PMC:509282 / 6574-12318 JSONTXT

{"project":"2_test","denotations":[{"id":"15287987-15057233-66505211","span":{"begin":142,"end":143},"obj":"15057233"},{"id":"15287987-8621018-66505212","span":{"begin":839,"end":841},"obj":"8621018"},{"id":"15287987-13990765-66505213","span":{"begin":986,"end":988},"obj":"13990765"},{"id":"15287987-10408254-66505214","span":{"begin":1188,"end":1190},"obj":"10408254"},{"id":"15287987-10949030-66505215","span":{"begin":1751,"end":1753},"obj":"10949030"},{"id":"15287987-1687745-66505216","span":{"begin":2074,"end":2076},"obj":"1687745"},{"id":"15287987-8538710-66505217","span":{"begin":2817,"end":2819},"obj":"8538710"},{"id":"15287987-7654879-66505218","span":{"begin":4475,"end":4477},"obj":"7654879"},{"id":"15287987-11697549-66505219","span":{"begin":4657,"end":4659},"obj":"11697549"},{"id":"15287987-9869010-66505220","span":{"begin":4834,"end":4836},"obj":"9869010"}],"text":"Discussion\nObesity is a major risk factor for several metabolic diseases, frequently clustering to form the metabolic syndrome or syndrome X [9]. Obese people have increased incidence of NIDDM with high percentage of mortality and morbidity [10]. Western style diet, which is abundant with calorically dense and saturated fatty foods, is considered to be the main factor in the development of obesity and insulin resistance. Our studies have shown that HFD causes increase in bodyweight when compared to NPD after four weeks of dietary manipulation in rats.\nHyperglycemia is observed in insulin resistance where glucose utilization is reduced. We saw significant elevations in blood glucose levels. Intraperitoneal glucose tolerance tests confirm severe glucose intolerance. Oversupply of dietary lipids causes insulin resistance in rats [11]. Randle glucose fatty acid cycle suggested that the body prefers excess lipid stores to glucose for metabolic oxidation in insulin resistance [12]. Our HFD model also exhibited high plasma triglyceride levels. Hence studies on our experimental model in compliance with Randle et al findings suggested that HFD feeding causes insulin resistance [13].\nInsulin resistance with compensatory hyperinsulinemia is a prominent feature of metabolic syndrome. The most common reason for the development of hyperinsulinemia in insulin resistance is obesity. It stands as one of the major cardiovascular risk factors in patients with obesity. The present study on HFD rats demonstrated higher plasma insulin levels than control values. This marked hyperinsulinemia could be due to a combination of increased β-cell mass and decreased insulin clearance, as well as failure of insulin to suppress hepatic gluconeogenesis [14].\nElevated cholesterol is also observed in insulin resistant individuals. For this reason we measured plasma cholesterol levels which were found to be more than normal values. Previous studies have reported a down regulation of LDL receptors and associated decrease in LDL clearance, increased total cholesterol levels [15].\nAccording to National Cholesterol Education Program's Adult Treatment Panel III (Third report) easily measured clinical findings for syndrome X includes increased abdominal circumference, elevated triglycerides, low high-density lipoprotein-cholesterol, and elevated fasting blood glucose and/or elevated blood pressure. Three of these five are required for diagnosis. Our study demonstrated three of the clinical parameters indicating conditions of syndrome X in HFD fed rats [16]. Insulin resistance along with other conditions of syndrome X might induce hypertension by a host of mechanisms involving insulin itself, increased sodium reabsorption and/or enhanced intra cellular concentration of free calcium in vascular smooth muscle [17]. Although the etiology of vascular disorders in metabolic syndrome has not completely been revealed, it is suggested that alterations in the reactivity of blood vessels to neurotransmitters and circulating hormones are responsible for the functional abnormalities of blood vessels.\nIn order to elaborate the pathways that connect syndrome X to hypertension we have studied the contractile responses to 5-HT and Ang II in both HFD and NPD fed rat thoracic aortae. Previously we have demonstrated increased contractile responses with synthetic alpha adrenoceptor agonist, phenylephrine, in HFD fed rat thoracic aorta [18]. This enabled us to explore the role of these endogenous mediators in the same animal model.\nThe present vascular studies demonstrated that the magnitude of responses to 5-HT and Ang II was significantly enhanced in HFD fed animals without change in pD2 value. Endothelial denudation obviates any related mechanisms such as impairment of NO release, increased destruction of EDRF and substrate availability for the production of EDRF. Hence, the probable reasons for these enhanced 5-HT and Ang II responses may be due to receptor mediated or non-receptor mediated pathways.\nThe role of non-receptor mediated contraction can be ruled out for there was no change in contractile response to KCl. Vascular studies have also shown functional evidence that hypertension developed in HFD fed rats may be associated with enhanced vasoreactivity to various vasoconstrictor agents. Further the enhanced responses to 5-HT in HFD fed rats could be due to increased PKC as previously reported with STZ and alloxan (ALL) induced diabetic animals [19]. Increased contractions to 5-HT can also be related to 5-HT2A upregulation as observed in spontaneously hypertensive rats or due to serotonin acting through alpha adrenoceptors [20].\nIncreased Ang II responses in HFD fed rats are may be due to upregulation of Ang II receptors as observed in hyperinsulinemia or via amplified secondary messenger systems [21]. A proposed scheme of events is given in Fig 4.\nFigure 4 Proposed events underlying syndrome X in HFD rats. HFD leads to condition, in rats, similar to syndrome X. This includes obesity, insulin resistance, hyperglycemia and dyslipidemia which all are interrelated. These events are the initial steps in the cascade towards hypertension. This could be mediated via increased contractile responses to various endogenous mediators such as 5-HT and Ang II. In summary, the present study has shown that HFD feeding in rats produces conditions similar to syndrome X. Increased vasocontractile responses observed in the model are not only mediated via alpha adrenoceptors but also due to 5-HT and Ang II (see Figure 4).\nMore robust studies on the secondary messenger systems of 5-HT and Ang II will provide valuable insights into the mechanisms underlying increased vascular contractility in insulin resistance."}