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 IB kinase  (IKK) attenuated insulin signaling in cultured cells, whereas IKK inhibition reversed insulin resistance. Thus, IKK, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikk^+/) protected against the development of insulin resistance during high-fat feeding and in obese Lep^ob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKpathway 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??