Kaempferol alleviates insulin resistance via hepatic IKK/NF-κB signal in type 2 diabetic rats

https://doi.org/10.1016/j.intimp.2015.07.018Get rights and content

Highlights

  • Kaempferol treatment may enhance insulin sensitivity in diabetic rats.

  • The possible mechanisms may be involved in the inhibition of IKKβ/NF-κB signal.

  • Kaempferol holds promise for preventing the deterioration of insulin resistance.

Abstract

Recent studies show that inflammation underlies the metabolic disorders of insulin resistance and type 2 diabetes mellitus. Since kaempferol, a naturally occurring flavonoid, has been described to have potent anti-inflammatory properties, we investigated whether kaempferol could ameliorate insulin resistance through inhibiting inflammatory responses. The model of diabetic rat was induced by 6-week high-fat diet plus streptozotocin. Animals were orally treated with kaempferol (50 or 150 mg/kg) and aspirin (100 mg/kg) for 10 weeks. The results showed that kaempferol ameliorated blood lipids and insulin in an dose-dependent manner. Kaempferol effectively restored insulin resistance induced alteration of glucose disposal by using an insulin tolerance test and the euglycemic–hyperinsulinemic clamp method. Western blotting results showed that KPF inhibited the phosphorylation of insulin receptor substrate-1 (IRS-1), IkB kinase α (IKKα) and IkB kinase β (IKKβ). These effects were accompanied with reduction in nucleic and cytosol levels of nuclear factor kappa-β (NF-κB), and further tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels. Aspirin had similar effects. These results provide in vivo evidence that kaempferol-mediated down-regulation of IKK and subsequent inhibition of NF-κB pathway activation may be associated with the reduction of hepatic inflammatory lesions, which is contributing to the improvement of insulin signaling defect in diabetes.

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.

Section snippets

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).

References (37)

  • R. Meshkani et al.

    Hepatic insulin resistance, metabolic syndrome and cardiovascular disease

    Clin. Biochem.

    (2009)
  • S. Wang et al.

    Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase

    J. Nutr.

    (2003)
  • V. Rotter

    Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-, overexpressed in human fat cells from insulin-resistant subjects

    J. Biol. Chem.

    (2003)
  • M. She et al.

    Melatonin rescues 3T3-L1 adipocytes from FFA-induced insulin resistance by inhibiting phosphorylation of IRS-1 on Ser307

    Biochimie

    (2014)
  • D. Cai et al.

    Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB

    Nat. Med.

    (2005)
  • M. Asrih et al.

    Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance

    J. Endocrinol.

    (2013)
  • S.E. Shoelson et al.

    Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance

    Int. J. Obes.

    (2003)
  • M.C. Arkan et al.

    IKK-beta links inflammation to obesity-induced insulin resistance

    Nat. Med.

    (2005)
  • Cited by (0)

    View full text