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.

OBJECTIVEInsulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular signaling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression. We determined, for the first time, the time course and relevance (to metabolic flux) of these molecular events during physiological hyperinsulinemia in vivo in a large animal model.RESEARCH DESIGN AND METHODS24 h fasted dogs were infused with somatostatin, while insulin (basal or 8× basal) and glucagon (basal) were replaced intraportally. Euglycemia was maintained and glucose metabolism was assessed using tracer, 2H2O, and arterio-venous difference techniques. Studies were terminated at different time points to evaluate insulin signaling and enzyme regulation in the liver.RESULTSHyperinsulinemia reduced HGP due to a rapid transition from net glycogen breakdown to synthesis, which was associated with an increase in glycogen synthase and a decrease in glycogen phosphorylase activity. Thirty minutes of hyperinsulinemia resulted in an increase in phospho-FOXO1, a decrease in GNG enzyme mRNA expression, an increase in F2,6P2, a decrease in fat oxidation, and a transient decrease in net GNG flux. Net GNG flux was restored to basal by 4 h, despite a substantial reduction in PEPCK protein, as gluconeogenically-derived carbon was redirected from lactate efflux to glycogen deposition.CONCLUSIONSIn response to acute physiologic hyperinsulinemia, 1) HGP is suppressed primarily through modulation of glycogen metabolism; 2) a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P2 and decreased fat oxidation; and 3) net GNG flux is not ultimately inhibited by the rise in insulin, despite eventual reduction in PEPCK protein, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.

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Coate KC, Scott M, Farmer B, Moore MC, Smith M, Roop J, Neal DW, Williams P, Cherrington AD. Chronic consumption of a high-fat/ high-fructose diet renders the liver incapable of net hepatic glucose uptake. Am J Physiol Endocrinol Metab 299: E887-E898, 2010. First published September 7, 2010; doi:10.1152/ajpendo.00372.2010.-The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD (n ϭ 10) or chow control (CTR, n ϭ 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ⌬AUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by Ϸ30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0 -90 min) and 2 (P2, 90 -180 min). During P1, somatostatin, basal intraportal glucagon, 4 ϫ basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mg·kg Ϫ1 ·min Ϫ1). Net hepatic glucose uptake during P1 and P2 was Ϫ0.4 Ϯ 0.1 [output] and 0.2 Ϯ 0.8 mg · kg Ϫ1 · min Ϫ1 in the HFFD group, respectively, and 1.8 Ϯ 0.8 and 3.5 Ϯ 1.0 mg · kg Ϫ1 · min Ϫ1 in the CTR group, respectively (P Ͻ 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 Ϯ 0.2 and 1.5 Ϯ 0.4 mg·kg Ϫ1 · min Ϫ1 in the HFFD and CTR groups, respectively (P Ͻ 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis. impaired glucose tolerance; glycogen synthesis; hyperinsulinemic euglycemic clamp; hyperinsulinemic hyperglycemic clamp; portal signal CHRONIC CONSUMPTION OF A WESTERN DIET, characterized by foods rich in sugar and abundant in total and saturated fat, has been suggested to play a role in the development of type 2 diabetes (9, 37, 38). Numerous studies have delineated the effects of dietary fat on whole body insulin sensitivity. For example, 3 days of high-fat feeding (59% of kcal from fat) was sufficient to produce hepatic insulin resistance in rats, as evidenced by a diminished ability of hyperinsulinemia to suppress hepatic glucose production (HGP) in the absence of an alteration in peripheral (skeletal muscle and white adipose tissue) insulin sensitivity (20,22,31). These findings were supported in a canine model, in which hepatic insulin resistance was also found to be the primary metabolic consequence associated with 12 wk of moderate-fat (44% of kcal from fat) feeding (18). However, other studies have demonstrated that peripheral insulin resistance precedes liver resistance in response to high dietar...