Assessment of Apo-B and TG/HDL-C Ratio as Indicators of Insulin Resistance in Patients with Metabolic Syndrome

The concept of metabolic Syndrome was first introduced as Syndrome X by Gerald Reaven He delivered the Banting Lecture in 1988 at the American Diabetes Association national meeting. He stated that Syndrome X is aggregation of independent, risk factors present in the same individual which are seen in coronary heart disease (CHD). The various risk factors included in the syndrome were insulin resistance, defined as the inability of insulin to optimally stimulate the transport of glucose into the body’s cell (hyperinsulinemia or impared glucose tolerance, hypertension, hypertriglyceridemia, and low, high-density lipotrotein cholesterol (HDL) [1]. Syndrome X is referred as,the deadly quartet by Kaplan [2] and Foster described it as,a secret killer [3]. Reaven in his Banting Lecture described the point that insulin resistance/hyperinsulinemia might be the underlying cause of the syndrome. Reaven also suggested that insulin resistance/hyperinsulinemia was an underlying risk factor for T2D, which, at the time, was referred to as noninsulin-dependent diabetes mellitus. In 1991, Ferrannini et al. [4] in his article published entitled,’ Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome,’ described Reaven’s point of view about insulin resistance and metabolic syndrome. Furthermore, use of the term MS acknowledges that this array of factors is associated with abnormal carbohydrate and lipid metabolism. These authors emphasized that insulin resistance was the underlying factor and, once acquired, those with a genetic predisposition would develop all the other aspects of the disorder. Haffner et al. [5] coined the term “insulin resistance syndrome” for the disorder to highlight the fact that insulin resistance preceded other aspects of the syndrome. Some individuals still use the term insulin resistance syndrome but now the term “metabolic syndrome” is more commonly used to describe the aggregation of multiple CHD and T2D risk factors. Metabolic syndrome is a pathophysiological process, meaning that it is either caused by a disease or represents a dysregulation of normal physiological mechanisms occurring due to long standing insulin resistance. The baseline cause of metabolic syndrome is obesity which is mainly due to accumulation of fat. Thus cluster of condition seen in metabolic syndrome are mainly due to fat storage condition and insulin resistance is feature of fat storage condition. Increased plasma free fatty acid concentrations are typically associated with many insulin-resistant states. It is demonstrated in the animal experimental study that fatty acids compete with glucose for substrate oxidation in heart muscle and diaphragm muscle. It is speculated that increased fat oxidation causes the insulin resistance associated with obesity [6-8]. The mechanism proposed to explain the insulin resistance was that an increase in fatty acids caused an increase in the intra mitochondrial acetyl CoA/CoA and NADH/NAD+ ratios, with sub- sequent inactivation of pyruvate dehydrogenase. This in turn would cause intracellular citrate concentrations to increase, leading to inhibition of phosphofructokinase, a key rate-controlling enzyme in glycolysis. Subsequent accumulation of glucose-6-phosphate would inhibit hexokinase II activity, resulting in an increase in intracellular glucose concentrations and decreased glucose uptake. The increase in plasma fatty acid concentrations initially induce insulin resistance by inhibiting glucose transport or phosphorylation activity, and that causes reduction in muscle glycogen synthesis and glucose oxidation resp. The reduction in insulin-activated glucose transport and phosphorylation activity in normal subjects is observed at high plasma fatty acid levels and leading to accumulation of intramuscular fatty acids (or fatty acid metabolites). This appears to play an important role in the pathogenesis of insulin resistance seen in obese patients and patients with type 2 diabetes. Moreover, fatty acids seem to interfere with a very early step in insulin stimulation of GLUT4 transporter activity or hexokinase II activity. Increasing intracellular fatty acid metabolites, such as diacylglycerol, fatty acyl CoA’s, or ceramides activates a serine/threonine kinase cascade (possibly initiated by protein kinase), leading to phosphorylation of serine/threonine sites on insulin receptor substrates. Serine-phosphorylated forms of these proteins fail to associate with or to activate PI 3-kinase, resulting in decreased activation of glucose transport and other downstream events, Any perturbation in these events results in accumulation of intracellular fatty acyl CoA’s or other fatty acid metabolites in muscle and liver, either through increased delivery or decreased metabolism, might be expected to induce insulin resistance.