Insulin Resistance: The Systemic Scene
Fasting Eur J Clin Invest. 2000 Jan;30(1):45-52. and postprandial Metabolism. 1992 Mar;41(3):264-72. plasma free fatty acid levels are higher in patients with obesity and insulin resistance syndrome. In fact, epidemiological studies seem to suggest that higher plasma FFA levels are independent predictors of progression to type 2 diabetes. Diabetologia. 1997 Sep;40(9):1101-6. The increased fatty acids induce apoptosis through excess nitric oxide production. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502. Increased lipolysis of triglyceride rich lipoproteins intravascularly as well as in the adipose tissues, along with decreased uptake by liver, adipose tissue, and other organs contributes to this excess FFA levels in the insulin resistant subject, such that the FFA turn over is higher in obese individuals. Endocr Rev. 2002 Apr;23(2):201-29 A resistance to insulin's suppressive action on the hormone sensitive lipase in adipose tissue is probable, Metabolism. 1992 Mar;41(3):264-72 accounting for the increased lipolysis in the insulin resistant individual although this has not been consistently borne out in all studies. Am J Physiol 263:E79–E84 Augmented TNF α expression seems to facilitate increased circulating FFA through antagonism of the antilipolytic properties of insulin. Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. The alternative hypothesis is that while hormone sensitive lipase remains sensitive to insulin action, the increasing amount of fat mass overwhelms insulin's suppressive effect on HSL. In keeping with this notion is that when normalized per total body fat, lipolysis is normal or reduced in the obese. Acta Med Scand. 1969 Apr;185(4):351-6.
Abnormalities in Fatty Acid binding proteins (FABP-2) could result in increased intestinal fat absorption resulting in higher fatty acid levels, Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1606-10 and insulin resistance Clin Biochem. 1998 Nov;31(8):609-12 although these polymorphisms and their fat absorptive effects is restricted to specific populations, J Clin Invest. 1995 Mar;95(3):1281-7. with inconsistencies in studies with regard to enhancement of intestinal fat absorption. Metabolism. 2001 Apr;50(4):473-6. On a similar note, defects or deficiency of fatty acid receptors or transporters (e.g. CD36, a scavenger receptor) could result in defective uptake of fatty acids into adipose tissue J Biol Chem. 2000 Oct 20;275(42):32523-9. with resultant higher serum free fatty acid levels and induction of insulin resistance in rodents, Lancet. 2001 Mar 3;357(9257):651-2. as well as in some human populations. Lancet. 2001 Mar 3;357(9257):686-7, although its physiological relevance if any, still remains unclear. Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1072-9. ASP or acyl stimulation protein is another adipocyte derived factor that may play a role in determining fatty acid esterification through a PKC-dependent pathway. J Biol Chem. 1999 Jun 25;274(26):18243-51. Although increased in obesity, its physiological contribution to the elevated FFA levels remains to be clarified. GPR40, a free fatty acid receptor on pancreatic beta cells may function as a signalling molecule and regulate insulin secretion Hepatol Res. 2005 Oct 5 and may be involved in the secretory abnormalities mediated by free fatty acids that accompany insulin resistance.
Abnormalities in Fatty Acid binding proteins (FABP-2) could result in increased intestinal fat absorption resulting in higher fatty acid levels, Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1606-10 and insulin resistance Clin Biochem. 1998 Nov;31(8):609-12 although these polymorphisms and their fat absorptive effects is restricted to specific populations, J Clin Invest. 1995 Mar;95(3):1281-7. with inconsistencies in studies with regard to enhancement of intestinal fat absorption. Metabolism. 2001 Apr;50(4):473-6. On a similar note, defects or deficiency of fatty acid receptors or transporters (e.g. CD36, a scavenger receptor) could result in defective uptake of fatty acids into adipose tissue J Biol Chem. 2000 Oct 20;275(42):32523-9. with resultant higher serum free fatty acid levels and induction of insulin resistance in rodents, Lancet. 2001 Mar 3;357(9257):651-2. as well as in some human populations. Lancet. 2001 Mar 3;357(9257):686-7, although its physiological relevance if any, still remains unclear. Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1072-9. ASP or acyl stimulation protein is another adipocyte derived factor that may play a role in determining fatty acid esterification through a PKC-dependent pathway. J Biol Chem. 1999 Jun 25;274(26):18243-51. Although increased in obesity, its physiological contribution to the elevated FFA levels remains to be clarified. GPR40, a free fatty acid receptor on pancreatic beta cells may function as a signalling molecule and regulate insulin secretion Hepatol Res. 2005 Oct 5 and may be involved in the secretory abnormalities mediated by free fatty acids that accompany insulin resistance.