To investigate the temporal response of the liver to insulin and portal glucose delivery, somatostatin was infused into four groups of 42-h-fasted, conscious dogs ( n ϭ 6/group), basal insulin and glucagon were replaced intraportally, and hyperglycemia was created via a peripheral glucose infusion for 90 min (period 1). This was followed by a 240-min experimental period (period 2) in which hyperglycemia was matched to period 1 and either no changes were made (CON), a fourfold rise in insulin was created (

Insulin inhibits glucose production through both direct and indirect effects on the liver; however, considerable controversy exists regarding the relative importance of these effects. The first aim of this study was to determine which of these processes dominates the acute control of hepatic glucose production (HGP). Somatostatin and portal vein infusions of insulin and glucagon were used to clamp the pancreatic hormones at basal levels in the nondiabetic dog. After a basal sampling period, insulin infusion was switched from the portal vein to a peripheral vein. As a result, the arterial insulin level doubled and the hepatic sinusoidal insulin level was reduced by half. While the arterial plasma FFA level and net hepatic FFA uptake fell by 40-50%, net hepatic glucose output increased more than 2-fold and remained elevated compared with that in the control group. The second aim of this study was to determine the effect of a 4-fold rise in head insulin on HGP during peripheral hyperinsulinemia and hepatic insulin deficiency. Sensitivity of the liver was not enhanced by increased insulin delivery to the head. Thus, this study demonstrates that the direct effects of insulin dominate the acute regulation of HGP in the normal dog. IntroductionHepatic glucose production (HGP) accounts for the majority of whole-body glucose production and is tightly regulated by insulin in the healthy individual. Since hepatic insulin resistance in diabetic patients results in excess HGP and fasting hyperglycemia (1), it is critical to understand the mechanisms by which insulin regulates this process. Insulin reduces HGP by acting both directly and indirectly on the liver (2); however, there is considerable controversy regarding the relative importance of insulin's direct versus indirect effects under physiological conditions. Insulin acts directly by binding to hepatic insulin receptors and thereby activating insulin signaling pathways in the liver. These effects have been demonstrated in various models. In isolated rat hepatocytes, insulin inhibits glucose production through inhibition of gluconeogenesis (3) and glycogenolysis (4). In the dog, an acute selective increase (5) or decrease (6) in hepatic insulin level (so that the arterial insulin level was kept constant) resulted in very rapid suppression or stimulation, respectively, of HGP. In addition, liver-specific insulin receptor knockout (LIRKO) mice, which lack hepatic insulin receptors from birth, demonstrate severe hepatic insulin resistance (7). These studies, and others, demonstrate that insulin acts directly on the liver to regulate HGP.Insulin's indirect effects include reduction of glucagon secretion at the pancreas (8), inhibition of lipolysis in fat (which reduces circulating lipids and glycerol availability for gluconeogenesis) (9), and decreased protein catabolism in muscle (which further reduces gluconeogenic precursor availability) (10), and in addition, recent studies in the mouse and rat suggest that hypothalamic insulin signaling may also play an important role ...

To examine the relationship between net hepatic glucose uptake (NHGU) and the insulin level and to determine the effects of portal glucose delivery on that relationship, NHGU was evaluated at three different insulin levels in seven 42-h-fasted, conscious dogs during peripheral glucose delivery and during a combination of peripheral and portal glucose delivery. During peripheral glucose delivery, at arterial blood glucose levels of -175 mg/dl and insulin levels reaching the liver of 51±2, 92±6, and 191±6 ,uU/ml, respectively, NHGUs were 0.55±0.30, 1.52±0.44, and 3.04±0.79 mg/kg per min, respectively. At hepatic glucose loads comparable to those achieved during peripheral glucose delivery and inflowing insulin levels of 50±4, 96±5, and 170±8 gU per ml, respectively, NHGUs were 1.96±0.48, 3.67±0.68, and 5.52±0.92 mg/kg per min when a portion of the glucose load was delivered directly into the portal vein. The results of these studies thus indicate that net hepatic glucose uptake is dependent on both the plasma insulin level and the route of glucose delivery and that under physiological conditions the "portal" signal is at least as important as insulin in the determination of net hepatic glucose uptake. (J. Clin. Invest. 1991.87:930-939.)

In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β (GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP.

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