Effects of fasting and glucocorticoids on hepatic gluconeogenesis assessed using two independent methods in vivo

Goldstein, Richard E.; Rossetti, Luciano; Palmer, Brett; Liu, Rong; Massillon, Duna; Scott, Melanie; Neal, Doss W.; Williams, Phillip E.; Peeler, Benjamin B.; Cherrington, Alan D.

doi:10.1152/ajpendo.00320.2002

Cited by 30 publications

(30 citation statements)

References 53 publications

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“…Hepatic gluconeogenic flux, as calculated by the AV difference approach for the subset, was 0.98 Ϯ 0.13 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 during the basal period and 1.14 Ϯ 0.16 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 during the last 30 min of hyperinsulinemia ( Table 4). The by the end of the study; a value similar to that previously determined using this technique (20) in untreated overnightfasted dogs (0.95 Ϯ 0.14, n ϭ 8) (Table 4). Data used to make estimates using the subset (n ϭ 4) and data taken from Goldstein et al (20) (n ϭ 8) are provided in Table 5.…”

supporting

confidence: 79%

“…The by the end of the study; a value similar to that previously determined using this technique (20) in untreated overnightfasted dogs (0.95 Ϯ 0.14, n ϭ 8) (Table 4). Data used to make estimates using the subset (n ϭ 4) and data taken from Goldstein et al (20) (n ϭ 8) are provided in Table 5. Table 6.…”

supporting

confidence: 79%

“…Hepatic gluconeogenic flux determined with the 14 C-PEP method was 0.98 Ϯ 0.18 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 during insulin infusion. Although this method only provides an end point measurement of gluconeogenic flux, basal gluconeogenic flux was estimated to be 0.95 Ϯ 0.14 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 (n ϭ 8) in untreated overnight-fasted dogs in earlier studies using the same approach (20), thus confirming that the small increase in insulin had no effect on gluconeogenic flux in the liver. It should be noted that our ability to detect small changes in gluconeogenic flux is limited by the variance inherent in the methods.…”

Section: Discussionmentioning

confidence: 62%

“…Because the PEP and UDPG pools are small and turn over rapidly, their specific activities reach steady state quickly and reflect gluconeogenesis at the time of sampling. For comparison, data obtained using this technique in overnight fasted untreated dogs were obtained from Goldstein et al (20).…”

Section: Effects Of Insulin On Glucose Metabolism ϫ Length Of Experimmentioning

confidence: 99%

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Small Increases in Insulin Inhibit Hepatic Glucose Production Solely Caused by an Effect on Glycogen Metabolism

et al. 2001

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Based on our earlier work, a 2.5-fold increase in insulin secretion should completely inhibit hepatic glucose production through the hormone's direct effect on hepatic glycogen metabolism. The aim of the present study was to test the accuracy of this prediction and to confirm that gluconeogenic flux, as measured by three independent techniques, was unaffected by the increase in insulin. A 40-min basal period was followed by a 180-min experimental period in which an increase in insulin was induced, with euglycemia maintained by peripheral glucose infusion. Arterial and hepatic sinusoidal insulin levels increased from 10 ؎ 2 to 19 ؎ 3 and 20 ؎ 4 to 45 ؎ 5 U/ml, respectively. Net hepatic glucose output decreased rapidly from 1.90 ؎ 0.13 to 0.23 ؎ 0.16 mg ⅐ kg ؊1 ⅐ min ؊1 . Three methods of measuring gluconeogenesis and glycogenolysis were used: 1) the hepatic arteriovenous difference technique (n ‫؍‬ 8), 2) the [ (1) showed that hepatic glucose production (HGP) can be inhibited by selective increases in the arterial or portal vein insulin concentration. In response to a 14-U/ml increase in arterial insulin (no change in portal insulin), a Ͼ50% reduction in net hepatic glucose output (NHGO) was observed. Likewise, a 14-U/ml increase in portal insulin (no change in arterial insulin) also resulted in a Ͼ50% reduction in NHGO. In addition, the above studies showed that insulin acted directly on the liver, with a rise in hepatic sinusoidal insulin quickly inhibiting HGP by reducing net hepatic glycogenolysis. The indirect effect of insulin on HGP, on the other hand, resulted from a decrease in gluconeogenic flux rate caused by a reduction in the flow of gluconeogenic amino acids and glycerol to the liver and diversion of carbon derived from glycogenolysis to lactate rather than glucose. The reduction in HGP in this group was also, in part, the result of a decrease in net hepatic glycogenolysis, which occurred as a result of a slight rise in the hepatic sinusoidal insulin level, which, in turn, occurred as a result of the rise in hepatic artery insulin. It took 1 h to detect a significant indirect effect of insulin on HGP.Sindelar et al.(1) created selective changes in the arterial or portal insulin level by infusing somatostatin to inhibit insulin secretion and replacing insulin by infusion through a peripheral and/or portal catheter. Stimulation of pancreatic insulin secretion, on the other hand, results in an increase in both portal and arterial levels of the hormone. Therefore, in the present study, our aim was to determine if a two-to threefold increase in insulin, occurring simultaneously in portal and peripheral blood, would inhibit HGP primarily through an effect on glycogen metabolism. Although Sindelar et al. (1) reported that portally delivered insulin did not affect gluconeogenic flux, their estimate of the latter relied solely on the measurement of the net hepatic uptake (arteriovenous [AV] difference) of gluconeogenic precursors. In the present study, we combined the hepatic AV difference technique, along...

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supporting

confidence: 79%

supporting

confidence: 79%

Section: Discussionmentioning

confidence: 62%

Section: Effects Of Insulin On Glucose Metabolism ϫ Length Of Experimmentioning

confidence: 99%

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Small Increases in Insulin Inhibit Hepatic Glucose Production Solely Caused by an Effect on Glycogen Metabolism

et al. 2001

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“…Gluconeogenic flux is equal to the sum of the net hepatic uptake rates of lactate, glycerol, and the gluconeogenic amino acids (alanine, glycine, serine, threonine, glutamine, and glutamate) converted to glucose equivalents (22). The net glycogenolytic rate was obtained by subtracting the gluconeogenic flux rate from the sum of net hepatic glucose output (NHGO), net hepatic lactate output, and glucose oxidation.…”

Section: Methodsmentioning

confidence: 99%

Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

et al. 2002

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In the present study, we examined how the arterial insulin level alters the ␣-cell response to a fall in plasma glucose in the conscious overnight fasted dog. Each study consisted of an equilibration (؊140 to ؊40 min), a control (؊40 to 0 min), and a test period (0 to 180 min), during which BAY R 3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally to decrease glucose output in each of four groups (n ‫؍‬ 5). In group 1, saline was infused. In group 2, insulin was infused peripherally (3.6 pmol ⅐ kg ؊1 ⅐ min ؊1 ), and the arterial plasma glucose level was clamped to the level seen in group 1. In group 3, saline was infused, and euglycemia was maintained. In group 4, insulin (3.6 pmol ⅐ kg ؊1 ⅐ min ؊1 ) was given, and euglycemia was maintained by glucose infusion. In group 1, drug administration decreased the arterial plasma glucose level (mmol/l) from 5.8 ؎ 0.2 (basal) to 5.2 ؎ 0.3 and 4.4 ؎ 0.3 by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels (pmol/l) and the hepatic portalarterial difference in plasma insulin (pmol/l) decreased (P < 0.01) from 78 ؎ 18 and 90 ؎ 24 to 24 ؎ 6 and 12 ؎ 6 over the first 30 min of the test period. The arterial glucagon levels (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) rose from 43 ؎ 5 and 5 ؎ 2 to 51 ؎ 5 and 10 ؎ 5 by 30 min (P < 0.05) and to 79 ؎ 16 and 31 ؎ 15 (P < 0.05) by 90 min, respectively. In group 2, in response to insulin infusion, arterial insulin (pmol/l) was elevated from 48 ؎ 6 to 132 ؎ 6 to an average of 156 ؎ 6. The hepatic portal-arterial difference in plasma insulin was eliminated, indicating a complete inhibition of endogenous insulin release. The arterial glucagon level (ng/l) and the hepatic portalarterial difference in plasma glucagon (ng/l) did not rise significantly (40 ؎ 5 and 7 ؎ 4 at basal, 44 ؎ 4 and 9 ؎ 4 at 90 min, and 44 ؎ 8 and 15 ؎ 7 at 180 min). In group 3, when euglycemia was maintained, the insulin and glucagon levels and the hepatic portal-arterial difference remained constant. In group 4, the arterial plasma glucose level remained basal (5.9 ؎ 1.1 mmol/l) throughout, whereas insulin infusion increased the arterial insulin level to an average of 138 ؎ 6 pmol/l. The hepatic portal-arterial difference in plasma insulin was again eliminated. Arterial glucagon level (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) did not change significantly (43 ؎ 2 and 9 ؎ 2 at basal, 39 ؎ 3 and 9 ؎ 2 at 90 min, and 37 ؎ 3 and 7 ؎ 2 at 180 min). Thus, a difference of ϳ120 pmol/l in arterial insulin completely abolished the response of the ␣-cell to mild hypoglycemia. Diabetes 51:3033-3042, 2002

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Control of Glucose Production in vivo by Insulin and Glucagon

Cherrington

2001

Comprehensive Physiology

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Effects of basal glucagon Effects of increments in glucagon Insulin and Glucose ProductionEffects of insulin deficiency Effects of increases in insulin Integration of insulin and glucagon's effects INSULIN AND GLUCAGON have been known to regulate glucose production by the liver for almost 40 yr. In 1959 Shoemaker et al. (115) used arteriovenous difference techniques to first demonstrate the ability of glucagon to stimulate net hepatic glucose output in vivo. This observation was eventually confirmed by others (21, 36, 71) using tracer methods. Since gluconeogenesis could not be measured at that time, it was not possible to determine whether the hormone was working through an action on glycogenolysis or gluconeogenesis. Likewise, since it was not possible to remove glucagon selectively, it was also unclear what the consequences of glucagon deficiency, if any, would be.The first consistent inhibitory effect of insulin on glucose production by the liver in vivo was reported by Madison et al. in 1960 (83). This finding was soon confirmed by Starzl et al. (122,123) and Steele et al. (124) using isotopic techniques. Unlike the case with glucagon, it was possible to demonstrate the consequences of acute insulin deficiency. In experiments on partially or totally depancreatized conscious dogs, sudden cessation of endogenous or exogenous insulin input resulted in a rapid increase in glucose production (134,141). As was the case for glucagon, it was not possible to determine the extent to which insulin's action resulted from changes in glycogenolysis or gluconeogenesis.In summary, by the early 1970s, both insulin and glucagon had been convincingly shown to regulate hepatic glucose production in vivo in animal models. Little was known, however, about their action in the human, about the dose-response relationships between their plasma lev-els and hepatic glucose output, or about the time courses of their effects on glucose production. In addition, it was unclear to what extent their actions involved effects on glycogenolysis and gluconeogenesis. The purpose of this chapter is to address these issues. ASSESSMENT OF GLUCOSE PRODUCTION IN VNOTo fully appreciate the effects of insulin and glucagon on glucose production in the whole animal, it is first necessary to discuss the methods used to measure glucose entry into the blood in vivo. The techniques employed have improved considerably over the past four decades. That should be kept in mind as one considers the quantitative aspects of some of the early studies of insulin and glucagon action in vivo. In general, two main approaches have been used: the arteriovenous (A-V) difference technique and the isotope dilution technique. The former consists of the measurement of glucose in the blood entering and leaving the liver and the simultaneous assessment of hepatic arterial and portal vein blood flows. The product of the A-V difference for glucose and hepatic blood flow yields the net hepatic glucose balance. The isotopic technique consists of infusion or injection of an isotope o...

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Effects of fasting and glucocorticoids on hepatic gluconeogenesis assessed using two independent methods in vivo

Cited by 30 publications

References 53 publications

Small Increases in Insulin Inhibit Hepatic Glucose Production Solely Caused by an Effect on Glycogen Metabolism

Small Increases in Insulin Inhibit Hepatic Glucose Production Solely Caused by an Effect on Glycogen Metabolism

Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

Control of Glucose Production in vivo by Insulin and Glucagon

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