. Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol Endocrinol Metab 287: E75-E81, 2004. First published March 16, 2004 10.1152/ ajpendo.00035.2004.-Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on glucose disposal in vivo was assessed in conscious dogs by use of tracer and arteriovenous difference techniques. After a basal period, each experiment consisted of three periods (P1, P2, P3) during which somatostatin, glucagon, insulin, and glucose were infused. The control group (C) received saline in P1, P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1 and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose and insulin concentrations increased to two-and fourfold basal, respectively, and glucagon remained basal. GLP-1 levels increased similarly in the PePe and PePo groups during P2 (ϳ200 pM), whereas portal GLP-1 levels were significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased slightly but not significantly in all groups. During P3, NHGU increased in PePe and PePo groups to a greater extent than in C, but no significant effect of the route of infusion of GLP-1 was demonstrated (16.61 Ϯ 2.91 and 14.67 Ϯ 2.09 vs. 4.22 Ϯ 1.57 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , respectively). In conclusion: GLP-1 increased glucose disposal in the liver independently of insulin secretion; its full action required long-term infusion. The route of infusion did not modify the hepatic response.glucagon-like peptide-1; glucose uptake; portal infusion; dog GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is synthesized from proglucagon in the L cells of the duodenum, distal ileum, and colon in response to meal absorption, after which it is rapidly released into the portal vein (22, 37). The main and active form of GLP-1, GLP-1-(7-36), is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) into GLP-1-(9 -36) in the intestinal tissues as well as in the blood (23, 27). The consequence is a rapid elimination of GLP-1 from plasma with a half-life estimated at 1-2 min in several species (22). The earliest biological effect of GLP-1 discovered was its ability to increase glucose-dependent insulin secretion (18, 28) as well as the transcription of the proinsulin gene and biosynthesis of insulin (12). The glucose-dependent effect of GLP-1 on insulin secretion has suggested a potential use of this agent in the treatment of diabetes without deleterious hypoglycemia. Indeed, it lowers postprandial glucose levels in both healthy and human subjects with type 2 diabetes by stimulating insulin secretion but also by inhibiting glucagon secretion from the ␣-cell and delaying gastric emptying (1,17,40).GLP-1 receptors are present on ␤-cells (38), and there are numerous reports of GLP-1 receptors on glucose-consuming tissues suc...

Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally, the PePo group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group (n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 ( approximately 50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 +/- 1.3 and 10.6 +/- 1.0 vs. 5.7 +/- 1.0 and 5.4 +/- 0.8 micromol.kg(-1).min(-1), respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.

Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal. Am J Physiol Endocrinol Metab 290: E9 -E16, 2006. First published August 16, 2005 doi:10.1152/ajpendo.00184.2005.-Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. We hypothesize that the sympathetic nervous system normally restrains NHGU, and portal glucose delivery relieves the inhibition. Two groups of 42-h-fasted conscious dogs were studied using arteriovenous difference techniques. Denervated dogs (DEN; n ϭ 10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n ϭ 10) underwent a sham procedure. After a 140-min basal period, somatostatin was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the hepatic glucose load (HGL) for 90 min (P1). In P2, glucose was infused intraportally (3-4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and the peripheral glucose infusion was reduced to maintain the HGL for 90 min. This was followed by 90 min (P3) in which portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. P1 and P3 were averaged as the peripheral glucose infusion period (PE). The average HGLs (mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in CON and DEN were 55 Ϯ 3 and 54 Ϯ 4 in the peripheral periods and 55 Ϯ 3 and 55 Ϯ 4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in CON averaged 1.7 Ϯ 0.3 during PE and increased to 2.9 Ϯ 0.3 during P2. NHGU (mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was greater in DEN than CON (P Ͻ 0.05) during PE (2.9 Ϯ 0.4) and failed to increase significantly (3.2 Ϯ 0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.autonomic nervous system; liver; canine POSTPRANDIAL HYPERGLYCEMIA is a concern for individuals with type 2 diabetes. The ability of the liver and peripheral tissues to increase their uptake of glucose after food injestion is therefore an area of interest. There are three major determinants of net hepatic glucose uptake (NHGU): the levels of insulin and glucagon in the blood, the glucose load reaching the liver, and the route of glucose delivery. NHGU increases with an increase in insulin concentration (31) and decreases with an elevation of glucagon (17). Likewise, hepatic glucose uptake is positively correlated with the glucose load. Finally, it has been shown that, when the glucose level is higher in the portal vein than in the hepatic artery, NHGU is augmented (2).The stimulus for this response has been termed the portal glucose signal. Previous studies carried out in our laboratory have shown that activation of the portal signal not only increases NHGU but also reduces glucose uptake by muscle (2, 18, 33).In the 1960s, Shimazu et al. (43,44) s...

Risperidone induces significant weight gain in female mice; however, the underlying mechanisms related to this effect are unknown. We investigated the effects of risperidone on locomotor activity, core body temperature, and uncoupling protein (UCP) and hypothalamic orexin mRNA expression. Female C57BL/6J mice were acclimated to individual housing and randomly assigned to either risperidone (4 mg/kg BW*day) or placebo (PLA). Activity and body temperature were measured over 48-hour periods twice a week for 3 weeks. Food intake and body weights were measured weekly. UCP1 (BAT), UCP3 (gastrocnemius), and orexin (hypothalamus) mRNA expressions were measured using RT-PCR. Risperidone-treated mice consumed more food (p=0.050) and gained more weight (p=0.0001) than PLA-treated mice after 3 weeks. During the initial 2-days of treatment, there was an acute effect of treatment on activity (p=0.046), but not body temperature (p=0.290). During 3 weeks of treatment, average core body temperatures were higher in risperidone-treated mice compared to controls during the light phase (p=0.0001), and tended to be higher during the dark phase (p=0.057). Risperidone-treated mice exhibited lower activity levels than controls during the dark phase (p=0.006); there were no differences in activity during the light phase (p=0.47). UCP1 (p<0.01) and UCP3 (p<0.05) mRNA expressions were greater in risperidone-treated mice compared to controls, whereas, orexin mRNA expression was lower in risperidone-treated mice (p<0.01). These results suggest that risperidone-induced weight gain in mice is a consequence of increased energy intake and reduced activity, while the elevation in body temperature may be a result of thermogenic effect of food intake and elevated UCP1, UCP3, and a reduced hypothalamic orexin expression.

An Z, DiCostanzo CA, Moore MC, Edgerton DS, Dardevet DP, Neal DW, Cherrington AD. Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog. Am J Physiol Endocrinol Metab 294: E300-E306, 2008. First published November 20, 2007 doi:10.1152/ajpendo.00380.2007.-To determine the role of nitric oxide in regulating net hepatic glucose uptake (NHGU) in vivo, studies were performed on three groups of 42-h-fasted conscious dogs using a nitric oxide donor [3-morpholinosydnonimine (SIN-1)]. The experimental period was divided into period 1 (0 -90 min) and period 2 (P2; 90 -240 min). At 0 min, somatostatin was infused peripherally, and insulin (4-fold basal) and glucagon (basal) were given intraportally. Glucose was delivered intraportally (22.2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and peripherally (as needed) to increase the hepatic glucose load twofold basal. At 90 min, an infusion of SIN-1 (4 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was started in a peripheral vein (PeSin-1, n ϭ 10) or the portal vein (PoSin-1, n ϭ 12) while the control group received saline (SAL, n ϭ 8). Both peripheral and portal infusion of SIN-1, unlike saline, significantly reduced systolic and diastolic blood pressure. Heart rate rose in PeSin-1 and PoSin-1 (96 Ϯ 5 to 120 Ϯ 10 and 88 Ϯ 6 to 107 Ϯ 5 beats/min, respectively, P Ͻ 0.05) but did not change in response to saline. NHGU during P2 was 31.0 Ϯ 2.4 and 29.9 Ϯ 2.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in SAL and PeSin-1, respectively but was 23.7 Ϯ 1.7 in PoSin-1 (P Ͻ 0.05). Net hepatic carbon retention during P2 was significantly lower in PoSin-1 than SAL or PeSin-1 (21.4 Ϯ 1.2 vs. 27.1 Ϯ 1.5 and 26.1 Ϯ 1.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Nonhepatic glucose uptake did not change in response to saline or SIN-1 infusion. In conclusion, portal but not peripheral infusion of the nitric oxide donor SIN-1 inhibited NHGU.3-morpholinosydnominine; nitric oxide; net hepatic glucose uptake; hyperglycemia THE LIVER IS A PIVOTAL ORGAN in disposal of ingested glucose and, therefore, in limiting postprandial hyperglycemia. It has been shown that the response to infusion of glucose directly in the hepatic portal vein mimics the response to oral glucose delivery in the conscious dog (5). In comparing the effects of peripheral vs. portal venous glucose delivery on net hepatic glucose uptake (NHGU) during hyperglycemic clamps, we found that NHGU was considerably greater in the presence of intraportal glucose delivery, even when the hepatic glucose loads were well matched and insulin and glucagon levels were equivalent between groups (1, 2, 26, 28). This led us to suggest that a "portal glucose signal" is at least as important as insulin in determining NHGU after an oral glucose load. In addition, the portal glucose signal reduces glucose uptake by nonhepatic tissues, primarily muscle, at the same time as it increases NHGU, thereby ensuring appropriate distribution of glucose to muscle and liver (2). To date, it remains unclear how these coordinated responses of muscle and liver come about.Nitric oxide (NO) is a potent biological mediato...