Kaempferol alleviates insulin resistance via hepatic IKK/NF-κB signal in type 2 diabetic rats
Introduction
Inflammation is independently and collectively correlated with the development of insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and subacute hepatic inflammation through NF-κB activation causes insulin resistance both locally in liver and systemically [1]. Accumulating evidences reveal that IkB kinase β (IKKβ) plays a crucial role in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus [2], [3]. The anti-diabetic effects of salicylate have been known for years which refer to the IKK-β/nuclear factor kappa-β (NF-κB) pathway [3]. The IkB kinase (IKK) complexes, including IKKα and IKKβ, are essential to control the stimulated activation of NF-κB, and the activation of IKK much depends on phosphorylation of its IKKβ subunit [4]. NF-κβ is a nuclear transcriptional activator that can induce a large range of transcription genes of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1α (IL-1α), and interleukin-1β (IL-1β), which can induce the development of insulin resistance [5].
Kaempferol (KPF, Fig. 1) is a typical dietary flavonoid which was found to have anti-diabetic properties of anti-oxidative [6], anti-inflammatory [7] and promoting functions of pancreatic β-cell [8]. In addition, some reports have demonstrated that KPF could work as a regulator of lipid metabolism [9]. Several studies demonstrated that KPF could stimulate insulin-dependent glucose uptake [10], [11] and other flavonoids including quercetin [12] and rutin [13] were reported to ameliorate insulin resistance through inhibiting inflammatory responses. It is significant that previous studies raised the possibility that KPF suppressed the inflammatory IKK and NF-κB, thereby significantly decreasing the proinflammatory cytokines [7], [14], [15]. So we hypothesize that KPF may possess therapeutic properties for insulin resistance by inhibiting IKK/NF-κB signal. Researches about the anti-inflammatory effect of KPF on insulin resistance in T2DM and its mechanisms have not been reported previously. Thus, the present study was aimed to investigate the protective effect and mechanisms of KPF on the pathological process of insulin resistance in diabetic rats.
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Experimental animals
Male Sprague–Dawley (SD) rats (140–160 g) were obtained from the Laboratory Animal Center, ChongQing Medical University (Chongqing, China). Rats were used after at least one-week quarantine and acclimation period. They were kept in the departmental animal house under controlled conditions of temperature of 23 °C ± 2 °C, relative humidity of 60% ± 5%, a light:dark cycle of 12 h each, and given free access to normal pellet diet and water. The guidelines of the committee for the purpose of control and
Effect of KPF on body weight, blood glucose and serum insulin
The results for body weight, blood glucose levels and insulin levels were presented in Fig. 2. Diabetic rats suffered mild weight loss [21], which also appeared in our study, but it was reversed by kaempferol (KPF) (Fig. 2A). Blood glucose level in DC (diabetic control group) was significantly higher than that in NC (normal control group) at 3rd and 9th weeks (P < 0.01, Fig. 2B); it means that the diabetic model was stable over the entire experimentation. Treatment with high dose of KPF
Discussion
KPF is an important flavonoid in herbal foods; other flavonoids including quercetin [12] and rutin [13] inhibit the inflammation effectively and ameliorate insulin resistant by beneficial regulation of IRS-1 function. KPF exhibits anti-diabetic effect in multiple mechanisms including anti-oxidative [6], anti-inflammatory [7], antihyperlipidemic [9] and pancreatic β-cell protection [8]. However, little is known about its effect on insulin resistance in diabetes. In this study, we focused on
Acknowledgment
This study was supported by the Foundation of Chongqing Public Health Bureau (2009-1-6).
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