1. PATHOGENESIS OF METABOLIC SYNDROME:
Metabolic syndrome is a cascade of events indicating several
metabolic anomalies occurring simultaneously in type II Diabetes
Mellitus. Although disturbance in metabolism are also evident in
victims of type I Diabetes but the clinical features of metabolic
syndrome are associated specifically with type I. Whatever would
be the clinical features of the disease, they are either “resulting”
from insulin resistivity or are “initiating “ because of it.
INSULIN RESISTIVITY:
It is described as the gradual loss in the sensitivity of the insulin
receptor which is a transmembrane 4 insulin receptor substrate 1-
4 and cytosolic domains of tyrosine kinase (part of 2nd
messenger
system) .It is to note here that in type I Diabetes - where
deficiency of insulin because of the destruction of B cells of
Langerhans is present - insulin resistivity does not occur for year
and cells respond normally well to intravenous insulin.
Abnormal fat constituent in obese and dyslipidemics,
understimulation of Glucose and insulin receptor due to
sedentary life style and such other contributing risk factors are
believed to be responsible for the lost expression of insulin
2. receptors and distortion of signal transduction pathway of insulin
in type II Diabetes. Less no. of receptors on cell surface in obese
people is found as compared to be lean individuals. Consequently
hyperinsulinemia (high conc. of insulin in plasma) develops
which is itself toxic.
METABOLIC DISTURBANCES:
Normally, when insulin binds to its receptor,
phosphorylation of its cytoplasmic tyrosine kinase residues
takes place initiating the autophosphorylation of IRS –
complexes which activate a variety of enzymes, initiating
uptake of glucose and amino acids, glycogenesis,
lipogenesis, protein synthesis, gene expression and overall
growth like effects. It is also a potent inhibitor of lipases and
glucagon.
But in insulin resistivity all these functions are reversed.
1. In Liver and Muscle Cells, soon after the meal reduced
expression of Glut-receptors and co-transporters due to
reduces activity of Glucokinase results in limited intake
of glucose and amino acid resulting hyperglycemia.
2. Due to lack of glucose inside the cell , cell does not
undergo energy storing processes such as glycogenesis
3. and lipogenesis (reduced activation of glycogen synthase
and lipid kinases)
3. Meanwhile antagonists of insulin i.e. glucagon and
lipases are activated to compensate for energy crisis in
between meals. Instead of glycolysis, metabolism is
shifted towards beta-oxidation of fatty acids which
produces accetoacetic acid as a byproduct several times
than that of its consumption, which leads to acidosis of
liver and muscles resulting decrease in blood PH. This
acidosis is corrosive in nature and microalbuminuria and
ketonemia develops.
4. Muscle cells undergo wasting and Liver becomes
secretory contributing abnormal lipids constituents such
as LDL and VLDL in systemic flow resulting
dyslipidemia (imbalance in plasma ratios of HDL and
LDL)
5. In Adipose tissue, role of insulin is to activate Lipid
Kinase and to inhibit hormone-sensitive Lipases. In
metabolic syndrome complementary processes start
resulting lipolysis. A burst of free fatty acids, TGs,
cholesterol from adipocytes into the blood take place and
hyperlipidemia (increase in plasma total fat) develops.
4. 6. A no. of inflammatory cytokines is also released along
with fat such as adipokines –leptin- TNF, IL-6, Resistin
and Adiponectin into the blood.
7. In almost all cells of the body (except brain cells), insulin
interacts with growth hormones and insulin like growth
factors synergistically and initiates protein synthesis. But
due to revert functions in metabolic syndrome , there is
reduction in long-term process of gene expression, DNA
synthase activity and repair mechanism (decrease
stimulation of P21, RAS, Raf-1, MEK, MAP kinases).Cells
become prone to inflammation. A mark) can be noted.
8. Additionally, able increase in prothrombic factors
(fibrinogen. Plasminogen activator inhibitor-I),
proinflammatory cytokines, CRP (an active acute phase
biomarker insulin acts as a vasodilator by secreting
eNOS from endothelial cells of vessels. Reduced insulin
activity, prothrombic factors and cytokines will cause
vasoconstriction and high blood pressure.
9. As a sequel of events atherosclerosis and high risk of
CVD develops if not managed.
10. Healthy visceral fat which forms a layer around
internal organs is protective in nature such that it absorb
5. high fat constituents from systemic circulation and fat
component of blood flow to internal organs is
maintained in normal range. Fat around abdomen is also
protective for short term because of the presence of
portal system –which shuttles in between Liver and
systemic flow. But when insulin sensitivity is lost then at
regular intervals under the activation of sympathetic
nervous system it secretes high amount of free fatty
acids into Liver then in systemic circulation leading to
obesity and fat around abdomen.
This document is for study purpose, unauthorized copy pasting is forbidden
References:
Text book of Medical physiology by Guyton and Hall
12th
edition
Harper’s illustrated biochemistry
26th
edition
6. high fat constituents from systemic circulation and fat
component of blood flow to internal organs is
maintained in normal range. Fat around abdomen is also
protective for short term because of the presence of
portal system –which shuttles in between Liver and
systemic flow. But when insulin sensitivity is lost then at
regular intervals under the activation of sympathetic
nervous system it secretes high amount of free fatty
acids into Liver then in systemic circulation leading to
obesity and fat around abdomen.
This document is for study purpose, unauthorized copy pasting is forbidden
References:
Text book of Medical physiology by Guyton and Hall
12th
edition
Harper’s illustrated biochemistry
26th
edition
