Obesity, insulin resistance and hepatic perfusion.

ABSTRACT

Insulin resistance brings together the collection of hyperglycemia, hyperinsulinemia, and dyslipidemia associated with pathologies such as obesity and type 2 diabetes. As such, it is an important target for the prevention of complications linked with these pathologies. To the extent that insulin resistance involves hyperglycemia and dyslipidemia, there are obvious associations between impaired insulin signaling and microvascular dysfunction. In fact, there is evidence that insulin resistance significantly participates in the microvascular damage that occurs with obesity and type 2 diabetes. Since the liver plays a critical role in glucose homeostasis and lipid metabolism, and the state of the microcirculation reflects its function, the impact of insulin resistance on hepatic microvascular perfusion deficits is important. However, as of yet, no single body of work has addressed the relationships that exist between insulin resistance and the derangements in hepatic microvascular perfusion. Although there is distinct hepatic microvascular dysfunction associated with insulin resistance, a controversy still arises as to whether this dysfunction occurs as a result of reductions to the sinusoidal lumen. Nonetheless, the literature appears to agree that the general effects of obesity and insulin resistance on the hepatic microcirculation are linked to the selective impairment of phosphatidylinositol 3'-kinase signaling, as well as the presence of swollen fatty hepatocytes and sinusoidal "capillarization." This manuscript sets out to review the main aspects of hepatic glucose homeostasis and lipid metabolism, as well as the cellular and molecular mediators regulating hepatic microvascular perfusion deficits during obesity and insulin resistance.