2H enrichment distribution of hepatic glycogen from 2H2O reveals the contribution of dietary fructose to glycogen synthesis

2013 ◽  
Vol 304 (4) ◽  
pp. E384-E391 ◽  
Author(s):  
Teresa C. Delgado ◽  
Fátima O. Martins ◽  
Filipa Carvalho ◽  
Ana Gonçalves ◽  
Donald K. Scott ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Glycogen Synthesis ◽  
Krebs Cycle ◽  
Hepatic Glycogen ◽  
Deuterated Water ◽  
Indirect Pathway ◽  
Triose Phosphate ◽  
Glucose Levels ◽  
Dietary Fructose ◽  
Glucose Synthesis

Dietary fructose can benefit or hinder glycemic control, depending on the quantity consumed, and these contrasting effects are reflected by alterations in postprandial hepatic glycogen synthesis. Recently, we showed that 2H enrichment of glycogen positions 5 and 2 from deuterated water (2H2O) informs direct and indirect pathway contributions to glycogenesis in naturally feeding rats. Inclusion of position 6 S 2H enrichment data allows indirect pathway sources to be further resolved into triose phosphate and Krebs cycle precursors. This analysis was applied to six rats that had fed on standard chow (SC) and six rats that had fed on SC plus 35% sucrose in their drinking water (HS). After 2 wk, hepatic glycogenesis sources during overnight feeding were determined by 2H2O administration and postmortem analysis of glycogen 2H enrichment at the conclusion of the dark period. Net overnight hepatic glycogenesis was similar between SC and HS rodents. Whereas direct pathway contributions were similar (403 ± 71 μmol/g dry wt HS vs. 578 ± 76 μmol/g dry wt SC), triose phosphate contributions were significantly higher for HS compared with SC (382 ± 61 vs. 87 ± 24 μmol/g dry wt, P < 0.01) and Krebs cycle inputs lower for HS compared with SC (110 ± 9 vs. 197 ± 32 μmol/g dry wt, P < 0.05). Analysis of plasma glucose 2H enrichments at the end of the feeding period also revealed a significantly higher fractional contribution of triose phosphate to plasma glucose levels in HS vs. SC. Hence, the 2H enrichment distributions of hepatic glycogen and glucose from 2H2O inform the contribution of dietary fructose to hepatic glycogen and glucose synthesis.

scholarly journals Effects of Meal Fructose/Glucose Composition on Postprandial Glucose Appearance and Hepatic Glycogen Synthesis in Healthy Subjects

2021 ◽  
Vol 10 (4) ◽  
pp. 596
Author(s):  
Cristina Barosa ◽  
Rogério T. Ribeiro ◽  
Rita Andrade ◽  
João F. Raposo ◽  
John G. Jones
Keyword(s):  
Plasma Glucose ◽  
Healthy Subjects ◽  
Glycogen Synthesis ◽  
Krebs Cycle ◽  
Hepatic Glycogen ◽  
Indirect Pathway ◽  
Metabolic Complications ◽  
Glucose Ratio ◽  
Dietary Fructose ◽  
P Sources

Dietary fructose overshadows glucose in promoting metabolic complications. Intestinal fructose metabolism (IFM) protects against these effects in rodents, by favoring gluconeogenesis, but the extent of IFM in humans is not known. We therefore aimed to infer the extent of IFM by comparing the contribution of dietary fructose to systemic glucose and hepatic glycogen appearance postprandially. Twelve fasting healthy subjects ingested two protein meals in random order, one supplemented with 50 g 5/95 fructose/glucose (LF) and the other with 50 g 55/45 fructose/glucose (HF). Sources of postprandial plasma glucose appearance and hepatic glycogen synthesis were determined with deuterated water. Plasma glucose excursions, as well as pre- and post-meal insulin, c-peptide, and triglyceride levels were nearly identical for both meals. The total gluconeogenic contribution to plasma glucose appearance was significantly higher for HF versus LF (65 ± 2% vs. 34 ± 3%, p < 0.001). For HF, Krebs cycle anaplerosis accounted for two-thirds of total gluconeogenesis (43 ± 2%) with one-third from Triose-P sources (22 ± 1%). With LF, three-quarters of the total gluconeogenic contribution originated via Krebs cycle anaplerosis (26 ± 2%) with one-quarter from Triose-P sources (9 ± 2%). HF and LF gave similar direct and indirect pathway contributions to hepatic glycogen synthesis. Increasing the fructose/glucose ratio had significant effects on glucose appearance sources but no effects on hepatic glycogen synthesis sources, consistent with extensive IFM. The majority of fructose carbons were converted to glucose via the Krebs cycle.

Plasma glucose concentration determines direct versus indirect liver glycogen synthesis

1986 ◽  
Vol 251 (5) ◽  
pp. E584-E590 ◽  
Author(s):  
C. H. Lang ◽  
G. J. Bagby ◽  
H. L. Blakesley ◽  
J. L. Johnson ◽  
J. J. Spitzer
Keyword(s):  
Plasma Glucose ◽  
Glucose Concentration ◽  
Infusion Rate ◽  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Hepatic Glycogen ◽  
Glucose Load ◽  
Indirect Pathway

In the present study hepatic glycogenesis by the direct versus indirect pathway was determined as a function of the glucose infusion rate. Glycogen synthesis was examined in catheterized conscious rats that had been fasted 48 h before receiving a 3-h infusion (iv) of glucose. Glucose, containing tracer quantities of [U-14C]- and [6-3H]glucose, was infused at rates ranging from 0 to 230 mumol X min-1 X kg-1. Plasma concentrations of glucose, lactate, and insulin were positively correlated with the glucose infusion rate. Despite large changes in plasma glucose, lactate, and insulin concentrations, the rate of hepatic glycogen deposition (0.46 +/- 0.03 mumol X min-1 X g-1) did not vary significantly between glucose infusion rates of 20 and 230 mumol X min-1 X kg-1. However, the percent contribution of the direct pathway to glycogen repletion gradually increased from 13 +/- 2 to 74 +/- 4% in the lowest to the highest glucose infusion rates, with prevailing plasma glucose concentrations from 9.4 +/- 0.5 to 21.5 +/- 2.1 mM. Endogenous glucose production was depressed (by up to 40%), but not abolished by the glucose infusions. Only a small fraction (7-14%) of the infused glucose load was incorporated into liver glycogen via the direct pathway irrespective of the glucose infusion rate. Our data indicate that the relative contribution of the direct and indirect pathways of hepatic glycogen synthesis are dependent on the glucose load or plasma glucose concentration and emphasize the predominance of the indirect pathway of glycogenesis at plasma glucose concentrations normally observed after feeding.

Evidence for the indirect utilization of glucose for the synthesis of hepatic glycogen in man

1992 ◽  
Vol 83 (6) ◽  
pp. 677-682
Author(s):  
R. F. G. J. King ◽  
M. Madan ◽  
D. Alexander ◽  
A. Boyd ◽  
K. Ibrahim ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Human Liver ◽  
Glycogen Synthesis ◽  
Hepatic Glycogen ◽  
Indirect Pathway ◽  
Abdominal Operation ◽  
Direct Pathway ◽  
Specific Activities ◽  
Glycogen Repletion ◽  
Indirect Route

1. This study was designed to test the hypothesis that three-carbon intermediates can be used in the ‘indirect’ pathway of glycogen synthesis in human liver (i.e. a route additional to the use of glucose by the ‘direct’ pathway). 2. After an overnight fast, 13 patients were given an infusion of 20% (w/v) glucose before elective abdominal operation. All received a 2.5 g bolus of 2220 kBq of selectively 3H- and 14C-labelled glucose before removal of a 1 g biopsy of liver. 3H and 14C were determined in purified glycogen as well as in glucose and lactate from samples of peripheral blood. 3. The ratio and specific activities of 3H and 14C in glycogen were found to be significantly lower than those in administered glucose. By calculation, 7–74% of glycogen repletion occurred by indirect pathways and not all of this was from the glucose supplied. 4. This study suggests that the operation of a direct pathway in man is not exclusive and that significant repletion of hepatic glycogen occurs by an indirect route.

Hepatic glycogen accurately reflected by acetaminophen glucuronide in dogs refed after fasting

1995 ◽  
Vol 269 (4) ◽  
pp. E766-E773 ◽  
Author(s):  
K. I. Rother ◽  
W. F. Schwenk
Keyword(s):  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Indirect Pathway ◽  
Isotopic Tracers ◽  
Glucose Flux ◽  
Liver Biopsies ◽  
The Mean ◽  
Acetaminophen Glucuronide ◽  
Group 2

To validate a method to “biochemically biopsy” the immediate precursor of intrahepatic glycogen [uridyl diphosphate (UDP)-glucose] using acetaminophen and to assess how fasting affects the direct and indirect pathways of glycogen synthesis, dogs were fasted overnight (group 1, n = 5) or for 2.5 days (group 2, n = 5) and then given a 4-h duodenal infusion of unlabeled glucose, [3-3H]glucose, and [U-14C]lactate to label hepatic glycogen via the direct and indirect pathways, respectively, and [1-13C]galactose to measure intrahepatic UDP-glucose flux. After 3 h for equilibration, acetaminophen was given and urine was collected for acetaminophen glucuronide. Multiple liver biopsies were obtained. The mean 3H/14C ratios of glucose derived from glycogen (10.4 +/- 4.1 and 1.1 +/- 0.3 for groups 1 and 2, respectively) and glucose derived from acetaminophen glucuronide (11.5 +/- 4.0 and 1.0 +/- 0.1 for groups 1 and 2, respectively) were similar. Fasting significantly increased UDP-glucose flux, the rate of glycogen synthesis, and the contribution of the indirect pathway. We conclude that, in dogs, 1) no functional hepatic zonation exists with regard to acetaminophen glucuronidation and liver glycogen synthesis and 2) with appropriate choice of isotopic tracers and study design, UDP-glucose flux can accurately reflect rates of hepatic glycogen synthesis.

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.

Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration

2012 ◽  
Vol 303 (7) ◽  
pp. E875-E885 ◽  
Author(s):  
Ana F. Soares ◽  
Rui A. Carvalho ◽  
Francisco J. Veiga ◽  
Marco G. Alves ◽  
Fátima O. Martins ◽  
...  
Keyword(s):  
De Novo ◽  
Glycogen Synthesis ◽  
Insulin Dependent Diabetes ◽  
De Novo Lipogenesis ◽  
Hepatic Glycogen ◽  
Insulin Administration ◽  
Indirect Pathway ◽  
Direct Pathway ◽  
Nocturnal Feeding ◽  
Insulin Dependent

Type 1 diabetes subjects are characterized by impaired direct pathway synthesis of hepatic glycogen that is unresponsive to insulin therapy. Since it is not known whether this is an irreversible defect of insulin-dependent diabetes, direct and indirect pathway glycogen fluxes were quantified in streptozotocin (STZ)-induced diabetic rats and compared with STZ rats that received subcutaneous or intraperitoneal insulin (I-SC or I-IP). Three groups of STZ rats were studied at 18 days post-STZ treatment. One group was administered I-SC and another I-IP as two daily injections of short-acting insulin at the start of each light and dark period for days 9–18. A third group did not receive any insulin, and a fourth group of nondiabetic rats was used as control. Glycogen synthesis via direct and indirect pathways, de novo lipogenesis, and gluconeogenesis were determined over the nocturnal feeding period using deuterated water. Direct pathway was residual in STZ rats, and glucokinase activity was also reduced significantly from control levels. Insulin administration restored both net glycogen synthesis via the direct pathway and glucokinase activity to nondiabetic control levels and improved the lipogenic pathway despite an inefficient normalization of the gluconeogenic pathway. We conclude that the reduced direct pathway flux is not an irreversible defect of insulin-dependent diabetes.

Glucose production in glycogen storage disease I is not associated with increased cycling through hepatic glycogen

1995 ◽  
Vol 269 (4) ◽  
pp. E774-E778 ◽  
Author(s):  
K. I. Rother ◽  
W. F. Schwenk
Keyword(s):  
Glycogen Storage Disease ◽  
Plasma Glucose ◽  
Storage Disease ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glycogen Storage ◽  
Endogenous Glucose Production ◽  
Hepatic Glycogen ◽  
Type I ◽  
Glucose Flux

Children with glycogen storage disease type I (GSD I) lack the ability to convert glucose 6-phosphate to glucose and yet are able to produce glucose endogenously. To test the hypothesis that the source of this glucose is increased cycling of glucose moieties through hepatic glycogen, six children with GSD I were studied on two occasions during which they received enteral glucose for 6 h at 35 or 50 mumol.kg-1.min-1 along with [6,6-2H2]glucose to measure plasma glucose flux and [1-13C]galactose to label intrahepatic uridyl diphosphate (UDP)-glucose. After 3 h, acetaminophen was given to estimate UDP-glucose flux (reflecting the rate of glycogen synthesis). Mean steady-state plasma glucose concentrations (4.8 +/- 0.2 vs. 5.8 +/- 0.1 mM) and total flux (34.8 +/- 1.7 vs. 47.5 +/- 2.0 mumol.kg-1.min-1) were increased (P < 0.05 or better) on the high-infusion day. Endogenous glucose production was detectable only on the low-infusion day (2.0 +/- 0.5 mumol.kg-1.min-1). UDP-glucose flux was increased (P < 0.05) on the high-infusion day (25.8 +/- 1.6 vs. 34.7 +/- 4.1), ruling out cycling of glucose moieties through glycogen with release of glucose by debrancher enzyme as the source of glucose production.

Exercise and exhaustion effects on glycogen synthesis pathways

1996 ◽  
Vol 81 (5) ◽  
pp. 2020-2026 ◽  
Author(s):  
Hans Gunderson ◽  
Nadja Wehmeyer ◽  
Diane Burnett ◽  
John Nauman ◽  
Cynthia Hartzell ◽  
...  
Keyword(s):  
Endurance Training ◽  
Glycogen Synthesis ◽  
Exhaustive Exercise ◽  
Hepatic Glycogen ◽  
Sprague Dawley ◽  
Indirect Pathway ◽  
Comparable Amount ◽  
Direct Pathway ◽  
Metabolic States ◽  
Metabolic Conditions

Gunderson, Hans, Nadja Wehmeyer, Diane Burnett, John Nauman, Cynthia Hartzell, and Scott Savage. Exercise and exhaustion effects on glycogen synthesis pathways. J. Appl. Physiol. 81(5): 2020–2026, 1996.—Female Sprague-Dawley rats were infused with [1-13C]glucose to measure the effect of endurance training and the effect of various metabolic conditions on pathways of hepatic glycogen synthesis. Four metabolic states [sedentary (S), trained (T), sedentary exhausted (SE), and trained exhausted (TE)] were studied. T and TE rats were trained on a motor-driven treadmill (30 m/min, 15% grade, 1.0 h/day, 5 days/wk) for 8–10 wk. After a 24-h fast, SE and TE rats were run to exhaustion (sedentary average = 78 min, trained average = 155 min) at a training pace and immediately infused with labeled glucose for 2 h. S and T rats were infused after a 24-h fast. After infusion, tissues were removed and glycogen was isolated and hydrolyzed to glucose. The glucose was measured for distribution of13C by using nuclear magnetic resonance. Glycogen was synthesized predominantly by the indirect pathway for all metabolic states, indicating that infused glucose was first metabolized primarily in the peripheral tissue. The direct-pathway utilization was greater in rested S than in rested T animals (30 vs. 14%); however, for exhausted animals, the trained use of the direct pathway was greater (22 vs. 9%). Both TE and rested T animals utilize the indirect pathway a comparable amount. Sedentary animals, on the other hand, dramatically decreased utilization of the direct pathway, with exhaustive exercise changing from 30 to 9%. The results indicate that endurance training modifies glucose utilization during glycogen synthesis after fasting and exhaustive exercise.

Effect of hepatic nerves on disposition of an intraduodenal glucose load

1993 ◽  
Vol 265 (3) ◽  
pp. E487-E496 ◽  
Author(s):  
M. C. Moore ◽  
G. I. Shulman ◽  
A. Giaccari ◽  
M. J. Pagliassotti ◽  
G. Cline ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Lactate Production ◽  
Glucose Infusion ◽  
Hepatic Glycogen ◽  
Indirect Pathway ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake ◽  
Hepatic Nerves ◽  
Glycogen Synthase Activity

We examined the disposition of a continuous 4-h intraduodenal glucose infusion (8 mg.kg-1 x min-1, labeled with [1-13C]glucose and [3-3H]glucose) in nine conscious hepatic-denervated dogs. Cumulative net hepatic uptakes (in grams of glucose equivalents) were 13.7 +/- 2.5 glucose, 3.1 +/- 0.6 gluconeogenic amino acids, and 0.8 +/- 0.1 glycerol. Net hepatic glycogen synthesis totalled 11.0 +/- 0.9 g, 55-62% via the direct pathway. All values were similar to those in hepatic-innervated dogs. Glycogen synthase activity and rate of glycogen synthesis were positively correlated (r2 = 0.913, P < 0.05). Variability in net hepatic glycogen synthesis and the mass of glycogen synthesized via the indirect pathway was reduced in hepatic-denervated dogs (P < 0.05). In conclusion, the glycemic response and rate of net glycogen synthesis during an intraduodenal glucose infusion was no different in hepatic-denervated and -innervated dogs. Net hepatic glucose uptake was sufficient to account for all net hepatic glycogen synthesis and lactate production, consistent with an intrahepatic source of gluconeogenic precursors for glycogen synthesis via the indirect pathway. Hepatic nerves appear responsible for much of the variability in net hepatic glycogen synthesis and in the mass of glycogen synthesized via the indirect pathway in normal dogs.

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