In the postprandial state, the liver takes up and stores glucose to minimize the fluctuation of glycemia. Elevated insulin concentrations, an increase in the load of glucose reaching the liver, and the oral/enteral/portal vein route of glucose delivery (compared with the peripheral intravenous route) are factors that increase the rate of net hepatic glucose uptake (NHGU). The entry of glucose into the portal vein stimulates a portal glucose signal that not only enhances NHGU but concomitantly reduces muscle glucose uptake to ensure appropriate partitioning of a glucose load. This coordinated regulation of glucose uptake is likely neurally mediated, at least in part, because it is not observed after total hepatic denervation. Moreover, there is evidence that both the sympathetic and the nitrergic innervation of the liver exert a tonic repression of NHGU that is relieved under feeding conditions. Further, the energy sensor 5'AMP-activated protein kinase appears to be involved in regulation of NHGU and glycogen storage. Consumption of a high-fat and high-fructose diet impairs NHGU and glycogen storage in association with a reduction in glucokinase protein and activity. An understanding of the impact of nutrients themselves and the route of nutrient delivery on liver carbohydrate metabolism is fundamental to the development of therapies for impaired postprandial glucoregulation.

These results suggest that CHO feedings during intermittent high-intensity exercise similar to that of team sports benefited both peripheral and CNS function late in exercise compared with a flavored placebo.

Context: Short-term aerobic exercise training can improve whole-body insulin sensitivity in humans with type 2 diabetes mellitus; however, the contributions of peripheral and hepatic tissues to these improvements are not known.Objective: Our objective was to determine the effect of 7-d aerobic exercise training on peripheral and hepatic insulin sensitivity during isoglycemic/hyperinsulinemic clamp conditions. Design: Subjects were randomly assigned to one of two groups. The energy balance group consumed an isocaloric diet consisting of 50% carbohydrate, 30% fat, and 20% protein for 15 d. The energy balance plus exercise group consumed a similar diet over the 15 d and performed 50-min of treadmill walking at 70% of maximum oxygen consumption maximum during the second 7 d of the 15-d study period. Each subject underwent an initial isoglycemic/hyperinsulinemic clamp after 1-wk dietary control and a second clamp after completing the study. Setting:The study was performed at Ohio State University's General Clinical Research Center.Participants: There were 18 obese, mildly diabetic humans included in the study.Intervention: Aerobic exercise training was performed for 7 d. Main Outcome Measures:Whole-body, peripheral, and hepatic insulin sensitivity were measured.Results: Exercise training did not have an impact on peripheral glucose uptake or endogenous glucose production during the basal state or low-dose insulin. Likewise, it did not alter endogenous glucose production during high-dose insulin. However, 1-wk of exercise training increased both whole-body (P Ͻ 0.05) and peripheral insulin sensitivity (P Ͻ 0.0001) during high-dose insulin.Conclusion: Improvements to whole body insulin sensitivity after short-term aerobic exercise training are due to gains in peripheral, not heptic insulin sensitivity. T ype 2 diabetes mellitus (DM) is a metabolic disease characterized by insulin resistance, relative ␤-cell dysfunction, and resultant hyperglycemia that can contribute to the development of both microvascular and macrovascular disease. Despite an apparently strong genetic influence on the development of DM, environmental factors such as obesity and physical inactivity can hasten this process in humans (1-3), while interven-

Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal–arterial gradient and thereby produced hepato-preferential effects.