The MS is a cluster of cardiovascular risk factors which include obesity, central obesity, atherogenic dyslipidemia and IR . Apart from its association with CVD and diabetes mellitus, it is a common soil for numerous other clinical disorders .
Our work is comparable to that of Kannappan and Aduradha , who were able to show that the HFD was able to impair insulin sensitivity and glucose tolerance. This was revealed by the significant elevation in AUC of the OGTT of group F. Such a finding was confirmed by the observed hyperglycemia, hyperinsulinemia and elevated HOMA of the same group, and is matched with those of Yadav et al. .
Increases in the fructose load to the liver, could elicit rapid responses that ultimately influence hepatic gene expression, glucose disposal, and insulin action. This may be attributed to the fact that fructose metabolism bypasses the regulatory step catalyzed by phosphofructokinase-1. Thus, fructose continuously enters the glycolytic pathway resulting in hyperglycemia . The extra glucose released into the blood stimulates more insulin secretion, leading to reduced insulin sensitivity .
Visceral adiposity is known to be increased by HFD . It is associated with IR as a result of the direct delivery of portal blood flow from visceral fat to the liver releasing FFAs . The greater lipolytic capacity of visceral than peripheral adipocytes releases more FFAs to the portal circulation. Furthermore, when visceral adipocytes enlarge, they become more insulin resistant than smaller adipocytes . Increased amounts of FFAs directly affect insulin signaling, diminish glucose uptake in muscle, and induce gluconeogenesis in the liver .
Although taurine was unable to improve the fasting hyperglycemia, it was able to attenuate the elevated AUC of the OGTT, as well as the observed hyperinsulinemia, and it greatly improved the elevated HOMA. It was speculated that in this diet-induced model, activation of serine kinases coupled with inhibition of tyrosine phosphorylation of the insulin receptor could result in IR. Changes in redox balance can activate certain stress-induced serine kinases which can in turn decrease the extent of tyrosine phosphorylation, and is consistent with the attenuation of insulin action . It was previously described that taurine modulates the insulin signal transduction pathways by inhibiting the cellular protein tyrosine phosphatase activity that negatively regulates insulin signaling. Thus, taurine has the potential ability to prolong as well as increase insulin signaling. It is also possible that taurine being an antioxidant, would make the cells less susceptible to the consequence of stress-induced activation of serine kinases .
The consumption of the HFD resulted in hypertriglyceridemia, hypercholesterolemia, and increased levels of both LDL-C and HDL-C. Fasting hypertriglyceridemia in IR has largely been attributed to apoB-100 containing TGs rich very low density lipoprotein (VLDL) overproduction and secretion by the liver, with a lesser contribution to the impaired VLDL removal . Fructose consumption can promote hepatic lipogenesis because it provides unregulated amounts of lipogenic substrates acetyl-CoA and glycerol-3-phosphate . Fructose can also activate sterol regulatory element binding protein-1c (SREBP-1c) independently of insulin, which then activates genes involved in de-novo lipogenesis . SREBP-1c over-expression was also reported to inhibit insulin receptor substrate-2 expression, which might contribute to a transitional switch from glycogen synthesis to lipogenesis . High density lipoprotein (HDL) is the major cholesterol lipoprotein carrier in rats , thus, the elevation of serum HDL-C could merely be a reflection to the observed increased serum T-Chol.
Taurine can upregulate 7-α-hydroxylase, the rate-limiting enzyme in bile acids production , and was shown to increase its mRNA levels . Taurine may also decrease cholesterol levels through upregulation of hepatic LDL receptor and/or through improving the binding of LDL to them. Thus, it increases the LDL turnover in blood . The ability of taurine to decrease the T-Chol level could be the main contributor to the reduced atherogenic index of group F + T.
The HHcy observed in the fructose-fed model of IR may be attributed to the reduction in the specific activity of two key enzymes of Hcy metabolism, namely, methyltetrahydrofolate reductase and cystathionine β synthase (CβS). Dicker-Brown et al. used cultured hepatocytes to show that chronic insulin addition was able to induce HHcy that was due to Hcy being transformed to either methionine or cysteine at a reduced rate .
Hyperhomocysteinemia could also be explained in light of the observed hypertriglyceridemia which might specifically promote lipid deposition in visceral adipose tissue as commonly associated with IR . N-nicotinamide methyltransferase (NNMT) is a major methyltransferase expressed in high amounts in human adipose tissue . It converts nicotinamide into N-methyl nicotinamide at the expense of S-adenosyl methionine as methyl-donating cofactor. The generated S-adenosyl homocysteine could further be converted to Hcy . Thus, the observed HHcy in the fructose-fed rat model of the current study could be attributed to the increased visceral adiposity accompanying overconsumption of fructose.
The high levels of Hcy could be metabolized into Hcy thiolactone, a physiological substrate of PON protein. Hcy thiolactone can cause HDL homocysteinylation  and consequently decreases its PON activity as revealed by the results of the current work. Under conditions of high oxidative stress, PON may be inactivated by S-glutathionylation, a redox regulatory mechanism characterized by the formation of a mixed disulfide between a protein thiol (i.e. cysteine-284 of PON enzyme) and oxidized glutathione . The lower PON activity observed in group F may also be due to the increased T-Chol that increases the susceptibility of LDL to oxidation. This process inactivates PON in an interaction between the lipid peroxides and the sulfhydryl groups of the enzyme as previously shown by Bajnok et al. . Systemic oxidative stress is associated with IR, which manifests as decreased TAC. This is possibly due to increased oxidative stress on one hand and decreased activities of different antioxidative enzymes on the other. Thus, the significant positive correlations revealed between TAC and PON activities of groups F and F + T are convenient.
The significant reduction of TAC in group F could be attributed to the fact that the high fructose delivery to the liver may generate stress-activating molecules, such as methylglyoxal and/or d-glyceraldehyde. These molecules can serve as substrates for AGEs . AGEs could activate NADPH oxidase in endothelial cells. Activation of NADPH oxidase could also occur cause endothelial cells lack CβS and Betaine:homocysteine methyltransferase. Thus, Hcy depends on the methionine synthase pathway for its elimination. HHcy may thus cause a deficiency of folic acid with subsequent deficiency of tetrahydrobiopetrin, and consequently, uncoupling of the endothelial NOS reaction producing superoxide anion (O 2•-) as well as ONOO- rather than NO . Hcy was also shown to reduce the expression of glutathione peroxidase and the secretion and expression of extracellular superoxide dismutase [53, 54]. Thus, in addition to directly producing ROS, Hcy also reduces the O 2•- anion scavenging capacity leading to further elevation of oxidative stress.
Hyperhomocysteinemia could also promote ROS production by increasing inducible NOS expression which subsequently increases nitrotyrosine formation . This fact could explain the significant elevation of NOx observed in group F. ROS could also reduce NO bioavailability by inactivating it to ONOO-. In this respect, the elevation of serum NOx might indeed reflect the impaired NO bioavailability since ONOO-, as well as NO, are metabolized into nitrites and nitrates . Recently, it has been shown that ONOO-, in the absence of known nitrosative stress-protecting enzymes, could be degraded by catalase enzyme into nitrate (70%) and nitrite (30%) . A finding that may aid in rationalizing the elevated NOx concentration in this fructose-fed model.
Taurine is synthesized from cysteine, the precursor of glutathione (GSH). Hence, taurine supplementation may spare cysteine, thus increasing tissue levels of GSH, restoring TAC as well as PON activity back to normal . In the present study, taurine supplementation was also able to improve the elevated NOx which may have been achieved through lowering inducible NOS gene expression as previously reported by Hsu et al. , or through scavenging O 2•- and NO, the precursors of ONOO- under conditions of elevated oxidative stress . These results are matched with those of Yalçınkaya et al. , who reported that taurine was not able to improve the diet-induced HHcy, although it was able to improve HHcy-induced ROS production. Thus, further studies are required to define or not whether different dosages and/or durations of taurine supplementation will be able to improve the observed HHcy in this model of IR.