Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats

1997 ◽  
Vol 272 (1) ◽  
pp. E163-E172 ◽  
Author(s):  
M. K. Hellerstein ◽  
R. A. Neese ◽  
J. M. Schwarz ◽  
S. Turner ◽  
D. Faix ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Total Production ◽  
Distribution Analysis ◽  
Intravenous Glucose ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Flow Through ◽  
Glucose Output

The net release of glucose from the liver, or hepatic glucose production (HGP), and apparent gluconeogenesis (GNG) are reduced by exogenous glucose. We investigated the changes in metabolic fluxes responsible. Flux through the hepatic GNG pathway was quantified by mass isotopomer distribution analysis (MIDA) from [2-13C]glycerol. Unidirectional flux across hepatic glucose-6-phosphatase (G-6-Pase), or total hepatic glucose output (THGO), and hepatic glucose cycling (HGC) were also measured by using glucuronate (GlcUA) to correct for glucose 6-phosphate (G-6-P) labeling. Infusion of glucose (15-30 mg.kg-1.min-1 iv) to 24 h-fasted rats caused two important metabolic alterations. First was a significant increase in hepatic glucose uptake and HGC: > 60% of THGO was from HGC. Second, although flux through hepatic G-6-P increased (from 15.7 to 17.7-22.7 mg.kg-1.min-1), the partitioning of G-6-P flux changed markedly [from 30-35% to 55-60% entering UDP-glucose (UDP-Glc), P < 0.01]. Total flux through the GNG pathway remained active during intravenous glucose, but increased partitioning into UDP-Glc lowered GNG flux plasma glucose by 50%. In summary, the suppression of HGP and GNG flux into glucose is not primarily due to reduced carbon flow through hepatic G-6-Pase or the hepatic GNG pathway. THGO persists, but hepatic G-6-P is derived increasingly from plasma glucose, and flow through GNG persists, but the partitioning coefficient of G-6-P into UDP-Glc doubles. These adjustments permit net HGP to fall despite increased total production of hepatic G-6-P during administration of glucose.

Evidence against important catecholamine compensation for absent glucagon counterregulation

1991 ◽  
Vol 260 (2) ◽  
pp. E203-E212 ◽  
Author(s):  
P. De Feo ◽  
G. Perriello ◽  
E. Torlone ◽  
C. Fanelli ◽  
M. M. Ventura ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Plasma Glucagon ◽  
Counterregulatory Hormones ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Clamp Study

To assess the counterregulatory role of glucagon and to test the hypothesis that catecholamines can largely compensate for an impaired glucagon response, four studies were performed in seven normal volunteers. In all studies, insulin was infused subcutaneously (15 mU.m-2.min-1) and increased circulating insulin approximately twofold to levels (26 +/- 1 microU/ml) observed with intensive insulin therapy. In study 1, plasma glucose fluxes (D-[3-3H]glucose) and plasma substrate and counterregulatory hormone concentrations were simply monitored; plasma glucose decreased from 87 +/- 2 mg/dl and plateaued at 51 +/- 2 mg/dl for 3 h. In study 2 [pituitary-adrenal-pancreatic (PAP) clamp], secretion of insulin and counterregulatory hormones (except for catecholamines) was prevented by somatostatin (0.5 mg/h i.v.) and metyrapone (0.5 g/4 h per os), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of glucagon response), the PAP clamp was performed with maintenance of plasma glucagon at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. The PAP clamp (study 2) reproduced glucose concentrations and fluxes observed in study 1. In studies 3 and 4, isolated lack of glucagon response did not affect glucose utilization but caused an early and persistent decrease in hepatic glucose production (approximately 60%) that caused plasma glucose to decrease to 38 +/- 2 mg/dl (P less than 0.01 vs. control 62 +/- 2 mg/dl), despite compensatory increases in plasma epinephrine. We conclude that, in a model of clinical hypoglycemia, glucagon's effect on hepatic glucose production is a dominant counterregulatory factor in humans and that its absence cannot be compensated for by increased epinephrine secretion.

scholarly journals Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?

2015 ◽  
Vol 100 (7) ◽  
pp. 2525-2531 ◽  
Author(s):  
Satya Dash ◽  
Changting Xiao ◽  
Cecilia Morgantini ◽  
Khajag Koulajian ◽  
Gary F. Lewis
Keyword(s):  
Plasma Glucose ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Physiological Role ◽  
Glucose Production ◽  
Insulin Concentration ◽  
Hepatic Glycogen ◽  
Hepatic Glucose ◽  
Glucose Output

Purpose: In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. Methods and Results: Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. Conclusions: The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.

Pentobarbital reduces basal liver glucose output and its insulin suppression in rats

1990 ◽  
Vol 258 (4) ◽  
pp. E701-E707 ◽  
Author(s):  
P. W. Clark ◽  
A. B. Jenkins ◽  
E. W. Kraegen
Keyword(s):  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious State ◽  
Hepatic Insulin Resistance ◽  
Glucose Turnover ◽  
Pentobarbital Anesthesia ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Conscious Animals

Recent reports conflict on the effect that pentobarbital anesthesia has on basal glucose turnover in the rat. It is also unclear whether pentobarbital alters insulin suppressibility of hepatic glucose production (Ra). We examined these issues by performing basal and hyperinsulinemic euglycemic clamp studies in anesthetized and conscious animals. Ra and glucose utilization (Rd) were estimated using a steady-state infusion of 3-[3H]glucose. Pentobarbital anesthesia in normothermic rats transiently elevated plasma glucose but resulted in a sustained suppression of basal Ra (10.4 +/- 0.3 vs. conscious 13.2 +/- 0.9 mg.kg-1.min-1, P less than 0.05). In the insulin-stimulated state (110 mU/l), despite similar plasma glucose and insulin levels, clamp glucose infusion rate was significantly reduced in anesthetized animals (11.1 +/- 0.9 vs. conscious 23.6 +/- 1.3 mg.kg-1.min-1, P less than 0.001). This can be attributed to both a significantly lower insulin-stimulated Rd (15.4 +/- 1.3 vs. conscious 22.8 +/- 1.4 mg.kg-1.min-1, P less than 0.005) and reduced insulin suppression of Ra (4.3 +/- 0.8 vs. conscious -0.8 +/- 0.5 mg.kg-1.min-1, P less than 0.001; i.e., anesthetized 59% vs. conscious 100% reduction of basal Ra). Thus pentobarbital anesthesia significantly reduces basal Ra and induces hepatic insulin resistance (reduces Ra suppressibility). Pentobarbital effects are not dependent on induced hypothermia, but this exacerbates the metabolic perturbation. Caution should be used in extrapolating from the anesthetized to the conscious state.

Peripheral effects of insulin dominate suppression of fasting hepatic glucose production

1990 ◽  
Vol 258 (6) ◽  
pp. E1020-E1032 ◽  
Author(s):  
M. Ader ◽  
R. N. Bergman
Keyword(s):  
Specific Activity ◽  
Hepatic Glucose Production ◽  
Insulin Dose ◽  
Glucose Production ◽  
Insulin Levels ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Gluconeogenic Substrates ◽  
Intraportal Infusion

Insulin may suppress hepatic glucose production directly, or indirectly via suppression of release of gluconeogenic substrates from extrasplanchnic tissues. To compare these mechanisms, we performed insulin dose-response experiments in conscious dogs at euglycemia, during somatostatin infusion, and intraportal glucagon replacement. Insulin was sequentially infused either intraportally (0.05, 0.20, 0.40, 1.0, 1.4, and/or 3.0; protocol I) or systemically at half the intraportal rate (0.025, 0.10, 0.20, 0.50, 0.70, and/or 1.5 mU.min-1.kg-1; protocol II). Exogenous glucose infused during clamps was labeled with 3-[3H]glucose (2 microCi/g) to prevent a fall in plasma specific activity (P greater than 0.2) that may have contributed to previous underestimations of hepatic glucose output (HGO). Portal insulins were up to threefold higher during intraportal infusion, but peripheral insulin levels were not different between the intraportal and systemic protocols [7 +/- 5 vs. 9 +/- 1, 12 +/- 4 vs. 13 +/- 6, 16 +/- 3 vs. 27 +/- 5, 70 +/- 23 vs. 48 +/- 8, 83 +/- 3 vs. 86 +/- 21, and 128 vs. 120 +/- 14 microU/ml for paired insulin doses; P greater than 0.06 by analysis of variance (ANOVA)]. Despite higher portal insulin levels in protocol I, HGO suppression was equivalent in the two protocols when systemic insulin was matched, from 3.3 +/- 0.1 to near-total suppression at 0.3 mg.min-1.kg-1 at the highest insulin infusion rate (3.0 mU.min-1.kg-1; P less than 0.0001) with intraportal insulin, from 2.9 +/- 0.8 to -0.8 +/- 0.2 mg.min-1.kg-1 in protocol II (P less than 0.001). Suppression of HGO was similar at matched systemic insulin, regardless of portal insulin, suggesting the primacy of insulin's action on the periphery in its restraint of hepatic glucose production.

scholarly journals Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

2013 ◽  
Vol 304 (7) ◽  
pp. E747-E756 ◽  
Author(s):  
J. J. Winnick ◽  
C. J. Ramnanan ◽  
V. Saraswathi ◽  
J. Roop ◽  
M. Scott ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hydroxysteroid Dehydrogenase ◽  
Endogenous Glucose Production ◽  
Exogenous Glucose ◽  
Basal Period ◽  
Therapeutic Value ◽  
Hepatic Glucose ◽  
Metabolic Challenge ◽  
Glucose Output

The aim of this study was to determine the effect of prolonged 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11β-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I ( P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11β-HSD1 inhibition ( P < 0.05) due to a reduction in net hepatic glycogenolysis ( P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization ( P < 0.05) and the suppression of lipolysis were increased ( P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11β-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.

Regulation of blood glucose concentration: hepatic action of insulin

1961 ◽  
Vol 201 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Jack R. Leonards ◽  
Bernard R. Landau ◽  
James W. Craig ◽  
F. I. R. Martin ◽  
M. Miller ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Specific Activity ◽  
Blood Glucose Concentration ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
High Carbohydrate Diet ◽  
Carbohydrate Diet ◽  
High Carbohydrate ◽  
Hepatic Glucose ◽  
Glucose Output

Insulin was administered intravenously with or without the concurrent infusion of glucose to dogs surgically prepared so that hepatic glucose production could be measured directly. In dogs fed a high protein diet, hepatic glucose output as directly measured did not significantly change on insulin administration. The threshold at which a net hepatic glucose uptake occurred on the administration of a glucose load was unaffected by the presence of insulin. In contrast, in dogs fed a high carbohydrate diet, on the simultaneous infusion of insulin and glucose, a net uptake of glucose by the liver occurred at lower than normal plasma glucose concentrations. Hepatic glucose production was also estimated indirectly by isotopic techniques. A brief decrease in the rate of decline of plasma glucose specific activity was observed following the injection of C14-labeled glucose and then insulin in both protein and carbohydrate-fed animals. The explanation for this phenomenon remains uncertain. It is concluded that dietary status is important in determining the action of insulin on the liver. In dogs fed a high carbohydrate diet an almost immediate and perhaps direct action of insulin on the liver appears demonstrable.

The inhibition of gluconeogenesis following alcohol in humans

1998 ◽  
Vol 275 (5) ◽  
pp. E897-E907 ◽  
Author(s):  
Scott Q. Siler ◽  
Richard A. Neese ◽  
Mark P. Christiansen ◽  
Marc K. Hellerstein
Keyword(s):  
Alcohol Consumption ◽  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Alcohol Ingestion ◽  
Precursor Pool ◽  
Hepatic Glucose ◽  
Before And After ◽  
Normal Men ◽  
Glucose Output

Accurate quantification of gluconeogenic flux following alcohol ingestion in overnight-fasted humans has yet to be reported. [2-13C1]glycerol, [U-13C6]glucose, [1-2H1]galactose, and acetaminophen were infused in normal men before and after the consumption of 48 g alcohol or a placebo to quantify gluconeogenesis, glycogenolysis, hepatic glucose production, and intrahepatic gluconeogenic precursor availability. Gluconeogenesis decreased 45% vs. the placebo (0.56 ± 0.05 to 0.44 ± 0.04 mg ⋅ kg−1 ⋅ min−1vs. 0.44 ± 0.05 to 0.63 ± 0.09 mg ⋅ kg−1 ⋅ min−1, respectively, P < 0.05) in the 5 h after alcohol ingestion, and total gluconeogenic flux was lower after alcohol compared with placebo. Glycogenolysis fell over time after both the alcohol and placebo cocktails, from 1.46–1.47 mg ⋅ kg−1 ⋅ min−1to 1.35 ± 0.17 mg ⋅ kg−1 ⋅ min−1(alcohol) and 1.26 ± 0.20 mg ⋅ kg−1 ⋅ min−1, respectively (placebo, P < 0.05 vs. baseline). Hepatic glucose output decreased 12% after alcohol consumption, from 2.03 ± 0.21 to 1.79 ± 0.21 mg ⋅ kg−1 ⋅ min−1( P < 0.05 vs. baseline), but did not change following the placebo. Estimated intrahepatic gluconeogenic precursor availability decreased 61% following alcohol consumption ( P < 0.05 vs. baseline) but was unchanged after the placebo ( P < 0.05 between treatments). We conclude from these results that gluconeogenesis is inhibited after alcohol consumption in overnight-fasted men, with a somewhat larger decrease in availability of gluconeogenic precursors but a smaller effect on glucose production and no effect on plasma glucose concentrations. Thus inhibition of flux into the gluconeogenic precursor pool is compensated by changes in glycogenolysis, the fate of triose-phosphates, and peripheral tissue utilization of plasma glucose.

The role of autoregulation of the hepatic glucose production in man. Response to a physiologic decrement in plasma glucose

Diabetes ◽  
1986 ◽  
Vol 35 (2) ◽  
pp. 186-191 ◽  
Author(s):  
I. Hansen ◽  
R. Firth ◽  
M. Haymond ◽  
P. Cryer ◽  
R. Rizza
Keyword(s):  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glucose
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