrations. True Ceylon cinnamon has negligible amounts of coumarin."

I have some cinnamon capsules. The suggested dose is 1g/d. Wikipedia says that 1g cinnamon bark might contain 2-4mg coumarin. They further say:

The German Federal Institute for Risk Assessment has established a tolerable daily intake of 0.1 mg coumarin per kg body weight, but also advises that, [if] this level is exceeded for a short time only, there is no threat to health.[5] For example, a person weighing 135 lbs or about 61 kg would have a TDI of approximately 6.1 mg of coumarin.

So a gram a day is safe according to them, but two grams might not be depending on your weight and/or the quality of the cinnamon.

[Gerald W. Gaston]

Yes, use ceylon cinnamon. 1250 times less (0.004% vs 5%) coumarin. I break these open on my oatmeal:

http://www.swansonvitamins.com/NWF038

Likely could get it uncapped for much less.

[Brain_Ischemia]

It's my impression that the beneficial compounds in cinnamon are water-soluble, but coumarin isn't. So you can avoid most of the coumarin by taking a cinnamon-extract supplement such as Cinnulin. Or, as a much more economical alternative, you can brew cinnamon powder in hot water and filter out the solids.

The opposite seems to be the case...

Chemist Richard Anderson says that his research has shown that most, if not all, of cinnamon's antidiabetic effect is in its water-soluble fraction, not the oil (the ground cinnamon spice itself should be ingested for benefit, not the oil or a water extraction). In fact, some cinnamon oil-entrained compounds could prove toxic in high concentrations.

I used to add cinnamon to my hot coffee every morning thinking the would be the best way to take it. All that you end up drinking is the cinnamon oil, while the actual spice ends up at the bottom of the mug.

[Brain_Ischemia]

BTW:

According to the German Federal Institute for Risk Assessment, 1 kg of (cassia) cinnamon powder contains approximately 2100 to 4400 mg of coumarin.[7] Powdered Cassia Cinnamon weighs 0.56 g/cc[8]; therefore, 1 kg of Cassia Cinnamon powder is equal to 362.29 teaspoons (1000 g divided by 0.56 g/cc multiplied by 0.20288 tsp/cc). This means 1 teaspoon of cinnamon powder contains 5.8 to 12.1 mg of coumarin, which may be above the Tolerable Daily Intake for smaller individuals.[7]

Remember, toxicity beyond 0.1mg per kg of body weight...

[s123]

Is it reasonable that we could use things like cinnamon and r lipoic acid as a substitute for Metformin when trying to improve insulin sensitivity for longevity purposes?

Why would you replace metformin? Unless of course if you suffer from side effects or have kidney problems or other contra-indications. It is cheap and has much more evidence than those other interventions. Furthermore metformin inhibits TORC1 signaling and I don't know if those other alternatives would do this.

[Ben K]

Chemist Richard Anderson says that his research has shown that most, if not all, of cinnamon's antidiabetic effect is in its water-soluble fraction, not the oil (the ground cinnamon spice itself should be ingested for benefit, not the oil or a water extraction).

Unless I'm reading it wrong, the second part of that sentence contradicts the first part. If the effect comes from the "water-soluble fraction," wouldn't you get that benefit from a water extraction?

[Logan]

Is it reasonable that we could use things like cinnamon and r lipoic acid as a substitute for Metformin when trying to improve insulin sensitivity for longevity purposes?

Why would you replace metformin? Unless of course if you suffer from side effects or have kidney problems or other contra-indications. It is cheap and has much more evidence than those other interventions. Furthermore metformin inhibits TORC1 signaling and I don't know if those other alternatives would do this.

Why would you risk taking something like metformin at such a young age. If you were 100 percent sure there would be absolutely no long term risks and only benefits, I would understand, but you do not know that. If I were much younger I would be simply taking great care of myself and wait till medications like metformin were researched more. There is already concern about metformin and alzheimer's.

http://www.google.co...o5ChMp1RH9OMJSg

[edward]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

[Gerald W. Gaston]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring.

Good point on the T. Mine stays a little on the high side, but I haven't had a male panel done since adding in Metformin, DIM, and upping the D3 and Beta-Sitosterol. Would have been a good thing to monitor before each change. I'm hoping that if D3 does raise T slightly that Metformin would counter it to some degree.

[Logan]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

What do you consider a low dose and how old are you, if you don't mind my asking.

[edward]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

What do you consider a low dose and how old are you, if you don't mind my asking.

I am 32 and I consider a low dose to be 500 mg SR at night and 250 mg SR morning. I have no diabetic issues I only take metformin for its life extension potential, to prevent damage associated with excess glucose and for its nutrient partitioning positive metabolic activity.

[Logan]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

What do you consider a low dose and how old are you, if you don't mind my asking.

I am 32 and I consider a low dose to be 500 mg SR at night and 250 mg SR morning. I have no diabetic issues I only take metformin for its life extension potential, to prevent damage associated with excess glucose and for its nutrient partitioning positive metabolic activity.

Have you noticed any difference in the way you feel or the way your body reacts to things since taking it?

[Logan]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

What do you consider a low dose and how old are you, if you don't mind my asking.

I am 32 and I consider a low dose to be 500 mg SR at night and 250 mg SR morning. I have no diabetic issues I only take metformin for its life extension potential, to prevent damage associated with excess glucose and for its nutrient partitioning positive metabolic activity.

Have you noticed any difference in the way you feel or the way your body reacts to things since taking it?

[edward]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

What do you consider a low dose and how old are you, if you don't mind my asking.

I am 32 and I consider a low dose to be 500 mg SR at night and 250 mg SR morning. I have no diabetic issues I only take metformin for its life extension potential, to prevent damage associated with excess glucose and for its nutrient partitioning positive metabolic activity.

Have you noticed any difference in the way you feel or the way your body reacts to things since taking it?

Previously I was on a pretty strict low carb Paleo diet, I am still eating roughly paleo but have increased my carbs to between 100 and 150 per day depending on the day. Previously when I did this I had blood sugar crashes and energy fluctuations, my normally ripped physique got softer, now with metformin these previous problems do not occur.

[Logan]

I would consider a low dose of metformin and lipoic acid (whatever flavor suits your wallet), pycnogenol (or generic pine bark), standardized green tea, resveratrol and grape seed. This is the core of my glucose regulation stack. Metformin is an amazing drug as long as you monitor testosterone levels (and really its effect on testosterone is not a scary one in my opinion like shut down or some estrogenic effect, from the studies I have read it is simply that metformin is convincing your body that it is experiencing some CR effects, and arguably a pro longevity state is not a pro reproductive virile state, though personally I want both (if thats even possible), hence the test monitoring)

What do you consider a low dose and how old are you, if you don't mind my asking.

I am 32 and I consider a low dose to be 500 mg SR at night and 250 mg SR morning. I have no diabetic issues I only take metformin for its life extension potential, to prevent damage associated with excess glucose and for its nutrient partitioning positive metabolic activity.

Have you noticed any difference in the way you feel or the way your body reacts to things since taking it?

Previously I was on a pretty strict low carb Paleo diet, I am still eating roughly paleo but have increased my carbs to between 100 and 150 per day depending on the day. Previously when I did this I had blood sugar crashes and energy fluctuations, my normally ripped physique got softer, now with metformin these previous problems do not occur.

I asked my primary care physician about taking metformin and she did not think it was a good idea. She expressed concern over me taking a low dose of lithium and other medications and my kidney and liver health. If I can't get her to prescribe it to me I'm not sure what doctor I will to get metformin if I decide I want to start taking it. Anyone in the Washington D.C. area that knows of a doctor that might buy into metformin being of some benefit for longevity and will prescribe it?

Wouldn't exercise, combined with resveratrol and some other supplements that increase insulin sensitivity and slow glucose uptake, give you the same benefits that you said you have experienced since taking metformin?

[Sillewater]

Previously I was on a pretty strict low carb Paleo diet, I am still eating roughly paleo but have increased my carbs to between 100 and 150 per day depending on the day. Previously when I did this I had blood sugar crashes and energy fluctuations, my normally ripped physique got softer, now with metformin these previous problems do not occur.

This is what I have been experiencing as well since increasing my carb intake as well. But I find that the supplements mentioned in the title and others definitely help.

[s123]

There is already concern about metformin and alzheimer's.

http://www.google.co...o5ChMp1RH9OMJSg

I've read the paper. One of the strange things is that they propose that it is the activation of AMPK by metformin who is responsible for the increase in amyloid-beta. However, resveratrol and calorie restriction both upregulate AMPK and have been shown to decrease amyloid-beta levels.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by Abeta peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta). Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against AD.

Source: Vingtdeux et al. AMPK signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem. 2010 Jan 14.

Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-beta (Abeta) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not beta- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD.

Source: Qin et al. Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J Alzheimers Dis. 2006 Dec;10(4):417-22.

Maybe the upregulation of SIRT-1 by CR and resveratrol offsets the negative effects of AMPK activation on amyloid-beta accumulation? However, this would still not explain why genetic activation of AMPK lowered amyloid-beta.

Nicotinamide adenine dinucleotide (NAD)+-dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD+-dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of beta-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic alpha-secretase processing of the amyloid precursor protein. Conversely, we found that the expression of constitutively active ROCK1 in vitro cultures significantly prevented SIRT1-mediated response, suggesting that alpha-secretase activity is required for SIRT1-mediated prevention of AD-type amyloid neuropathology. Consistently we found that the expression of exogenous human (h) SIRT1 in the brain of hSIRT1 transgenics also resulted in decreased ROCK1 expression and elevated alpha-secretase activity in vivo. These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment.

Source: Qin et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54.

Recent evidence suggests that metformin shows beneficial effects in experimental models of neuroinflammatory diseases. The aim of the present study was to determine the effect of metformin on phagocytosis and acidification of lysosomal/endosomal compartments in rat primary microglia in the presence of lipopolysaccharide (LPS) and/or beta-peptides (25–35), (1–40), and (1–42). Metformin increased the phagocytosis of fluorescent microspheres in the presence or absence of all the beta-peptides. However, the drug had no effect on the phagocytosis in LPS-stimulated microglia regardless of the presence of all the beta-peptides. Metformin acidified the lysosomal/endosomal compartments in the presence or absence of the beta-peptide 1–40 in both resting and activated microglia. To elucidate the mechanism of metformin action, we used 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside as an activator of adenosine monophosphate-activated protein kinase (AMPK) and compound C as a confirmed pharmacological inhibitor of AMPK. We have shown that metformin increased AMPK activity in microglial cells and that all observed effects are AMPK-dependent because the pretreatment of microglia with compound C reversed the effects of the drug. Since degradation of proteins in lysosomal/endosomal compartments depends largely on their phagocytosis and acidification, metformin may be beneficial in proteinopathies affecting the brain.

Source: Łabuzek et al. Metformin increases phagocytosis and acidifies lysosomal/endosomal compartments in AMPK-dependent manner in rat primary microglia. Naunyn-Schmiedeberg's Archives of Pharmacology, 2009, 381(2): 171-186.

Edited by s123, 04 March 2010 - 12:26 PM.

[tintinet]

http://jn.nutrition....tract/140/3/527


Dietary Anthocyanin-Rich Bilberry Extract Ameliorates Hyperglycemia and Insulin Sensitivity via Activation of AMP-Activated Protein Kinase in Diabetic Mice1–3,
Masahito Takikawa4, Seiya Inoue4, Fumihiko Horio5 and Takanori Tsuda4,*

4 College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi 487-8501, Japan; 5 Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan

Blueberries or bilberries contain large amounts of anthocyanins, making them one of the richest sources of dietary anthocyanin. These berries are widely consumed as fresh and dried fruits, jams, or juices. Considerable attention has been focused on the health benefits of bilberry fruits beyond their antioxidant content or their ability to improve vision. In this study, we tested the effect of dietary bilberry extract (BBE) on hyperglycemia and insulin sensitivity in type 2 diabetic mice. We found that dietary BBE ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase (AMPK). Dietary BBE significantly reduced the blood glucose concentration and enhanced insulin sensitivity. AMPK was activated in white adipose tissue (WAT), skeletal muscle, and the liver of diabetic mice fed BBE. This activation was accompanied by upregulation of glucose transporter 4 in WAT and skeletal muscle and suppression of glucose production and lipid content in the liver. At the same time, acetyl-CoA carboxylase was inactivated and PPAR{alpha}, acyl-CoA oxidase, and carnitine palmitoyltransferase-1A were upregulated in the liver. These changes resulted in improved hyperglycemia and insulin sensitivity in type 2 diabetes. These findings provide a biochemical basis for the use of bilberry fruits and have important implications for the prevention and treatment of type 2 diabetes via activation of AMPK.

* To whom correspondence should be addressed. E-mail: tsudat@isc.chubu.ac.jp.

Manuscript received 29 October 2009. Initial review completed 21 November 2009. Revision accepted 17 December 2009.

Published online 20 January 2010.