Endocrine Abstracts

Hypertriglyceridemia (HTG) is known to be a risk factor for cardiovascular diseases, such as atherosclerosis and hypertension. Although the association between insulin resistance (IR) and HTG has long been recognized, the causal relationship between them has not been elucidated yet. Proper understanding of the effect of IR on HTG may better start with the realization that IR implies much more than mere impairment of glucose uptake in tissues. Given that the role of insulin is widely different from tissue to tissue, metabolic disruptions due to IR would be very tissue-specific. Furthermore, IR would not necessarily develop simultaneously in the whole body but instead develop first predominantly in the muscle tissue with a low cell turnover and then progress to the adipose tissues and to the liver with higher cell turnovers. This may warrant that IR be subdivided better into tissue-specific IRs, such as the muscle insulin resistance (MIR), adipose insulin resistance (AIR), and hepatic insulin resistance (HIR). It is believed that HTG is related particularly with AIR. The AIR – failure of insulin action in adipose tissues – would not only impair glucose uptake into adipose tissues thereby elevating plasma glucose (PG) significantly, but also let adipose tissue lipases, such as hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), be inhibited not enough even in the fed state. Consequently, adipose tissues under AIR would not only undergo uninhibited lipolysis to release constantly fatty acids (FAs) into the plasma but also fail to entrap the fatty acids (FAs) released from the triglyceride-rich lipoproteins (TRLs), such as very low-density lipoproteins (VLDLs) and chylomicrons, that undergo, with the help of lipoprotein lipase (LPL), delipidation, which elevates severely the plasma fatty acid (PFA). Then, a significant fraction of severely elevated PFAs would also transport into the liver and subsequently, along with the FAs being released when the remnant TRLs taken up by the liver undergo hepatic breakdown, be formed into VLDLs and secreted back into the plasma, thereby contributing to severe elevation of plasma triglyceride (PTG), i.e., hypertriglyceridemia (HTG). As well known, chylomicrons of dietary fat origin delipidate much faster than VLDLs, which explains why VLDLs constitute the major component of PTG. In summary, AIR renders adipose tissues unable to esterify FAs into fats, which inevitably elevates PFA severely, which in turn enhances hepatic VLDL generation and secretin, thereby elevating PTG severely and thus leading to HTG.