Effects of FFA on Hepatic Glucose Metabolism

Endogenous glucose production and hepatic insulin resistance are increased in type 2 diabetes (32,129,148). Elevation of FFAs has been linked to increased HGP in dogs (149) and have been shown to stimulate gluconeo-genesis (145,150). This has been attributed to an increased intracellular pool of acetylCoA, derived from FFA ^-oxidation, which can activate pyruvate carboxylase and increase NADH and ATP, which serve as co-factor and source of energy, respectively, for the gluconeogenic pathway. In addition, FFA elevation induced experimentally by infusion of Intralipid (an exogenous source of TG) and heparin (to stimulate LPL, which hydrolyzes intralipid TGs, thereby raising plasma FFAs) has been shown to increase levels of citrate formed from FA oxidation, thereby inhibiting phosphofructokinasel and stimulating glucose production (151). Two additional pathways have been proposed to explain FFA-mediated induction of gluconeogenesis: the glyoxalate and pentose-5-phosphate pathways (152). In some cases, however, the net effect of FFAs on HGP is not clear, owing to a compensatory decrease in glycogen breakdown and release as glucose (153-156). This counterregulation has been referred to as "hepatic auto-regulation". Both intra- and extrahepatic mechanisms contribute to this phenomenon. Intrahepatic mechanisms include activation of glycogen synthase, whereas the phosphorylase is inhibited by increased intra-

cellular levels of glucose-6-phosphate from gluconeogenesis (154,157). The extrahepatic explanation relies on the ability of elevated FFAs to induce secretion of insulin and changes in portal levels of insulin. The effect of FFAs on HGP has been questioned, because in conditions where insulin levels are clamped, HGP is not increased (158-161), and the auto-regulatory compensation is abolished, presumably because, at hyperinsulinemic levels, glycogenolysis is already fully suppressed (9,162-164). Indeed, it has been demonstrated that when endogenous insulin secretion is blocked by use of somatostatin, and an insulin infusion allows for maintenance of basal insulin level, HGP is induced (165), although opposite findings have also been reported (154).

Feeding a high fat diet has been shown to increase basal HGP in overnight fasted rats (166). In addition, in the same model, prolonged elevation of FFAs increased HGP despite elevation of insulin secretion and higher insulin levels (151). From these observations it appears that the auto-regulation is not effective when glycogen stores are depleted. It may be hypothesized that elevated FFAs induce hepatic insulin resistance in the basal state, with impaired insulin-mediated suppression of glycogenolysis as a consequence. Along the same line, reduction of FFAs by nicotinic acid in type 2 diabetic subjects did not lead to reduced gluconeogenesis (167), and net HGP was increased owing to absence of induction of the glycogenolytic pathway. Thus, altered hepatic auto-regulation was paralleled by, and likely owing to, impairment of insulin sensitivity.

FFAs per se may diminish the ability of insulin to suppress HGP (i.e., impaired insulin signaling). Several mechanisms may be involved. For instance, LCFA-CoAs accumulate in liver when increased FFA exposure is combined with inhibition of fatty acid oxidation owing to elevated malonyl-CoA (168). In vitro studies suggest that accumulation of LCFA-CoA intracellularly leads to inhibition of glucokinase, inhibition or stimulation of glucose-6-phosphatase, inhibition of glycogen synthase, and stimulation of glycogen phosphorylase (82). Another possibility is that LCFA-acylCoA and their esterified derivatives (DAG, ceramides) accumulate in the liver, leading to alteration in kinase (PKC-0, -e, -8 and and AMPK) regulatory cascades (152,169). Alternatively, the so-called hexosamine pathway has been proposed as a nutrient-sensing regulatory pathway (170). Although insulin acts directly on hepatic insulin receptors to suppress hepatic glucose production (7), and hepatic insulin resistance therefore leads to impaired suppression of HGP, it is important to appreciate that insulin-mediated reduction of FFA release from adipose tissue participates indirectly in the inhibition of HGP (8,9). Therefore, impaired insulin action in adipose tissue may lead to increased HGP either directly or indirectly by increasing exposure of the liver to FFAs.

In summary, FFAs increase the de novo synthesis of glucose by the liver. Under physiological conditions, a counter-regulatory mechanism is set up to prevent increased HGP. However, in pathological conditions, as seen in insulin resistance and type 2 diabetes, this mechanism is defective, and chronic elevation of FFAs leads to increased HGP.

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