Insulin resistance and inflammation are recognized as important links between obesity and cardiovascular disease (CVD).
Plasma free fatty acids (FFA), either released from the abnormally enlarged adipose tissue or as part of the excessive nutrient intake, produce
insulin resistance and inflammation. Both insulin resistance and inflammation are tightly linked to several independent CVD risk
factors such as type 2 diabetes (T2DM), hypertension, dyslipidemia and disorders of blood coagulation. Several hypotheses have been
proposed to explain how increased plasma FFA levels can cause insulin resistance including a) the lipid metabolite hypothesis, b) the inflammation
hypothesis, c) the hyperinsulinemia hypothesis and d) the endoplasmic reticulum (ER) stress hypothesis. The latter does not
require presence of elevated plasma FFA levels and thus provides a mechanism to explain the development of insulin resistance and inflammation
in all obese individuals, i.e., those with and without elevated plasma FFA levels.
Hyperinsulinemia per se has been suspected to cause CVD based on epidemiologic studies which have associated chronic hyperinsulinemia
with CVD without, however, establishing a cause and effect relationship. There are, however, newer results which support the hypothesis
that chronic hyperinsulinemia per se can promote the development of CVD. For instance, hyperinsulinemia can activate triglyceride
formation, several matrix metalloproteinases (MMP), and the tissue factor pathway of blood coagulation, all of which are known to
be associated with CVD, even in the presence of “metabolic insulin resistance”.