Annatto-extracted tocotrienols improve glucose homeostasis and bone properties in high-fat diet-induced type 2 diabetic mice by decreasing the inflammatory response

Abstract

Diabetes is a risk factor for osteoporosis. Annatto-extracted tocotrienols (TT) have proven benefits in preserving bone matrix. Here, we evaluated the effects of dietary TT on glucose homeostasis, bone properties, and liver pro-inflammatory mRNA expression in high-fat diet (HFD)-induced type 2 diabetic (T2DM) mice. 58 male C57BL/6 J mice were divided into 5 groups: low-fat diet (LFD), HFD, HFD + 400 mgTT/kg diet (T400), HFD + 1600 mgTT/kg diet (T1600), and HFD + 200 mg metformin/kg (Met) for 14 weeks. Relative to the HFD group, both TT-supplemented groups (1) improved glucose homeostasis by lowering the area under the curve for both glucose tolerance and insulin tolerance tests, (2) increased serum procollagen I intact N-terminal propeptide (bone formation) level, trabecular bone volume/total volume, trabecular number, connectivity density, and cortical thickness, (3) decreased collagen type 1 cross-linked C-telopeptide (bone resorption) levels, trabecular separation, and structure model index, and (4) suppressed liver mRNA levels of inflammation markers including IL-2, IL-23, IFN-γ, MCP-1, TNF-α, ITGAX and F4/80. There were no differences in glucose homeostasis and liver mRNA expression among T400, T1600, and Met. The order of osteo-protective effects was LFD ≥T1600 ≥T400 = Met >HFD. Collectively, these data suggest that TT exerts osteo-protective effects in T2DM mice by regulating glucose homeostasis and suppressing inflammation.

Mechanisms Mediating Anti-Inflammatory Effects of Delta-Tocotrienol and Tart Cherry Anthocyanins in 3T3-L1 Adipocytes

“…Tocotrienols share structural homology with tocopherols, but because of the unsaturation in the hydrophobic chain, they incorporate better into the membranes and demonstrate better functional properties [42]. Furthermore, we had determined previously that DT3 reduces inflammation in an in vivo model [16]. Based on this, we used DT3 isomer alone and found that it had comparable effects to TRF on inflammation and this was consistent with our previously reported anti-inflammatory effects of DT3 in diet-induced obese mice [20].…”

“…Vitamin E, comprised of 4 isoforms each of tocopherols and tocotrienols (α,β,δ,γ), has been extensively studied for its anti-inflammatory effects [15][16][17][18][19]. Related to our current study, tocotrienols, T3 s, exhibit anti-inflammatory properties in both in vitro and in vivo studies [15][16][17][18][19].…”

“…Individually, both tocotrienols and anthocyanins [15,16,19,21] are known for their anti-inflammatory effects but their combinatorial effects have not been examined. Our lab previously demonstrated DT3 and TCA to exhibit anti-inflammatory effects.…”

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

“…beneficial effects of metformin on systemic inflammatory markers, such as serum levels of TNF, IL-6, PAI-1 and the neutrophil-to-lymphocyte ratio, in patients with type 2 diabetes [113][114][115] or patients with polycystic ovary syndrome (PCOS) 115 (BOX 2). However, most of the data supporting anti-inflammatory properties of metformin came from in vivo studies in HFD-fed obese mice [116][117][118][119] and a zebrafish model of obesity 120 , or in vitro and ex vivo experiments with supra-therapeutic concentrations of the drug in various immune cell types, particularly macrophages 115,[121][122][123][124][125][126][127] . In line with this, metformin was found to inhibit the lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6 and TNFα) in both mouse peritoneal macrophages and human monocyte-derived macrophages 121,124 .…”

The Molecular Mechanism of Vitamin E as a Bone-Protecting Agent: A Review on Current Evidence

“…Palm-derived T3 (21.9% αTF, 24.7% αT3, 4.5% βT3, 36.9% γT3, and 12.0% δT3) and annatto-derived T3 (16% γT3 and 84% δT3) reduced the levels of inflammatory markers (IL-1α and IL-6), concurrent with improvements of bone microstructure in the MetS animals [31,32,33]. Recently, it was also found that high-fat diet-induced type 2 diabetes caused inflammation as well as degeneration of bone microstructure in the femur and lumbar of male mice [92]. In this study, the authors found that annatto T3 (10% γT3 and 90% δT3) improved glucose and insulin tolerance, elevated serum procollagen I intact N-terminal propeptide (P1NP, a bone formation marker), decreased serum carboxyl-terminal telopeptide of type I collagen (CTX, a bone resorption marker), improved trabecular and cortical microstructure, as well as suppressed the expression of inflammation markers (MCP-1, IL-2, IL-23, IFN-γ, and TNF-α) in the liver of high-fat diet-induced diabetic mice [92].…”