Obesity and Type 2 diabetes currently represent a public
health problem of stunning proportions in India, one that has long been
associated with a constellation of metabolic disorders. It is one of the most
common consequences of chronic inflammation that is caused by the failure of
cells to respond to insulin, a state known as insulin resistance. Insulin
signals a cell to import glucose by binding to a cell surface receptor that is
a member of the receptor tyrosine kinase (RTK) family. When insulin binds to
the receptor on the external surface of the cell, a downstream signal is
transmitted, activating the intrinsic tyrosine kinase activity of the receptor.
The two halves of the insulin-bound dimeric receptor phosphorylate one another
on tyrosine residues and these residues then act as docking sites for other
proteins in the signaling cascade. The IRS proteins subsequently act as adapter
molecules for transmitting the insulin signal to downstream molecules such as
the kinases PI3 kinase and Fyn, and the docking proteins Grb2 and SHP2.
However, if the IRS proteins are phosphorylated on serine residues by IRS
serine/threonine kinases, their signaling capacity is inhibited. Inflammatory
cytokines such as IL-6, IL-1 and TNF-? bind to cell-surface receptors and
signal the activation of kinases, including JNK, which phosphorylate IRS-1 on
serine residues, inhibiting its activity. Malfunctions in energy
homeostasis resulting from genetic predisposition can lead to obesity. In this
review we have tried to elucidate different triggers that contribute towards
the development of Type II Diabetes.
ADIPOSITY AND INSULIN RESISTANCE
Insulin resistance is a critical component of T-2D that develops in response
to an excess nutrient ?ux. Several dietary factors like saturated fatty acids
and glucose followed by changes in the gut microbiota have been proposed as
triggers of this meta-inflammation through the activation of
pattern-recognition receptors (PRRs), in?ammasomes and nucleotide
oligomerization domain (NOD) that activate production of pro-in?ammatory
cytokines and recruitment of immune cells such as macrophages and T lymphocytes
in the metabolic tissues. Hypoxia triggered as a result of this, worsens the
situation even more. In?ammatory cytokines activate several kinases like IKK?,
mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with
insulin signaling and action in adipocytes and hepatocytes.
AND ITS INFLUENCE ON THE GUT MICROBOTA
TLRs play a crucial role in sensing pathogens
via pathogen-associated molecular patterns (PAMPs) and to detect tissue injury
through the danger-associated molecular patterns (DAMPs). TLR2 and TLR4 reportedly
play an important role in in?ammation and insulin resistance during obesity.
TLR4 expression is pretty much elevated in obese and diabetic