Is Insulin Resistance Really Bad?
Various questions have troubled the medical community for sometime. Is insulin resistance the consequence of obesity? Or does insulin resistance lead to obesity? Did the obese individual have a NEED for insulin resistance as a protective phenomenon? Or in other words, is insulin resistance a good thing that has gone terribly wrong?
The lipotoxicity hypothesis assumes the latter view. Excess carbohydrates are stored as glycogen normally. When glycogen stores are replete, further fate of the carbohydrates is entry into the lipogenic pathway (conversion to acetyl coA and then malonyl CoA). Malonyl coA inhibits fatty oxidation (lipolysis) by beta-oxidation, through inhibition of the CPT-1 (carnitine palmitoyl transferase 1) enzyme, while favouring fat deposition ( lipogenesis), while the cell which is insulin sensitive continues to utilize glucose for its energy needs. The proposed disadvantage of this scenario is that the fat that does not undergo beta oxidation here, can be metabolised by other pathways leading to toxic products facilitating apoptosis and lipotoxicity. Annu Rev Med. 2002;53:319-36. Development of insulin resistance (to the uptake of glucose into cells) results in diversion of the stored triglycerides into the preferred beta oxidation pathway avoiding generation of toxic substances including nitric oxide and ceramide. Trends Endocrinol Metab. 2003 Nov;14(9):398-403. But if this was to be as simplistic as it sounds, insulin resistance would have ultimately produced total lipolysis thus limiting the fat accumulation and restoring insulin sensitivity! It is important to realise that it is postulated that insulin resistance in this context may be selective for glucose uptake and not for lipogenesis. In other words, the cell remains sensitive to the lipogenic action of insulin through mechanisms as SREBP1c up regulation, Endocr Rev. 2002 Apr;23(2):201-29. facilitating continued deposition of fat as long as excess dietary supply of carbohydrates or calories is maintained.
The lipotoxicity hypothesis assumes the latter view. Excess carbohydrates are stored as glycogen normally. When glycogen stores are replete, further fate of the carbohydrates is entry into the lipogenic pathway (conversion to acetyl coA and then malonyl CoA). Malonyl coA inhibits fatty oxidation (lipolysis) by beta-oxidation, through inhibition of the CPT-1 (carnitine palmitoyl transferase 1) enzyme, while favouring fat deposition ( lipogenesis), while the cell which is insulin sensitive continues to utilize glucose for its energy needs. The proposed disadvantage of this scenario is that the fat that does not undergo beta oxidation here, can be metabolised by other pathways leading to toxic products facilitating apoptosis and lipotoxicity. Annu Rev Med. 2002;53:319-36. Development of insulin resistance (to the uptake of glucose into cells) results in diversion of the stored triglycerides into the preferred beta oxidation pathway avoiding generation of toxic substances including nitric oxide and ceramide. Trends Endocrinol Metab. 2003 Nov;14(9):398-403. But if this was to be as simplistic as it sounds, insulin resistance would have ultimately produced total lipolysis thus limiting the fat accumulation and restoring insulin sensitivity! It is important to realise that it is postulated that insulin resistance in this context may be selective for glucose uptake and not for lipogenesis. In other words, the cell remains sensitive to the lipogenic action of insulin through mechanisms as SREBP1c up regulation, Endocr Rev. 2002 Apr;23(2):201-29. facilitating continued deposition of fat as long as excess dietary supply of carbohydrates or calories is maintained.