Impact of portal glucose delivery on glucose metabolism in conscious, unrestrained mice

Abstract

Previous studies in mice suggest that portal venous infusion of glucose at a low rate paradoxically causes hypoglycemia; this does not occur in dogs, rats, and humans. A possible explanation is that fasting status in the mouse studies may have altered the response. We sought to determine whether the response to portal glucose delivery in the mouse was similar to that seen in other species and whether it was dependent on fasting status. Studies were performed on chronically catheterized conscious mice. Catheters were placed into the portal and jugular veins and carotid artery 5 days before study. After a 5-or 16-h fast, glucose was infused into either the portal (PO) or the jugular vein (JU) for 6 h at 25H]glucose was infused into the JU to measure glucose turnover. In 5-h-fasted mice, PO and JU exhibited similar increases in arterial blood glucose from 155 Ϯ 11 to 173 Ϯ 19 and 147 Ϯ 8 to 173 Ϯ 10 mg/dl, respectively. Endogenous glucose production decreased and arterial insulin increased to the same extent in both PO and JU. A similar response was observed in 16-h-fasted mice; however, the proportion of hepatic glycogen synthesis occurring by the indirect pathway was increased by fasting. In summary, portal glucose delivery in the mouse did not cause hypoglycemia even when the duration of the fast was extended. The explanation of the differing response from previous reports in the mouse is unclear. portal vein; hyperglycemia; fasting THE LIVER PLAYS A MAJOR ROLE in blood glucose homeostasis by being able to rapidly transition from a site of glucose production in the fasting state to a site of glucose utilization in the fed state. The magnitude of hepatic glucose utilization during feeding is dependent on both the plasma insulin and glucose levels and the route of glucose delivery. In fact, significant hepatic glucose utilization is not observed if only hyperglycemia and hyperinsulinemia are present, but an intraportal or intraduodenal glucose infusion prompts substantial hepatic glucose uptake (24). Portal vein glucose delivery is known to produce a signal ("portal signal"), which enhances net hepatic glucose uptake and hepatic glycogen deposition in humans (9, 29) and rats (7,12,27). The portal signal also impairs peripheral glucose utilization in dogs and rats (20), thus augmenting the importance of the liver in whole body glucose disposal following a meal.A series of studies in the mouse suggested that delivery of glucose into the portal vein at a rate of 25 g⅐g Ϫ1 ⅐min Ϫ1 , which is similar to the basal endogenous glucose production (EGP) paradoxically induced hypoglycemia (5, 6). Hypoglycemia was precipitated by an activation of peripheral glucose clearance. This response was inhibited by somatostatin infusion and dependent upon GLP-1 receptor activation (4). Prior work observed an inhibitory or no effect of the portal signal on glucose clearance using somatostatin with insulin and glucose replacement to allow careful matching of the insulin and insulin concentrations (7,20,28). However, the use of somatosta...

Portal glucose delivery stimulates muscle but not liver protein metabolism

“…The main focus of this study was the liver, since it is a primary regulator of the nutrient supply to the other tissues and organs, because ingested carbohydrates and AAs go to the liver via the portal vein before entering the systemic circulation. In the presence of the portal glucose signal, net hepatic glucose uptake in the current studies was greater than during peripheral glucose delivery, as demonstrated in previous studies (15,25,39,47). In the current case (portal vein AA infusion), the hepatic fractional extraction of glucose was augmented fourfold by the portal glucose signal.…”

“…In a previous study in which only gluconeogenic AAs (as opposed to all AAs) were infused intraportally along with glucose, the portal glucose signal seemed to be blunted (38). The portal glucose signal has been associated with a translocation of glucokinase from the nucleus to the cytoplasm in the liver of rats and mice, where it exerts its activity and induces increased glucose uptake and glycogen synthesis (14,15). Under postprandial conditions, one of the major fates of gluconeogenic AAs in the liver is glycogen synthesis (6).…”

Is There Glucose Production Outside of the Liver and Kidney?

“…Such a purity criterion leaves room for nonnegligible amounts of radioactive impurities, which could have been carried to the glucose isolated from the venous blood. Also, the amount of radioactivity counted in glucose was a minuscule fraction of the radioactivity infused as [U- 14 In 1986, Hahn & Wei-Ning (28) reported data from incubations of fragments of small intestinal mucosa of rats or rabbits in KrebsRinger bicarbonate buffer containing 10 mM unlabeled glutamate and 10 mM [ 14 C]lactate. They reported low rates of gluconeogenesis from lactate in the intestinal mucosa of suckling rats and rabbits.…”

“…The blood flow through the small intestine was measured using radioactive microspheres in other rats, similarly prepared but not infused with [3-3 H]glucose (39). [3-3 H]Glucose is commonly used to trace glucose metabolism (14,33) because all its label is released to [ 3 H]water when the hexose skeleton is split to triose phosphates. Thus, a simple way to measure the specific activity of plasma glucose involves (a) deproteinization of plasma, (b) assay of glucose concentration in the protein-free extract, and (c) complete evaporation of the extract to eliminate [ 3 H]water, followed by redissolution in water, and liquid scintillation counting.…”

13C MRS Studies of the Control of Hepatic Glycogen Metabolism at High Magnetic Fields

“…A positive differential in glucose concentration between the portal vein and hepatic artery, as results from feeding, increases hepatic glycogen synthesis. This so-called "portal signal" [5] has been observed in several species [6,7] and has been shown to be likely neurally mediated [8]. Lastly, hepatic glycogen synthesis is under tight hormonal control.…”