Kev 2010-04-12 14:11:51
Aspirin is more than just a pain killer. It has the potential to prevent
insulin resistance and enhance insulin sensitivity, especially in obesity.
This, of course, will help with weight loss.
Science. 2001 Aug 31;293(5535):1673-7.
Reversal of obesity- and diet-induced insulin resistance with salicylates or
targeted disruption of Ikkbeta.
We show that high doses of salicylates reverse hyperglycemia,
hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin
signaling. Activation or overexpression of the IkappaB 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 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 IKKbeta pathway as a target
for insulin sensitization.
J Clin Invest. 2001 Aug;108(3):437-46.
Prevention of fat-induced insulin resistance by salicylate.
Howard Hughes Medical Institute, Department of Internal Medicine, Yale
University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes
and may involve fat-induced activation of a serine kinase cascade involving
IKK-beta. To test this hypothesis, we first examined insulin action and
signaling in awake rats during hyperinsulinemic-euglycemic clamps after a
lipid infusion with or without pretreatment with salicylate, a known
inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were
estimated using [3-(3)H]glucose infusion, and glucose uptake in individual
tissues was estimated using [1-(14)C]2-deoxyglucose injection during the
clamp. Here we show that lipid infusion decreased insulin-stimulated glucose
uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but
that salicylate pretreatment prevented these lipid-induced effects. To
examine the mechanism of salicylate action, we studied the effects of lipid
infusion on insulin action and signaling during the clamp in awake mice
lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout
mice did not exhibit altered skeletal muscle insulin signaling and action
following lipid infusion. In summary, high-dose salicylate and inactivation
of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by
blocking fat-induced defects in insulin signaling and action and represent a
potentially novel class of therapeutic agents for type 2 diabetes.
J Biol Chem. 2003 Jul 4;278(27):24944-50. Epub 2003 Apr 24.
Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in
tumor necrosis factor-treated cells through targeting multiple serine
The hypoglycemic effects of high dose salicylates in the treatment of
diabetes were documented before the advent of insulin. However, the
molecular mechanisms by which salicylates exert these anti-diabetic effects
are not well understood. In this study, we analyzed the effects of aspirin
(acetylsalicylic acid) on serine phosphorylation of insulin receptor
substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha.
Phosphorylation of IRS-1 at Ser307, Ser267, and Ser612 was monitored by
immunoblotting with phospho-specific IRS-1 antibodies. In 3T3-L1 and Hep G2
cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment
correlated with phosphorylation of JNK, c-Jun, and degradation of
IkappaBalpha. Moreover, phosphorylation of IRS-1 at Ser307 in embryo
fibroblasts derived from either JNK or IKK knockout mice was reduced when
compared with that in the wild-type controls. Taken together, these data
suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is
mediated, in part, by JNK and IKK. Interestingly, aspirin treatment
inhibited the phosphorylation of IRS-1 at Ser307 as well as the
phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. Furthermore,
other serine kinases including Akt, extracellular regulated kinase,
mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha
(as assessed by phospho-specific antibodies). Phosphorylation of IRS-1 at
Ser267 and Ser612 correlated with the activation of these kinases.
Phosphorylation of Akt and the mammalian target of rapamycin (but not
extracellular regulated kinase or PKCzeta) in response to TNF-alpha was
inhibited by aspirin treatment. Finally, aspirin rescued insulin-induced
glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. We conclude
that aspirin may enhance insulin sensitivity by protecting IRS proteins from
serine phosphorylation catalyzed by multiple kinases.