Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog

Abstract

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...

Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake

“…Additionally, treatment of lean rats with L-NAME for 4 wk resulted in greater insulin sensitivity, increased hepatic glycogen content, and increased insulin-stimulated phosphorylation of protein kinase B/Akt and glycogen synthase kinase-3 in liver, consistent with enhanced hepatic insulin signaling (38). Moreover, during a hyperinsulinemic hyperglycemic clamp concomitant with portal glucose infusion, intraportal infusion of SIN-1 significantly reduced net hepatic carbon retention in the dog (2). Thus, providing increased NO produced the effect opposite from reducing it.…”

“…There is evidence to link hepatic NO levels and the magnitude of NHGU. Infusion of SIN-1 into the hepatic portal circulation of conscious dogs significantly blunted NHGU in the presence of hyperinsulinemia, hyperglycemia, and intraportal glucose delivery (2), conditions that mimic the postprandial state. Therefore, the current study was undertaken to quantify NHGU under hyperglycemic and hyperinsulinemic conditions in the presence of a reduction of endogenous NO brought about by intraportal infusion of L-NAME.…”

Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake

“…Hematocrit levels, glucose, glucagon, insulin, C-peptide and NEFA levels in plasma, and lactate, alanine, and glycerol concentrations in blood were determined using standard procedures as previously described (2,10,27). Plasma triglyceride (TG) levels were measured using a serum TG determination kit (Sigma-Aldrich, St. Louis, MO).…”

“…With this calculation, positive values reflect net hepatic production and negative values represent net hepatic uptake. To avoid any potential errors arising from incomplete mixing of the intraportally infused glucose in the portal vein blood, net hepatic glucose balance (NHGB) and hepatic glucose load (HGL) were also calculated by an indirect (I) method (2,32). Thus, the load of glucose entering the liver was calculated as…”

“…Indirect NHGB was thus calculated as NHGB ϭ Load out Ϫ Load in (I) NHGB and HGL calculated using the indirect method did not differ significantly from those obtained using the direct calculation, but only the data derived from the indirect method are reported in this paper. Net hepatic fractional substrate extraction (NHFX), hepatic sinusoidal hormone concentrations, nonhepatic glucose uptake (non-HGU), net hepatic carbon retention, and direct glycogen synthesis were calculated as described previously (2,32). The rates of glucose appearance (R a) and disappearance (Rd) were calculated using Steele's steadystate equation (34).…”