Assessment of Apo-B and TG/HDL-C Ratio as Indicators of Insulin Resistance in Patients with Metabolic Syndrome | Chapter 02 | Recent Advances in Biological Research Vol. 3
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.
Author Details:
Dr. Parineeta Samant
Department
of Biochemistry, MGM Medical College, Navi-Mumbai, India.
View Volume: https://doi.org/10.9734/bpi/rabr/v3
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