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Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Tuesday, October 5, 2010

Aspirin for Insulin Resistance?

I have just recently come across what seems to be a treasure trove of research indicating salicylates (e.g. acetylsalicylic acid aka aspirin) improve insulin sensitivity and lower blood glucose levels.  Much of the research is in rodents, but the glycemic lowering properties of this common drug are well known (apparently) and documented in humans, but seemingly ignored?  

Here's one:  Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkß  (Full text is available with FREE registration for anyone interested.  You fill out name and they ask for phone/fax info but I left that blank and had no issues.)

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the Ikappa B kinase beta  (IKKbeta ) attenuated insulin signaling in cultured cells, whereas IKKbeta  inhibition reversed insulin resistance. Thus, IKKbeta , rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta +/-) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.
 
Some excerpts and commentary:

High doses of salicylates [4 to 10 g per day (g/day)], including sodium salicylate and aspirin, have been used to treat inflammatory conditions such as rheumatic fever and rheumatoid arthritis. These high doses are thought to inhibit nuclear factor kappa B (NF-kB) (1) and its upstream activator the IkB kinase b (IKKb) (2),... High doses of salicylates also lower blood glucose concentrations (3–7), although their potential for treating diabetes has been all but forgotten by modern biomedical science. ...
We have found that reduced signaling through the IKKb pathway, either by salicylate inhibition or decreased IKKb expression, is accompanied by improved insulin sensitivity in vivo.
Cautionary note:  These studies were in genetically obese Zucker rats and ob/ob mice.

The aspirin treatment (120 mg/kg/day) resulted in lower blood glucose levels and reduced insulin levels.  Injecting untreated animals with insulin had almost no effect, but the aspirin treated animals did.  This demonstrates that insulin sensitivity was improved (vs. more insulin being produced).  

Increased triglyceride concentrations in the blood of Zucker rats fell from 494 ± 68 mg/dl to 90 ± 58 mg/dl during 3 weeks of aspirin treatment (Fig. 1F). The concentrations of free fatty acid (FFA) dropped as well, from 3.1 ± 0.3 mM to 1.1 ± 0.2 mM. The decrease in the amount of circulating FFA occurred within 1 week of aspirin treatment, preceding reductions in the amounts of triglyceride and glucose in the blood. This is consistent with the hypothesis that increased FFA concentrations contribute to the pathogenesis of hyperglycemia and hypertriglyceridemia.

The reversal is consistent with previous posts, for example in The Progression of IR, the cited article stated that elevated NEFA precedes hyperglycemia (and NEFA are elevated when adipose tissue becomes insulin resistant/dysfunctional).



Our findings demonstrate that increased IKK activity promotes insulin resistance, in obese rodents (12) when the kinase is overexpressed, or when IKK is activated by known stimulators. Conversely, reductions either in IKK activity or in the expression of its IKKb subunit significantly improved insulin sensitivity. Even a 50% reduction in gene dosage improved in vivo glucose and lipid metabolism, which may explain why weak inhibitors of IKKb, such as aspirin and sodium salicylate, have significant effects on glucose and lipid homeostasis. Although not recognized previously, there is an overlap between stimuli that activate IKK and conditions that promote insulin resistance, including proinflammatory cytokines such as TNFa, hyperglycemia, phorbol esters and protein kinase C (PKC) enzymes, Ser-Thr phosphatase inhibitors, and bacterial lipopolysaccharide. These are either in vivo mediators of insulin resistance or experimental mimics in cultured cells. Our findings are consistent with potential links between chronic subacute inflammation and insulin resistance (26, 27), whether this is mediated by TNF-a produced in fat (28–31) or through TNF-a–independent mechanisms. As a potentially important example of the latter, in rodent muscle, FFA infusion activates PKC-u (32), a known activator of IKK (33), and FFA-induced insulin resistance is suppressed by aspirin treatment and in Ikkb1/2 mice (34). IKK activation through any mechanism initiates NF-kB–mediated transcription, which in certain cells would enhance the production of TNF-a.  This positive feedback loop could perpetuate a vicious cycle of low-level inflammatory signaling, leading to insulin resistance. Our findings predict that IKK inhibition breaks this cycle. Too few tools are currently available to treat patients with insulin resistance and type 2 diabetes; IKKb may provide a valuable target for the discovery of new drugs to treat these conditions.


So:  Stuffed adipocytes become insulin resistant and "spill" excessive free fatty acids in the blood.  The elevated NEFA/FFA stimulate IKK that may in turn increase production of TNF-α (tumor necrosis factor α), a known inflammatory.  

Aspirin to "cure" your fat-ache??

9 comments:

Matt Stone said...

This 2006 article by Ray Peat may shed some light on why aspirin is effective in stopping FFA production (it opposes estrogen, and stops the production of prostaglandins synthesized from Peat's diablo - unsaturated fats) and therefore decreasing insulin resistance.

http://raypeat.com/articles/aging/aspirin-brain-cancer.shtml

Matt Stone said...

By the way, I'm thoroughly enjoying the depth of your investigation, like where you are coming from in your approach to studying this vast topic, and am glad I found you. Hope to get caught up reading all your posts carefully as well as let others know what a gem this blog is.

CarbSane said...

Welcome Matt! Thanks for the link. I'll check it out when I get a chance. And thanks for your kind remarks. I've read a bit on your blog over the past year or so. I tend to be in agreement with your thoughts on dieting making us fat!

Sanjeev said...

At first blush I thought many of the mice must have died from overdose - surely that dose is close to the ld50, but for rats it's 1600mg per kilo.

ld50 for mice is 250 mg/kg

Surprised the heck out of me, I thought aspirin's a lot more toxic than that. the ld50 for salt is 3g per kilo, just less than double the salicilate dose.

CarbSane said...

I found a paper on "high dose" aspirin in advance of cardiac surgery to prevent stroke. It involved "only" 1300 mg/day for 3 months. That's 4X the normal dose of 325 mg, but nowhere near the doses given to treat rheumatoid arthritis stated in the article as 4-10 grams!! Yikes!

Melchior Meijer said...

Hi Carb Sane,

I don’t know where to put it best, but I think this popular article about insulin signaling will interest you. Impaired isulin signaling seems to be a causal factor in such widely different conditions as depression, cancer end osteoporis. Our bones (partly) determine if we become glucose intolerant. Amazing and highly confusing for a guy who thusfar believed that physiological insulin resistance is just adaptive and harmless (Peter). Did the Inuit have such brittle bones because of low carb induced insulin resistance? On the other hand, they didn’t have cancer and they weren’t depressed. It’s all just mind boggling complicated.

http://www.the-scientist.com/article/display/57704/

Sorry for my Denglish (Dutch English).

CarbSane said...

Awesome article (at first glance, will investigate more thoroughly as time permits) Melchior. Thanks!

This is right "up my ally" in terms of whether LC (especially VLC/HF) diets are wise in the long run if they allow for the progression of IR. I'm not saying either way, but, readers of this blog should recognize this is a major area of interest for me. And as y'all know by now I'm obsessed with the adipose IR/elevated NEFA issue!

Melchior Meijer said...

Any tissue that communicates with insulin can become insulin resistant. I guess that's about any tissue except RBC's. From the article above we learn that impaired insulin signaling in bone cells induces systemic insulin resistance and several features of 'metabolic syndrome' in just a couple of weeks. Would it be far fetched to suggest that prolongued insulin resistance in any tissue (be it the liver, adipose tissue, bone cells or even the brain) will adversely affect the whole system?

I have probably missed it in your extensive writings, but have you seen evidence that elevated NEFA's cause insulin resistance, in stead of being an innocent bystander? Many people with stubborn overweight, glucose intolerance, etc. seem to do really well on a paleoish, low carb regimen. If anthing, their glucose tolerance improves. They must have 'elevated' NEFA's, but they get better insulin sensitivity. Or is this a wild assumption (I mean, are they 'secretly' insulin resistant while at the same time showing all the typical improvements usually associated with insulin sensitivity)?

On the other hand there are slim, fit, young people who become severely insulin resistant on a low carb diet. I was shocked by a test done by the Swedish lowcarb doctor Andreas Eenfeldt. He did a prolongued OGTT after eating a typical (high but not sky high carb) lunch at an obesity conference in Stockholm.

His numbers were horrible, hovering around 8 or 10 mmol/l far too long, if I remember well. My biggest question is: is this (reversible) insulin resistance (read: reduced insulin signaling) a bad thing? Will it trigger bone loss and other unpleasant things in the long run?

Regarding Gary... Can't help it, but he still is a heroe to me (but I'm a journalist too ;-) ). I don't think he's in this business for the money and I do think he is a truth seeker. I sincerely hope he will adress your important questions in depth here.

Cheers!

CarbSane said...

@Melchior:

I have probably missed it in your extensive writings, but have you seen evidence that elevated NEFA's cause insulin resistance, in stead of being an innocent bystander?

I realize due to the "spam" holdup on this comments, it predates a lot of posts since, but it seems an almost indisputable "fact" that NEFA is at the root of insulin resistance, although the exact mechanisms of which are still in question to some degree or another.

On the other hand there are slim, fit, young people who become severely insulin resistant on a low carb diet. I was shocked by a test done by the Swedish lowcarb doctor Andreas Eenfeldt. He did a prolongued OGTT after eating a typical (high but not sky high carb) lunch at an obesity conference in Stockholm.

His numbers were horrible, hovering around 8 or 10 mmol/l far too long, if I remember well. My biggest question is: is this (reversible) insulin resistance (read: reduced insulin signaling) a bad thing? Will it trigger bone loss and other unpleasant things in the long run?


That, my friend, remains the $20,000 dollar question. I don't know. All I can say is that I keep hoping to come across research demonstrating that insulin resistance is not harmful in the long run so long as someone never "challenges" their system with a glucose load. But I keep coming across information about more and more roles of insulin that one would characterize as protective so that it's not just glucose clearance we should be concerned about.

In the absence of a definitive answer, I've decided that an insulin-sensitizing approach is probably the best overall (now if I could get my butt in gear with the exercise more deliberately/consistently).

As to GT answering my questions, I'm doubtful he has bothered to even read much here. As of now, I asked him a few respectful questions that are on the first page of his comments (there's no way to link to the exact comment unfortunately): http://www.garytaubes.com/2010/12/inanity-of-overeating/comment-page-1/ (search on carbsane and you'll find it)

So far no response there either.

Holds breath .... ;)

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