scholarly journals Limitations of detection of anaplerosis and pyruvate cycling from metabolism of [1-13C] acetate

2015 ◽  
Vol 21 (2) ◽  
pp. 108-109 ◽  
Author(s):  
Shawn C Burgess ◽  
Mathew E Merritt ◽  
John G Jones ◽  
Jeffrey D Browning ◽  
A Dean Sherry ◽  
...  
Keyword(s):  
Pyruvate Cycling

scholarly journals The impact of obesity, sex, and diet on hepatic glucose production in cats

2009 ◽  
Vol 296 (4) ◽  
pp. R936-R943 ◽  
Author(s):  
Saskia Kley ◽  
Margarethe Hoenig ◽  
John Glushka ◽  
Eunsook S. Jin ◽  
Shawn C. Burgess ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Citrate Synthase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Metabolism ◽  
Peripheral Insulin Resistance ◽  
Pyruvate Cycling ◽  
Hepatic Glucose ◽  
The Impact

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using 2H2O, [U-13C3]propionate, and [3,4-13C2]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin ( P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats ( P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP ( P < 0.003). Female obese cats had ∼1.5 times higher fluxes through phosphoenolpyruvate carboxykinase ( P < 0.02) and citrate synthase ( P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold ( P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals

2012 ◽  
Vol 303 (3) ◽  
pp. R340-R352 ◽  
Author(s):  
Cory D. Champagne ◽  
Dorian S. Houser ◽  
Melinda A. Fowler ◽  
Daniel P. Costa ◽  
Daniel E. Crocker
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Production ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Endogenous Glucose Production ◽  
Large Contribution ◽  
Protein Loss ◽  
Elephant Seals ◽  
Pyruvate Cycling ◽  
Northern Elephant Seals

Animals that endure prolonged periods of food deprivation preserve vital organ function by sparing protein from catabolism. Much of this protein sparing is achieved by reducing metabolic rate and suppressing gluconeogenesis while fasting. Northern elephant seals ( Mirounga angustirostris) endure prolonged fasts of up to 3 mo at multiple life stages. During these fasts, elephant seals maintain high levels of activity and energy expenditure associated with breeding, reproduction, lactation, and development while maintaining rates of glucose production typical of a postabsorptive mammal. Therefore, we investigated how fasting elephant seals meet the requirements of glucose-dependent tissues while suppressing protein catabolism by measuring the contribution of glycogenolysis, glycerol, and phosphoenolpyruvate (PEP) to endogenous glucose production (EGP) during their natural 2-mo postweaning fast. Additionally, pathway flux rates associated with the tricarboxylic acid (TCA) cycle were measured specifically, flux through phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate cycling. The rate of glucose production decreased during the fast (F1,13= 5.7, P = 0.04) but remained similar to that of postabsorptive mammals. The fractional contributions of glycogen, glycerol, and PEP did not change with fasting; PEP was the primary gluconeogenic precursor and accounted for ∼95% of EGP. This large contribution of PEP to glucose production occurred without substantial protein loss. Fluxes through the TCA cycle, PEPCK, and pyruvate cycling were higher than reported in other species and were the most energetically costly component of hepatic carbohydrate metabolism. The active pyruvate recycling fluxes detected in elephant seals may serve to rectify gluconeogeneic PEP production during restricted anaplerotic inflow in these fasting-adapted animals.

scholarly journals Elimination of KATPChannels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

2008 ◽  
Vol 283 (25) ◽  
pp. 17238-17249 ◽  
Author(s):  
Changhong Li ◽  
Itzhak Nissim ◽  
Pan Chen ◽  
Carol Buettger ◽  
Habiba Najafi ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Aminobutyric Acid ◽  
Pyruvate Cycling ◽  
Mouse Islets

scholarly journals Kinetic modelling of β-cell metabolism reveals control points in the insulin-regulating pyruvate cycling pathways

2021 ◽  
Author(s):  
Rahul Rahul ◽  
Adam Stinchcombe ◽  
Jamie Joseph ◽  
Brian P Ingalls
Keyword(s):  
Drug Targets ◽  
Kinetic Modelling ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Second Phase ◽  
Β Cells ◽  
Glucose Levels ◽  
Pyruvate Cycling ◽  
Elevated Glucose

Insulin, a key hormone in the regulation of glucose homeostasis, is secreted by pancreatic β-cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in β-cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP as well as other key metabolic signals, including a rise in the NADPH:NADP+ ratio. Experimental evidence indicates that pyruvate-cycling pathways play an important role in the elevation of the NADPH:NADP+ ratio in response to glucose. In this work we developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. We successfully validated our model against recent experimental observations and performed local and global sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier (DIC) and pyruvate transporter (PYC) are the most important regulators of pyruvate cycling and NADPH production. In contrast, our analysis showed that variation in the pyruvate carboxylase (PC) flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICDm) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for treatment of type 2 diabetes.

scholarly journals The contribution of pyruvate cycling to loss of [6-3H]glucose during conversion of glucose to glycogen in hepatocytes: effects of insulin, glucose and acinar origin of hepatocytes

1993 ◽  
Vol 289 (1) ◽  
pp. 255-262 ◽  
Author(s):  
L Agius ◽  
D Tosh ◽  
M Peak
Keyword(s):  
Guinea Pig ◽  
High Glucose ◽  
Glucose Concentration ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glycogen Synthesis ◽  
Rat Hepatocytes ◽  
Human Hepatocytes ◽  
Pyruvate Cycling ◽  
Stimulation Of ◽  
In Cells

1. During conversion of [6-3H,U-14C]glucose to glycogen in liver, loss of 6-3H can occur either by cycling via pyruvate (between glycolysis and gluconeogenesis) or by other mechanisms. We used mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, to determine the extent to which pyruvate cycling contributes to loss of 6-3H during glucose conversion to glycogen in hepatocytes. 2. Mercaptopicolinate increased the 3H/14C ratio in glycogen during incubation of rat, guinea pig, pig and human hepatocytes with [6-3H,U-14C]glucose. The increase in the 3H/14C ratio in glycogen caused by mercaptopicolinate was greater in periportal than in perivenous rat hepatocytes, indicating that cycling of glucose via pyruvate is more prominent in cells with a higher gluconeogenic relative to glycolytic capacity. 3. The effect of mercaptopicolinate on the 3H/14C ratio in glycogen was observed both in the absence and in the presence of insulin, indicating that stimulation of glycogen synthesis by insulin is not associated with inhibition of pyruvate cycling. In rat and guinea pig but not in pig hepatocytes, the effects of mercaptopicolinate on the 3H/14C ratio in glycogen were greater at 10-15 mM glucose than at 30 mM glucose, suggesting diminished cycling via pyruvate at high glucose concentrations. 4. Insulin increased the loss of 6-3H during stimulation of conversion of glucose to glycogen in hepatocytes from all species. This was due in part to an increase in pyruvate cycling and in part to other mechanisms that are not inhibited by mercaptopicolinate. 5. These results suggest that pyruvate cycling is a significant, but not exclusive, component of the loss of 6-3H in the hepatocyte during glucose conversion to glycogen. The extent of pyruvate cycling is dependent on the acinar origin of the hepatocytes and on the glucose concentration and presence of insulin.

scholarly journals β-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion

2010 ◽  
Vol 299 (6) ◽  
pp. E910-E917 ◽  
Author(s):  
Malathi Srinivasan ◽  
Cheol S. Choi ◽  
Pushpankur Ghoshal ◽  
Lioudmila Pliss ◽  
Jignesh D. Pandya ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mouse Model ◽  
Pyruvate Dehydrogenase ◽  
Isolated Islets ◽  
Male Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pyruvate Cycling ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion (GSIS) by β-cells requires the generation of ATP from oxidation of pyruvate as well as generation of coupling factors involving three different pyruvate cycling shuttles. The roles of several key enzymes involved in pyruvate cycling in β-cells have been documented using isolated islets and β-cell clonal lines. To investigate the role of the pyruvate dehydrogenase (PDH) complex (PDC) in GSIS, a murine model of β-cell-specific PDH deficiency (β-PDHKO) was created. Pancreatic insulin content was decreased in 1-day-old β-PDHKO male pups and adult male mice. The plasma insulin levels were decreased and blood glucose levels increased in β-PDHKO male mice from neonatal life onward. GSIS was reduced in isolated islets from β-PDHKO male mice with about 50% reduction in PDC activity. Impairment in a glucose tolerance test and in vivo insulin secretion during hyperglycemic clamp was evident in β-PDHKO adults. No change in the number or size of islets was found in pancreata from 4-wk-old β-PDHKO male mice. However, an increase in the mean size of individual β-cells in islets of these mice was observed. These findings show a key role of PDC in GSIS by pyruvate oxidation. This β-PDHKO mouse model represents the first mouse model in which a mitochondrial oxidative enzyme deletion by gene knockout has been employed to demonstrate an altered GSIS by β-cells.

scholarly journals Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion

2009 ◽  
Vol 296 (6) ◽  
pp. E1354-E1362 ◽  
Author(s):  
Emma Heart ◽  
Gary W. Cline ◽  
Leon P. Collis ◽  
Rebecca L. Pongratz ◽  
Joshua P. Gray ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Malic Enzyme ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Pyruvate Cycling ◽  
Mouse Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Interfering Rna ◽  
Rat Insulinoma

Pyruvate cycling has been implicated in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. The operation of some pyruvate cycling pathways is proposed to necessitate malate export from the mitochondria and NADP+-dependent decarboxylation of malate to pyruvate by cytosolic malic enzyme (ME1). Evidence in favor of and against a role of ME1 in GSIS has been presented by others using small interfering RNA-mediated suppression of ME1. ME1 was also proposed to account for methyl succinate-stimulated insulin secretion (MSSIS), which has been hypothesized to occur via succinate entry into the mitochondria in exchange for malate and subsequent malate conversion to pyruvate. In contrast to rat, mouse β-cells lack ME1 activity, which was suggested to explain their lack of MSSIS. However, this hypothesis was not tested. In this report, we demonstrate that although adenoviral-mediated overexpression of ME1 greatly augments GSIS in rat insulinoma INS-1 832/13 cells, it does not restore MSSIS, nor does it significantly affect GSIS in mouse islets. The increase in GSIS following ME1 overexpression in INS-1 832/13 cells did not alter the ATP-to-ADP ratio but was accompanied by increases in malate and citrate levels. Increased malate and citrate levels were also observed after INS-1 832/13 cells were treated with the malate-permeable analog dimethyl malate. These data suggest that although ME1 overexpression augments anaplerosis and GSIS in INS-1 832/13 cells, it is not likely involved in MSSIS and GSIS in pancreatic islets.

scholarly journals Assessment of Hepatic Mitochondrial Oxidation and Pyruvate Cycling in NAFLD by 13 C Magnetic Resonance Spectroscopy

2016 ◽  
Vol 24 (1) ◽  
pp. 167-171 ◽  
Author(s):  
Kitt Falk Petersen ◽  
Douglas E. Befroy ◽  
Sylvie Dufour ◽  
Douglas L. Rothman ◽  
Gerald I. Shulman
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Pyruvate Cycling ◽  
Mitochondrial Oxidation
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