Editorial
Copyright ©2007 Baishideng Publishing Group Inc.
World J Gastroenterol. Jul 14, 2007; 13(26): 3540-3553
Published online Jul 14, 2007. doi: 10.3748/wjg.v13.i26.3540
Table 2 Pathophysiology of insulin resistance
Actions of insulinMechanism of action of insulinAlterations in insulin resistant statesNet metabolic effect
(a) Stimulatory Increases glucose transport: In adipocytes In myocytes-Insulin binds to its membrane receptor to cause up regulation of GLUT-4 via mediation of IRS-1/2(activated by phosphorylation at tyrosine sites)-Impaired post receptor signaling involving IRS proteins -Abnormal phosphorylation of IRS-1 makes it inhibitor of the receptor kinase -Activation of IKK-β by free FA and cytokines leads to activation of NF-κB which further inhibits the genes involved in GLUT synthesis-Hyperglycemia -Decreased glucose utilization as energy source -Reactive hyperinsulinemia
Increases glycogenesis In hepatocytes In myocytes-By providing the building blocks -Increases expression and activity of glycogen synthase and inhibiting the glycogenolytic enzymes-Decreased glycogen synthesis-Hyperglycemia -Decreased postprandial glycogen stores in liver
Increases lipogenesis In adipose tissue In liver (DNL)-Increases the supply of substrates -Postprandial stimulation of FAS, ACC and SCD1 -Increases supply of free FA in AT-Further increase in lipogenesis,esp. DNL -Increased delivery of free FA to liver -Decreased oxidation in hepatocytes-Excessive fat storage in AT and in other tissues (lipotoxicity) -Hepatic steatosis -Increased adiposity
Increases protein synthesis in muscles-Activates the translational machinery -Activates protein kinase B which activates the protein synthesizing enzymes -In long term exposure increases ribosome in cells-Decreased protein synthesis-Sarcopenia
Increases glucose oxidative pathways-Enhances glycolysis and Kreb's cycle by activating all the key regulator enzymes-Inhibited -Lipid oxidation preferentially used for energy purposes-Hyperglycemia -Oxidative stress in hepatocytes
(b) Inhibitory Decreases gluconeogenesis in liver-Inhibits pyruvate carboxylase, glucose 6 phosphatase and PEP kinase -Shuttles substrates to lipogenesis-Enhanced gluconeogenesis -Decreased inhibition of keyregulatory enzymes -Activation of AMPK-Increased hepatic glucose output -Excessive availability of substrates for lipogenesis -Fasting hyperglycemia
Decreases hepatic glucose output-Decreases gluconeogenesis -Increases glycogen synthesis -Increases oxidation of glucose-Increased gluconeogenesis -Decreased glycogenesis and oxidative disposal of glucose-Hyperglycemia
Suppresses lipolysis in adipose tissue-Suppression of HSL-Increased rate of free FA release in fasting state in lean and obese -When corrected for body weight in obese, postprandial lipolysis may seem to be normal or even decreased-Increased plasma free FA both in fasting and post-prandial states(May be due to a mass effect of overall expansion of body fat depots in case of obese) -Increased free FA efflux -Increased VLDL
Decreases apolipoprotein secretion-Insulin decreases the synthesis and secretion of Apo-B and Apo-C-Hyperinsulinemia causes further suppression of expression of apolipoprotein genes and also inhibits post translational modifications and secretion -Enhanced synthesis of Apo-B 48 in intestines-Trapping of TAG inside the liver -Hepatic steatosis -Increased VLDL
Suppresses β oxidation of fatty acids-Insulin acts via binding to SREBP-1 transcription factor to cause increased expression of ACC-1 leading to generation of FAS substrates for lipogenesis-Reactive hyperinsulinemia with unrestricted effect on SREBP causes further inhibition of β-oxidation of free FA in hepatocytes mitochondria-Hepatic steatosis -CYP system over expression and generation of ROS