Abstract | The liver is the primary site of insulin clearance in humans (1). In passing from the portal vein into the systemic circulation, a substantial and variable proportion of newly secreted insulin is extracted by the liver (2). The metabolic role of this process is unclear. Early reports (3) suggested that hepatic insulin extraction might contribute to the control of systemic insulin concentrations, and more recently it has been suggested that reduction in hepatic insulin extraction could be part of the compensatory hyperinsulinemic response to maintain normal glucose levels in the presence of insulin resistance (4, 5). Alternatively, hepatic insulin extraction may contribute to the control of insulin-sensitive metabolic pathways in the liver, such as glucose production and lipogenesis (6, 7). The liver plays a pivotal role in lipid metabolism, importing serum free fatty acids and manufacturing, storing, and exporting lipids and lipoproteins (8). Insulin exposure is an integral part of hepatic lipid homeostasis. In the liver, insulin resistance seems, paradoxically, to be associated with a reduced ability of insulin signaling to inhibit glucose production, whereas insulin-stimulated lipogenesis is enhanced (9). Nonalcoholic fatty liver disease (NAFLD) is a common condition characterized by the deposition of fat, mainly triglyceride, within the liver, and it is associated with both whole body and hepatic insulin resistance (10, 11). Close, but complex relationships might therefore be expected between hepatic lipid accumulation, hepatic insulin exposure, and insulin resistance. Further levels of complexity may be anticipated if basal or post-glucose hepatic insulin exposure, hepatic or peripheral glucoregulatory insulin sensitivity, or antilipolytic insulin sensitivity and adiposity in different regional fat depots are taken into account. These considerations justify an investigation in which variation in a sophisticated measure of intrahepatocellular lipid (IHCL) is related to equally differentiated measures of hepatic insulin exposure, adiposity, and insulin sensitivity. To our knowledge, the relationship between hepatic lipid accumulation, hepatic insulin exposure, and insulin resistance has not previously been studied in a group of males with NAFLD and age- and gender-matched controls. We hypothesized that NAFLD is associated with increased exposure of the liver to insulin, and the aim of this study was to confirm this in the above cohort. |
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