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 ...

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...

After a meal, glucagon-like peptide-1 (GLP-1) levels in the hepatic portal vein are elevated and are twice those in peripheral blood. The aim of this study was to determine whether any of GLP-1's acute metabolic effects are initiated within the hepatic portal vein. Experiments consisted of a 40-min basal period, followed by a 240-min experimental period, during which conscious 42-h-fasted dogs received glucose intraportally (4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and peripherally (as needed) to maintain arterial plasma glucose levels at ϳ160 mg/dl. In addition, saline was given intraportally (CON; n ϭ 8) or GLP-1 (1 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was given into the hepatic portal vein (POR; n ϭ 11) or the hepatic artery (HAT; n ϭ 8). Portal vein plasma GLP-1 levels were basal in CON, 20ϫ basal in POR, and 10ϫ basal in HAT, whereas levels in the periphery and liver were the same in HAT and CON. The glucose infusion rate required to maintain hyperglycemia was significantly greater in POR (8.5 Ϯ 0.7 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , final 2 h) than in either CON or HAT (6.0 Ϯ 0.5 or 6.7 Ϯ 1.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , respectively). There were no differences among groups in either arterial plasma insulin (24 Ϯ 2, 23 Ϯ 3, and 23 Ϯ 3 U/ml for CON, POR, and HAT, respectively) or glucagon (23 Ϯ 2, 30 Ϯ 3, and 25 Ϯ 2 pg/ml) levels during the experimental period. The increased need for glucose infusion reflected greater nonhepatic as opposed to liver glucose uptake. GLP-1 infusion increased glucose disposal independently of changes in pancreatic hormone secretion but only when the peptide was delivered intraportally. dog; liver; glucagon-like peptide-1; hepatic portal vein GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is an incretin hormone released from the L cells of the gut in response to an orally delivered nutrient load. It is widely recognized (6, 23) that GLP-1 induces insulin secretion in a dose-and glucose-dependent manner. GLP-1 also decreases inappropriately high glucagon levels in diabetic patients (23). GLP-1 receptors (GLP-1R) are G protein coupled and expressed not only in the pancreatic islets but also in the kidneys, lungs, heart, hepatic portal vein, and central nervous system (6). There is debate over the presence of G protein-coupled GLP-1 receptors in the liver, muscle, and adipose (26). Recent data suggest, however, that GLP-1R outside the pancreas may play a greater role in glucoregulation than once thought (17,21,26).When GLP-1 is secreted, it enters capillary blood in the gut, where it is rapidly degraded by dipeptidyl peptidase IV (DPP-IV). It then enters the hepatic portal vein blood, thereby exposing the liver to a high level of the hormone. The short half-life of injected GLP-1 (1-2 min) reflects its rapid degradation by DPP-IV in plasma and throughout the vascular system (10). Nevertheless, after an orally delivered nutrient load, active GLP-1 levels in blood increase five-to 10-fold, with levels in the portal vein being approximately twice those in peripheral blood (5). This creates a situation in which GLP-1R in the portal vein are exposed ...

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.

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.