Molecular Basis of Pathogenesis of Diabetes Mellitus Type 2- a New Perspective

Decreased insulin secretion due to beta cell dysfunction of the pancreas and defective utilization of
insulin due to insulin resistance / Hyperinsulinemia are two important issues in the pathogenesis of
DM2. There are many explanations in the literature to account for these two observed phenomena
and their interrelationship. DM2 is believed to occur due to a complex interplay of environmental and
Behavioural factors in genetically predisposed persons. Among the theories explaining the
pathogenesis of DM2, the viscera- Portal hypothesis, the Ectopic fat hypothesis and the adipose
tissue as an endocrinal gland are prominent. Besides, the role played by oxidative stress, metabolic
stress, mitochondrial dysfunction, endoplasmic reticulum stress, etc. are also advanced. It is felt that
basic to and at the core of all the observed facts, is the shift of energy metabolism from normal
glycolysis to B- oxidation of fats. Hence, how B - oxidation prevails over glycolysis is the fundamental
issue to be addressed together with its interrelationships with insulin resistance, as to which is the
cause and which is the effect. At the molecular level, an attempt to find answers to the above
questions is made in this paper.
To this extent, the Randle fatty acid cycle (Substrate competition theory of Randle) is suitably
modified and applied to explain the switch of Energy metabolisms in DM2. Defective disulfide bond
formation of the insulin receptor which makes it physiologically ineffective, is suggested as the cause
of the insulin resistance where as the prevailing molecular mechanisms stress on post-receptor
signaling defect. The cause and effect of both are discussed. This line is considered to be a departure
from traditional approaches broached above and briefly outlined in this article.